MXPA00008938A

MXPA00008938A - PROCESSES FOR THE PREPARATION OF (R)-&agr;- (2,3-DIMETHOXYPHENYL)- 1-[2-(4- FLUOROPHENYL)ETHYL]- 4-PIPERIDINEMETHANOL

Info

Publication number: MXPA00008938A
Application number: MXPA/A/2000/008938A
Authority: MX
Inventors: Alan G Bina; Edward D Daugs; Jonathan C Evans; Hanswolfram Flemming; Gerard Guillamot; Robert A Hawthorne; Thomas H E Hilpert; James E Hitt; Chihsin R King; Johannes N Koek; Frederick M Laskovics; John R Lefler; Alexey L Margolin; Sharon K Minish; Thomas T Ortyl; Lian G Rajewski; Marvin J Sack; Paul F Skultety; Sandra K Stolzdunn; Alonzo L Tigner
Original assignee: Aventis Pharma Deutschland Gmbh; Aventis Pharmaceuticals Inc
Priority date: 1998-03-13
Filing date: 2000-09-12
Publication date: 2002-07-25

Abstract

The present invention provides various processes for the preparation of (R)-&agr;-(2, 3-dimethoxyphenyl)- 1-[2-(fluorophenyl)ethyl]-4- piperidinemethanol. These processes may be characterized by scheme (A).

Description

PROCESSES FOR THE PREPARATION OF (R) -a- (2,3-PIMETOXIFENIL) -1-r2- (4-FLUOROFENIUETIU-4- PIPERIDINAMETANOL FIELD OF THE INVENTION The present invention is directed to novel processes for the preparation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol.

BACKGROUND OF THE INVENTION a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol has been described generically in US Patent No. 5,169,096, issued on December 8 of 1992, the description of which is incorporated herein by reference. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol was described later in U.S. Patent No. 5, 134, 149, issued on 28 July 1992, the description of which is incorporated herein for reference. U.S. Patent No. 5,700.81 3, issued December 23, 1997, U.S. Patent No. 5,700,812, issued December 23, 1997, and the U.S. Patent. No. 5,561, 144, issued October 1, 1996, the description of each of which is incorporated herein by reference, describes the use of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol as 5HT2 receptor antagonists in the treatment of a number of disease states, including schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, peripheral vasospasms or coronary, fibromyalgia, cardiac arrhythmias, thrombotic affection and to control the extrapyramidal symptoms associated with neuroleptic therapy. The preparation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol reported previously includes the esterification of - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol with the (+) - isomer of a-methoxyphenylacetic acid to yield a diastereomeric mixture. The diastereomers were then separated by chromatography and the (+, +) - diastereomer was hydrolyzed to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol .

F DESCRIPTION OF THE INVENTION The present invention provides various processes for the preparation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). Thus, in one embodiment, a process is provided for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) which comprises reacting (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) with a suitable 4-fluorophenylethyl alkylating agent of the structure: wherein X is halide or methanesulfonate.

The alkylation of a piperidine using a 4-chloro- (2-haloethyl) benzene has been described by Gilligan et al, in J ed. Chem. 1992, 35, 4344-4361. In another embodiment of the present invention there is provided a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) which comprises reacting 4 - [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) with a chiral reducing agent, such as (+) - β -chlorodiisopinocanfenilborane. In still another embodiment, there is provided a process for preparing (R) -a- (2,3-dimethoxyf in yl) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3) which it comprises reacting 4- [1-oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) with a suitable chiral reducing agent, such as (+) - β-chlorodiisopinocanphenylborane . In yet another embodiment of the present invention, there is provided a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) comprising the steps of: a) reacting- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) with (2S, 3S) - (+) - di- (p-anisoyl) tartaric to give a racemic mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S ) - (+) - di- (p-anisoyl) tartaric (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3b); b) Separate the (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di - (p-anisoyl) (3a) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) etl] -4-piperidinemethanol, acid salt (2S) , 3S) - (+) - di- (p-anisoyl) tartaric (3b) by selective crystallization; and c) react (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 35) - (+) - di- (p-anisoyl) tartaric (3a) with a suitable base, extract with a suitable solvent and isolate in the usual way to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol (3). In yet another embodiment of the present invention, there is provided a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) comprising the steps of: a) subjecting- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5a) to selective enzymatic hydrolysis, using for example lipase of Candida cylindracea, to provide a mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and (S) -a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5b); and b) separating (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol (3) from (S) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5b). In yet another embodiment, a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3) comprising use ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24). In still another embodiment of the present invention, there is provided a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) comprising use N-4-fluorophenylacetyl) -4-carboxylpiperidine (21). In yet another embodiment, a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) comprising using 1 - ( 4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25).

In yet another embodiment, there is provided a process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) comprising the steps of: a) react lithiated veratrole with 4-pyridinecarboxaldehyde (9) in the presence of a suitable aprotic solvent to provide 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10); b) submitting 4- [1-hydroxy-1 - (2,3-dimethoxy-phenyl) methyl] pyridine (10) to catalytic hydrogenation to provide 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11); c) reacting 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl) piperidine (11) with a suitable 4-fluorophenylacetylation reagent, in the presence of a suitable base and a suitable solvent to provide 4- [ 1-h id roxy-1 - (2, 3-di methoxy in il) methyl] -N-2- (4-f luorof en-1-oxo-ethyl) piperidine (20); d) reacting 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) with a suitable reducing agent in the presence of a suitable solvent to provide a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5); e) reacting- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) with (2S, 3S) - (+) - di- (p-) acid ^ Anisyl) tartaric to give a racemic mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S ) - (+) - di- (p-anisoyl) tartaric (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 -12- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3b); f) separating (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3b) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - ( +) - di- (p-anisoyl) tartaric (3a) by selective crystallization; and g) reacting 10 (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) with a suitable base to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3).

Another embodiment of the present invention provides (R) -α-2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) having a particle size range of about 25 μm to about 250 μm and a process for preparing the same comprising: a) in a vessel, using from about 20 4% to about 20% of (R) -a- (2,3-dimethoxyphenyl) -1 - [ 2- (4- fluorophenyl) ethyl] -4-piperidinemethanol (3) to crystallize, yielding a saturated solution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) containing seminal crystals of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- 25 piperidinemethanol (3) as seminal crystals and; b) in another mm kt? ? i? M ttiáááh ^? ^^^ * u »a? ^ ju ^ iui ??? ^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) remaining on dissolving (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in a solvent wherein (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) shows a high degree of solubility at moderate temperature (ie, temperatures from about 35 ° C to about 75 ° C) such that the solvent will produce a supersaturated solution when combined with the seminal crystals present in the solution formed in step a); c) adding the solution formed in step b) to the solution formed in step a) while adjusting the solvent composition by the addition of a suitable anti-solvent to maintain an acceptable product by minimizing the solubility at the isolation temperature; and d) leaving (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in solution crystallize from the seed crystals.

Also included by the present invention are certain novel intermediate compounds useful in the preparation of (R) -a- 20 (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) , which are: (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1); 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4); 3) (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p -anisoil) tartaric (3a); 4) 4- [1-hydroxy-1 - (2,3-25-dimethoxyphenyl) methyl] pyridine (10); 5) 4- (2,3-dimethoxybenzoyl) pyridine ^ l - - T'-fliá-l (12); and 6) 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20). Certain new processes are also provided herein for preparing various intermediate compounds useful in the Preparation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). For example, a process for preparing 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) comprising 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) is provided. ) methyl] pyridine (10) to catalytic hydrogenation using a suitable catalyst, such as rhodium on carbon. A process for preparing (R) -4- (1-hydroxy-1- (2, 3-dimethoxyphenyl) -1-piperidicarboxylic acid is provided, 1,1-dimethylethyl ester (8) which comprises reacting 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethyl ethyl ester (7) with a chiral reducing agent, such as (+) - β -chlorodiisopinocanfenylborane or potassium 9-O- (1, 2-isopropylidine-5-deoxy-aD-xylofuranosyl-9-borabicyclo [3.3.1] nonane A process for preparing (R) -a- (2,3-dimethoxyphenyl) is also provided ) -4-piperidinemethanol (1) comprising the steps of a) reacting 4- [1-hydrox1-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) with a suitable chiral acid, such as (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid or (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid, to give a racemic mixture of (R ) -4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, chiral acid salt and (S) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine , salt of chiral acid; b) separating (R) -4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine, to the acid Chiral of (S) -4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine, salt of '** »t * ^ - iaA chiral acid; and c) reacting (R) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, a salt of chiral acid with a suitable base to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1). Also provided is a process for preparing 4- [1-hydroxy-1 - (2,3,5-dimethoxyphenyl) methyl] piperidine (11) which comprises reacting 4- (2,3-dimethoxybenzoyl) pyridine (12) with a suitable reducing agent, such as catalytic hydrogenation with rhodium / alumina or rhodium / carbon as catalysts. In addition, a process is provided for preparing 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-10-ethyl) piperidine (20) which comprises reacting 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) with a suitable reducing agent. In a further embodiment, pharmaceutical compositions are provided. In another embodiment, methods are provided for treating schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, peripheral or coronary vasospasm, fibromyalgia, cardiac arrhythmias, thrombotic affection and to control the associated extrapyramidal symptoms with neuroleptic therapy comprising administering an effective amount of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol wherein (R) -a- ( 2,3-dimethoxy-phenyl] -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol has a particle size range of about 25 μm to about 250 μm.

In an additional mode, they are provided - "- and pharmaceutical compositions containing effective amounts of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, including compositions wherein (R) - a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol has a particle size range of about 25 μm to about 250 μm. processes for preparing pharmaceutical compositions containing effective amounts of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol.

DETAILED DESCRIPTION OF THE INVENTION Scheme A represents the various processes of the present invention for the preparation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). 15 Scheme A "• ** ^. 'E -» »ae- In Scheme A, step a, the piperidine functionality of (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) is reacted with a 4-fluorophenylethyl alkylation agent of structure (2) to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) using techniques and well-known procedures for one of ordinary skill in the art, for example, (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) with an enantiomeric excess (ee) of between about 80% a > 99% can be reacted with the 4-fluorophenylethyl alkylating agent of structure (2), wherein X is a suitable leaving group such as halide, methanesulfonate and the like, in the presence of a suitable base, such as potassium carbonate , optionally in the presence of a suitable catalyst such as sodium iodide, in a suitable organic solvent, such as acetonitrile and aqueous tetrahydrofuran. A temperature of from about room temperature to 1000 ° C for a period of time ranging from about 2 hours to about 25 hours. The resulting (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) can be recovered from the reaction zone by extractive methods as are known in the art. matter and typically will have an ee of from about 85% up to > 99% The suitable (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-solvent or mixture of solvent, such as ethanol / toluene, and stir with silica gel a a temperature range of from about 5 ° C to about 30 ° C for a period of time ranging from about 30 minutes to 5 hours; or 2) rinsing the organic extracts from the extractive preparation with an aqueous solution of sodium metabisulfite to give the material having an ee of from about 90 to about > 99% The resulting material can be further purified by crystallization from a suitable solvent, such as isopropanol. The ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol (3) prepared by Scheme A, step a, can be increased by selective enzymatic ester hydrolysis techniques as described hereinafter in Scheme E or by diastereomeric salt separation techniques using acid (2S, 3S ) - (+) - di- (p-anisoyl) tartaric as described hereinafter in Schemes B, C and D or as described in Scheme A, step c, Table 1. In Scheme A, step b, 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) is converted to (R) -a- (2, 3-di methoxy in il) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3). For example, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) is contacted with a suitable chiral reducing agent, such as (+) - ß-chlorodiisopinocanphenylborane, in a suitable solvent, such as tetrahydrofuran. The reagents are typically stirred together at a temperature range of from about 5 ° C to about 30 ° C for a period of time ranging from about 2 hours to 100 hours. The reaction is typically cooled with acetaldehyde, and the (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) recovered from the reaction zone by extractive methods as are known in the art, and can be purified by chromatography to typically give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in about 60% ee up to about 85% ee. The ee of (R) -a- (2 > 3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) prepared by Scheme A, step b, may be increased by techniques of selective enzymatic ester hydrolysis as hereinafter described in Scheme E or by diastereomeric salt separation techniques using acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric as described hereinafter in Schemes B, C and D or as described in Scheme A, step c, Table 1. In Scheme A, step c, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) is converted to (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). For example, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) is contacted with a suitable chiral reducing agent, such as (+) -β-chlorodiisopinocanphenylborane, in a suitable solvent, such as tetrahydrofuran. The reagents are typically stirred together at a temperature range of from about 5 ° C to about 30 ° C for a period of time ranging from about 20 minutes to 10 hours. The reaction is typically treated with a suitable oxidizing agent, such as hydrogen peroxide, and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ( 3) recovered from the reaction zone by extractive methods as are known in the art, and can be purified by chromatography to typically give material at >75% of us The (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) ee prepared by scheme A, step c, can be increased by techniques of selective enzymatic ester hydrolysis as hereinafter described in Scheme E or by diastereomeric salt separation techniques using (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid as described herein in further in Schemes B, C and D. Alternatively, various other chiral acids may be used as shown in Table 1: a The equal molar amounts of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and the chiral acid were dissolved * & *: *** 'in acetone; The resulting solution was slowly evaporated at room temperature until dried to provide the salt. b MeOH was used to dissolve the chiral acid. c% diastereomeric excess was determined by the conversion of the salt to (R) -a- (2,3-dimethoxy-phenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) with 1 M NaOH in H2O / EtOAc followed by HPLC analysis. In Scheme A, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is optically purified to give (R) -a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) by either diastereomeric salt separation techniques or selective enzymatic hydrolysis. Diastereomeric salt separation techniques to convert a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) to (R) -a-15 (2,3 -Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) are described in Schemes B, C, and D. The techniques of selective enzymatic hydrolysis are described in Scheme A. used herein the term "a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5)" refers to material having an enantiomeric purity of about 0 % to approximately 5%. In Scheme B and Scheme C, the samples of varying the optical purity of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) are improved in terms of optical purity to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- 25 piperidinemethanol (3) by diastereomeric salt separation techniques using acid ( 2S, 3S) - (+) - di- (p-anisoyl) tartaric.

M * Éám * ~ me *, 1,,,,, f-.i.ic.t K. ? »•« -. - -. -. • -,, -. , - »n-. . try ^ .., ^, and ... ^ ... .. ... . . "..., ._ *. ^ a-cJ. In Scheme B, step a, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is reacted with (2S, 3S) - (+) - di- (p-anisoyl) tartaric to give a mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-an? Soil) tartaric acid (3b). In Scheme B, step b, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3a) is separated from the mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) and (S) -a- (2,3- rc. ., .. t | F gthn iim dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3b) by filtration . For example, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) etl] -4-piperidinemethanol (5) is contacted with (2S, 3S) - (+) - di- (p-anisoyl) tartaric in a suitable organic solvent or solvent mixture, such as 2-butanone, methanol, methanol / water, ethyl methyl acetone, ethanol, ethyl methyl acetic acid / acetone, acetic acid / water, or acid acetic / methanol, with methanol being preferred, at a temperature of 50 ° C at the reflux temperature of the solvent or solvent mixture chosen for a period of time ranging from the time necessary to form a homogeneous solution to about 24 hours. The reaction mixture is then typically cooled to a temperature range of from 0 ° C to 40 ° C for a period of time ranging from 20 minutes to 20 hours, optionally simulated with (R) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) having a high enantiomeric excess (> 95%). In addition, when the crystallization appears complete, a few drops of concentrated sulfuric acid can be added and the mixture maintained at a temperature range of from room temperature to about 50 ° C for a period of time ranging from 10 minutes to 5 hours. When acetic acid / water is used in Scheme B, step a, the melting point of (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - ( +) - di- (p-anisoyl) tartaric (3a) is 1 70 ° C-1 72 ° C, whereas when methanol is used in Scheme B, step a, the melting point of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) is 1 1 0 ° C-1 1 5 ° C. In addition, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p -anisoil) tartaric (3a) formed in acetic acid / water is less soluble in acetone, requiring the addition of water for its solution. These findings indicate that (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) recovered from acetic acid / water and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) recovered from methanol are different crystalline forms, with a more stable form being (R) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) recovered from acetic acid /Water. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) tartaric (3a) is typically precipitated from the reaction mixture and is typically recovered from the reaction zone by filtration (3a), leaving most (S) -a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3b) in the filtrate. Typically, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p -anisoyl) tartaric (3a) recovered from the reaction zone has an enantiomeric excess (ee) of between about 75% to about 95%. In Scheme C, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di - (p-anisoyl) tartaric (3a) is converted to (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). Scheme C In Scheme C, step a, the ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) can be optionally improved by recrystallization one or more times, typically using acetic acid, acetic acid / water, acetone, acetone / water, methanol, ethyl methyl acetone, methanol / water, or ethanol as a crystallization solvent. After recrystallization, the mixture becomes homogeneous after heating, then it is typically cooled to a temperature range of from 0 ° C to 40 ° C for a period of time ranging from 20 minutes to 20 hours, optionally -r-t i, - •! - «I-. . c-l - ii-e-J - i. i. -r ^^^^ - ^ _ ^ _ ^^^ > ^^ i ^ - ^ fc ^^^ M¡ga¡ ^ > simulated with (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p -anisoil) tartaric (3a) which has a high enantiomeric excess (> 95%). Such recrystallization typically gives (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric with ee's typically from about 85% to 100%. As used herein, the designation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') refers to the material that has been recrystallized once, the designation of (R) -a- (2,3-dimethoxyfen) -1 - [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ") refers to material that has been recrystallized twice and the designation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di - (p-anisoyl) tartaric (3a "') refers to the material that has been recrystallized three times. As one of ordinary skill in the art will readily appreciate, the ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ', 3a "or 3a"') will typically vary with the ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) etl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) as it is isolated from the zone of reaction as well as the number of recrystallizations used. In Scheme C, step b, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3a ', 3a "or 3a"') is converted to (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) by treatment with a suitable base. For example, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ', 3a "or 3a"') having an enantiomeric excess typically in the range of from about 95% up to > 99% is typically contacted with a suitable base, such as aqueous bases (ie, aqueous ammonium, aqueous sodium hydroxide, aqueous potassium carbonate, and the like), or such as organic bases (ie, triethylamine and the like) , in a suitable organic solvent, such as toluene, aqueous toluene, methanol / toluene, aqueous methanol / toluene, aqueous methanol / tetrahydrofuran, tetrahydrofuran or aqueous tetrahydrofuran at a temperature between 0 ° C to 75 ° C for a period of time that it varies from about 1 5 minutes to about 5 hours. The (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically recovered from the reaction zone by extractive methods as known in the art. and can be purified by recrystallization one or more times, with for example, 2-propanol, methanol, methanol / water, or a mixture of 2-propanol / methanol / water to give typically (R) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) with an enantiomeric excess of between about 97% and > 99% In Scheme C, step b, acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric can be recovered from the basic aqueous phase by treating the basic aqueous phase with an appropriate acid, such as hydrochloric acid. The recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is typically recovered from the reaction zone by filtration and can be recycled for use in Scheme B, step a. In Scheme C, step c, the mother solution (s) or filtrate (s) from the recrystallization (s) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) (Scheme C, step a) contains (n) ) an essentially racemic mixture of (R) -a- (2,3-10-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) acid -di- (p-anisoyl) tartaric (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3b) and can be treated with a suitable aqueous base to give a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- 15 piperidinemethanol (5), which can be recycled for use in Scheme B, step a. For example, the mother solution (s) or filtrate (s) from the recrystallization (s) of (R) -a- (2,3-dimethoxyphenyl) -1- [2- (4 - fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-20 anisoyl) tartaric acid (3a) (Scheme C, step a) containing (n) essentially a mixture racemic (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p) acid salt - anisoyl) tartaric (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-25 anisoyl) tartaric (3b) a water base is typically contacted -A- -a-ea-E suitable, such as ammonium, sodium hydroxide, potassium carbonate and the like, in a suitable organic solvent, such as toluene, aqueous toluene, methanol / toluene, aqueous methanol, tetrahydrofuran or aqueous tetrahydrofuran at a temperature between 0 ° C to 75 ° C for a period of time ranging from about 1 5 minutes to about 5 hours. The essentially racemic mixture, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5), is typically recovered from the reaction zone by extractive methods as are known from the material and can be purified by recrystallization one or more times before being used in Scheme B, step a. In Scheme C, step c, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid can be recovered from the basic aqueous phase by treating the basic aqueous phase with an appropriate acid, such as hydrochloric acid. The recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is typically recovered from the reaction zone by filtration and can be recycled for use in Scheme B, step a. In Scheme D, the mother solution or filtrate resulting from the resolution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric in Scheme B, step b, contains (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3b) as its main component which can be converted to a- (2,3-dimethoxyphenyl) - 1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) and recycled for use in Scheme B, - * - * - »-" »-« stage a.Scheme O In Scheme D, step a, the stock solution or filtrate resulting from the resolution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt in Scheme B, step b, containing (S) -a- (2,3-dimethoxyphenyl) -1 - [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of 15 (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3b) as its main component becomes (S) -a - (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) by treatment with a suitable base. Alternatively, (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p - 20 anisoyl) tartaric (3b) can be isolated from the mother liquor or filtrate resulting from Scheme B, step b, before treatment with a suitable base as described above. For example, the stock solution or filtrate resulting from the resolution of (R) -a- (2, 3-d imethoxy in il) -1 - [2- (4-f luorof in yl) ethyl] -4- 25 piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt in the a * te__¡_b __- £ MJ _ ^ _ ta- ^. r .i i i? i '^ and? ^? rr.

Scheme B, step b, containing (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3b) as its main component is typically treated with a suitable base, such as ammonium, sodium hydroxide, potassium carbonate, and the like, in a suitable organic solvent, such as toluene , aqueous toluene, methanol / toluene, aqueous methanol, tetrahydrofuran or aqueous tetrahydrofuran at a temperature between 0 ° C to 75 ° C for a period of time ranging from about 15 minutes to about 5 hours. The (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) can be recovered from the reaction zone by extractive methods or filtration as are known in matter and can be purified by recrystallization. In Scheme D, step a, the (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid can be recovered from the basic aqueous phase by treating the basic aqueous phase with an appropriate acid, such as hydrochloric acid. The recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is typically recovered from the reaction zone by filtration and can be recycled for use in Scheme B, stage a. In scheme D, step b, (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) is racemized to give a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) for treatment with a suitable acid. For example, (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) is contacted with a suitable acid, such as sulfuric acid or hydrochloric acid in a suitable solvent such as tetrahydrofuran, aqueous tetrahydrofuran, methanol, isopropanol / water, aqueous glyme, typically at the reflux temperature of the chosen solvent for a period of time ranging from about 2 hours to about 40 hours. The α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is typically recovered from the reaction zone by extractive methods or filtration as is known in the art and it can be purified by recrystallization before being used in Scheme B, step a. As previously stated, Scheme A, step d, includes the optical purification of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) to (R) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) by either diastereomeric salt separation techniques or selective enzymatic hydrolysis. Schemes B, C and D describe diastereomeric salt separation techniques to convert a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) to give (R) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3), while Scheme E describes selective enzymatic ester hydrolysis techniques to convert a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5), through its butyrate ester, in (R) -a- (2,3-dimethoxyphenyl) - 1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). to ? ?? ? - «- t ------- h-h-fa-ta-a-Mit- < - «-'- Esq? Ema E • tapen c 10 -? In Scheme E, step a, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is converted to its butyrate ester using well-known techniques and procedures for someone with ordinary experience in the field. For example, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is contacted with butyryl chloride, preferably in the presence of a suitable acid scavenger, such as triethylamine, and a suitable catalyst, such as ,., "Dimethylaminopyridine, such as chloroform at reflux temperatures for a period of time ranging from 2 hours to 24 hours. The α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5a) is typically recovered from the reaction zone by extractive methods as are known in the art. matter and can purified by chromatography. In Scheme E, step b, the α- (2,3-dimethoxyphenyl) -1 - [2- (4- dßd || a ágjjaatUgej ^ fluorofenil) etil] -4-piperidinamethanol, butyrate ester (5a) is subjected to enzymatic hydrolysis using, for example, lipase from Candida cylindracea, in a suitable medium, such as 0.1 M phosphate buffer ( pH 7.0) at a temperature range of from about 35 ° C to about 50 ° C for a period of time ranging from about 5 hours to 5 days. The enzyme selectively hydrolyzes the (R) -ester butyrate giving a mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and ( S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5b). In Scheme E, step c, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is separated from (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5b), for example, by chromatography. The initial materials for use in Scheme A can be prepared by a variety of methods. For example, (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) for use in Scheme A, step a, can be prepared by a variety of methods as shown in Scheme F. 4- [1 -Oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo) ethyl) piperidine (4) for use in Scheme A, step b, can be prepared as in Scheme J a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) for use in Scheme A, step c, may be prepared as described in US Patent No. 5, 1 69,096, as described in Scheme C, Scheme D or Scheme I. . .. .. , ... .. ... i. .. . . . .. ... ..., _ " , "...,,. . , ^, ...

As stated above, (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) for use in Scheme A, step b, can be prepared as described in Scheme F. Scheme F In Scheme f, step a, the functionality of the acetone of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) is selectively reduced to give acid (R) -4- (1-hydroxy) -1 - (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8). For example, 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) is contacted with a suitable chiral reducing agent, such as (+) - ß-chlorodiisopinocanphenylborane or potassium 9-O - (1,2-isopropylidine-5-deoxy-aD-xylofuranosyl) -9-borabicyclo [3.3.1] nonane. Typically, the reagents are contacted in a suitable solvent, such as tetrahydrofuran, at a temperature of about -50 ° C to room temperature for a period of time ranging from 10 hours to about 10 days. (R) -4- (1-Hydroxy) -1 - (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) can be recovered from the reaction zone by extractive methods as is known well in the art, typically (R) -4- (1-hydroxy) -1 - (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) with an enantiomeric excess of about 80% up to >99% In Scheme F, step b, the protecting group of 1,1-dimethylethyl ester of (R) -4- (1-hydroxy) -1 - (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1, 1 - dimethylethyl ester (8) is removed to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1). For example, (R) -4- (1-hydroxy) -1 - (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) is contacted with a suitable acid, such as hydrochloric acid or trifluoroacetic acid, at a temperature range of from about 5 ° C to about room temperature for a period of time ranging from about 5 minutes to 5 hours. (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) is recovered from the reaction zone by extractive methods or filtration as are known in the art and can be purified by recrystallization.

TO . . .. Aa ** ^ ». ~ In Scheme F, step c, the functionality of the acetone of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) is reduced and The protecting group 1,1-dimethyl ester is removed to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11). For example, 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) is contacted with sodium borohydride in a suitable solvent, such as tetrahydrofuran at a temperature of about 0 ° C to room temperature for a period of time ranging from approximately 30 minutes to 10 days. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine intermediate, 1,1-dimethylethyl ester (not shown) can be recovered from the reaction zone by extractive methods as is known in the art and can be purified by chromatography. The protecting group of 1,1-dimethylethyl ester can be removed and 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11) can be recovered from the reaction zone essentially as described above in Scheme F, stage b. Alternatively, the functionality of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 1,1-dimethyl ethyl ester (7) can be removed first by treatment with acid as described above to give 4- (2,3-dimethoxybenzoyl) -1-piperidine, which is then reduced as described above to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11). In Scheme F, step d, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrola to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10). For example, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrola in the presence of a suitable aprotic solvent, such as hexane, tetrahydrofuran, toluene, mixtures of hexane and tetrahydrofuran, mixtures of hexane and toluene, mixtures of tetrahydrofuran and toluene, or mixtures of hexane, tetrahydrofuran and toluene, at a temperature of from about -25 ° C to above 30 ° C for a period of time ranging from about 30 minutes to 10 hours. 4- [1-Hydroxy-1 - (2,3-10-dimethoxyphenyl) methyl] pyridine (10) is recovered from the reaction zone by extractive methods as are known in the art and can be purified by recrystallization. In Scheme F, step e, the pyridine functionality of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10) is reduced to Give 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11). For example, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10) is subjected to catalytic hydrogenation, using 5% rhodium in carbon or rhodium in alumina as a catalyst in a suitable solvent, such such as methanol, toluene, acetic acid, or mixtures thereof. The reaction is typically conducted at about 55 to about 150 psig at a temperature of from about room temperature to 80 ° C for a period of time ranging from about 2 hours to about 20 hours. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) can be recovered from the zone of ---- '- ^ - - -' 'tiMÉtimiítsir * 1- • - - reaction by filtration of the catalyst followed by concentration. In Scheme F, step f, c (1) is separated from racemic 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (1 1) using diastereomeric salt separation techniques. For example, 4- [1-hydroxy-1- (2,3-dimethoxy-phenyl) methyl] piperidine (11) is contacted with a suitable chiral acid, such as (2R, 3R) - (-) - di - (p-toluoyl) tartaric or (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid, in the presence of a solvent Suitable, such as isopropanol, at reflux temperatures. After cooling, (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, the acid salt is selectively crystallized and can be separated from (S) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, acid salt by filtration as generally described previously in Scheme B.

The enantiomeric excess of (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, acid salt can be further increased by recrystallization as previously described in Scheme C, step a for (R) -a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a).

Treatment with a suitable base as previously described in Scheme C, step b, for (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) produces (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) which typically has a enantiomeric excess in the range of from about 85% to > 99% The excess --- * ai- - "-" * - • - enantiomeric of (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) can be further increased by selective enzymatic hydrolysis techniques as previously described in Scheme E for (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). In addition, similar techniques as previously described in Schemes B, C and D can be used for recovering the resolving agent and recovering 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine ( 1 1) from recrystallization and salt-forming parent solutions. In Scheme F, step g, the pyridine and acetone functionalities of 4- (2,3-dimethoxybenzoyl) pyridine (12) are reduced to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11). For example, 4- (2,3-dimethoxybenzoyl) pyridine (1 2) is subjected to catalytic hydrogenation using a suitable catalyst, such as rhodium on carbon or rhodium on alumina in a suitable solvent, such as methanol. The hydrogenation is typically carried out at about 55 psig at room temperature for a period of time ranging from about 10 hours to 48 hours. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) is typically recovered from the reaction zone by filtration of the catalyst and concentration. In Scheme F, step h, (R) -4- (1-hydroxy-1- (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) can be racemised to 4- ( 1-Hydroxy-1- (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (11) by treatment with a suitable acid, such as hydrochloric acid or trifluoroacetic acid, with heating to a range of temperature from about 35 ° C to about 100 ° C for a period of time ranging from about 15 minutes to 15 hours The 4- (1-hydroxy-1- (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (11) can be recovered from the reaction zone by extractive methods as are known in the art: 4- (2,3-Dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) ) for use in Scheme F, steps a and c, can be prepared as described in Scheme G. 4- (2,3-Dimethoxybenzoyl) pyridine (12) for use In Scheme F, step g, can be prepared as described in Scheme H. As stated above, 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) to be used in Scheme F, step a and c, can be prepared as described in Scheme G.

Scheme G In Scheme G, step a, the functionality of the piperidine of 4-piperidinecarboxylic acid (13) is protected to give 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14). For example, 4-piperidinecarboxylic acid (13) is contacted with di-tert-butyldicarbonate in the presence of a suitable base, such as sodium hydroxide, in a suitable solvent such as t-butanol, aqueous ethanol, or ethanol, at a temperature range from about 0 ° C to about 50 ° C for a period of time ranging from about 30 minutes to 24 hours. After cooling carefully with a suitable acid, such as hydrochloric acid, 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is typically recovered from the reaction zone by extractive methods as are known in the art. In Scheme G, step b, the functionality of the 4-carboxylic acid of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is reacted with N, O-dimethylhydroxylamine hydrochloride to give anhydride. - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15). For example, 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is first contacted with a suitable reagent to form an activated form of 1,4-piperidinedicarboxylic acid, 1- (1, 1 - dimethylethyl) ester (14), such as 1,1 '-carbonyldiimidazole or oxalyl chloride. When 1, 1 '-carbonyldiimidazole is used, the suitable solvents are methylene chloride and the like and the reagents are typically contacted at room temperature for a period of time ranging from about 30 minutes to 5 hours. When oxalyl chloride is used, the suitable solvents are toluene and the like, and are preferably contacted in the presence of a suitable catalyst, such as N, N-dimethylformamide. The reagents are typically contacted at a temperature range of from about 1 5 ° C to about 50 ° C for a period of time ranging from about 10 minutes to 2 hours. The activated form of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester is then contacted with N, O-dimethylhydroxylamine at room temperature for a period of time ranging from about 3 hours to 1 5 hours. Regardless of the reagent used, 4 - [(methoxymethyllamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) can be recovered from the reaction zone by extractive methods as are known in the art and it can be recrystallized from a suitable solvent, such as heptane or a mixture of heptanes. In Scheme G, step c, 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) is reacted with lithiated veratrola to give 4- (2,3-dimethoxybenzoyl) acid - 1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7). For example, 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is typically contacted with a veratrole solution lithiated in tetrahydrofuran at a temperature range from about -78 ° C to approximately room temperature for a period of time ranging from about 6 hours to 24 hours. The 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) can be recovered from the reaction zone by extractive methods as are known in the art and can be purified by chromatography. In Scheme G, step d, 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is reacted with lithiated veratrola to give 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7). For example, 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is first contacted with a solution of n-butyl lithium in a suitable solvent, such as tetrahydrofuran, at a temperature range of from about -78 ° C to 0 ° C for a period of time ranging from about 15 minutes to 2 hours. The reaction mixture is then treated with litiated veratrola, typically as a solution of tetrahydrofuran, at a temperature range of from about -5 ° C to about room temperature for a period of time ranging from about 2 hours to 24 hours. The 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) can be recovered from the reaction by extractive methods as are known in the art and can be purified by chromatography. In Scheme G, step e, 4- (2,3-dimethoxybenzoyl) piperidine (16) is protected to give 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7). For example, 4- (2,3-dimethoxybenzoyl) piperidine (16) is contacted with di-tert-butyldicarbonate in the presence of a suitable base, such as sodium hydroxide, and a suitable solvent, such as aqueous ethanol, at room temperature. environment for a period of time ranging from approximately 30 minutes to 10 hours. The 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) can be recovered from the reaction zone by extractive methods as are known in the art. 4- (2,3-Dimethoxybenzoyl) piperidine (16) for use in Scheme G, step e, may be prepared as described in U.S. Patent No. 5,169,096 or as described in Scheme L. As established previously, 4- (2,3-dimethoxybenzoyl) pyridine (12) for use in Scheme F, step g, may be prepared as described in Scheme H. Scheme H In Scheme H, step a, 4-cyanopyridine (17) is reacted with litiated veratrola to give 4- (2,3-dimethoxybenzoyl) pyridine (1 3). For example, 4-cyanopyridine (17) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, diethyl ether, hexane, toluene, or mixtures thereof, at a temperature range of below 6 ° C. at room temperature for a period of time ranging from 30 minutes to 5 hours. After cooling with a suitable acid, such as hydrochloric acid, 4- (2,3-dimethoxybenzoyl) pyridine (13) is recovered from the reaction zone by extractive methods as are known in the art. In Scheme H, step b, 4-pyridinecarboxylic acid (18) is reacted with N, O-dimethylhydroxylamine hydrochloride to give 4-5 [(methoxymethylamino) carbonyl] pyridine (1 9). For example, 4-pyridinecarboxylic acid (18) is first contacted with a suitable reagent to form an activated form of 4-pyridinecarboxylic acid (18), such as 1,1'-carbonyldiitnidazole or oxalyl chloride. When 1, 1'-carbonyldiimidazole is used, the suitable solvents are methylene chloride and the like and the reagents are typically contacted at room temperature for a period of time ranging from about 30 minutes to 5 hours. When oxalyl chloride is used, the suitable solvents toluene and the like, and are preferably contacted in the presence of a suitable catalyst, such as N, N-dimethylformamide. The reagents are typically contacted at a temperature range of from about 1 5 ° C to about 50 ° C for a period of time ranging from about 10 minutes to 12 hours. The activated form of 4-pyridinecarboxylic acid is then contacted with N, O-dimethylhydroxylamine at room temperature for a period of time ranging from about 3 hours to 1 5 hours. Regardless of the reagent used, 4- [(methoxymethylamino) carbonyl] pyridine (19) can be recovered from the reaction zone by extractive methods as are known in --- '• - - ** ~ - - - - - < - * - »- '- * - -" "" "*' • aA - ife'a- matter and can be purified by distillation. In Scheme H, step c, 4- [(methoxymethylamino) carbonyl] pyridine (1 9) is reacted with litiated veratrola to give 4- (2,3-dimethoxybenzoyl) pyridine (12). For example, 4 - [(methoxymethylamino) carbonyl] pyridine (19) is contacted with litiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range from about -78 ° C to room temperature for a period of time which It varies from approximately 1 hour to 24 hours. After cooling with a suitable acid, such as acetic acid or hydrochloric acid, 4- (2,3-dimethoxybenzoyl) pyridine (12) is recovered from the reaction zone by extractive methods as are known in the art. In Scheme H, step d, 4-pyridinecarboxylic acid (18) is reacted with lithiated veratrola to give 4- (2,3-dimethoxybenzoyl) pyridine (12). For example, 4-pyridinecarboxylic acid (18) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range from about -78 ° C to room temperature for a period of time ranging from about 6 hours. up to 24 hours. After cooling with a suitable acid, such as acetic acid or hydrochloric acid, 4- (2,3-dimethoxybenzoyl) pyridine (12) is recovered from the reaction zone by extractive methods as are known in the art. • rifet - * - 'J "-" * As previously stated, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) for use in the Scheme A, step c, is described in the US Pat. No. 5,169,096 or can be prepared as described in Scheme C, Scheme D or Scheme I. As stated above, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol (5) for use in Scheme A, step c, can be prepared as described in Scheme I. Scheme I In Scheme I, step a, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) -piperidine (4) is reduced to give a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). For example, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) -piperidine (4) is contacted with a suitable reducing agent, such as bis (2-methoxyethoxy) aluminum or borane sodium hydride, in a suitable solvent, such as toluene, tetrahydrofuran, or mixtures of toluene / tetrahydrofuran, at a temperature range of from about -1 5 ° C to about 60 ° C for a period of time ranging from about 30 minutes to about 10 hours. After cooling with a suitable base, such as sodium hydroxide or diethylenetriamine, the α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) can be recovered from the reaction zone by extractive methods as are known in the art and can be purified by recrystallization. In Scheme I, step b, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) is reduced to give a- (2, 3-d methoxy in l) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemetan or I (5). For example, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) is contacted with a suitable reducing agent, such as sodium borohydride or lithium aluminum hydride, in a suitable solvent, such as ethanol for sodium borohydride and tetrahydrofuran for lithium aluminum hydride, at a temperature range of from about 0 ° C to room temperature, for a period of time ranging from about 2 hours. hours up to 24 hours. The α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) can be recovered from the reaction zone by extractive methods as are known in the art and can be purified by recrystallization In Scheme I, step c, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) p -pepdine (20) is reduced to give a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). For example, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) is contacted with a suitable reducing agent, such as a borane or borane-dimethylsulfide complex, in a suitable solvent, such as toluene, tetrahydrofuran, and the like, at a temperature range of from about -20 ° C to about 60 ° C for a period of time ranging from about 1 hour to 5 hours. After cooling with a suitable base, such as diethylenetriamine, the α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) can be recovered from the reaction zone by extractive methods as are known in the art or by filtration. 4- [1 -Oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) for use in Scheme I, step a, can be prepared as described in Scheme J. 4- [1 -Oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) for use in Scheme I, step b, it can be prepared as described in U.S. Patent No. 5, 169,096 or as described in Scheme K, 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4- fluorphenyl-1 -oxo-ethyl) piperidine (20) for use in Scheme I, step c, can be prepared as described in Scheme M. As stated above, 4- [1 -Oxo-1 - (2,3 -dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) for use in Scheme I, step a, can be prepared as described in Scheme J.

Scheme J In Scheme J, step a, 4- (2,3-dimethoxybenzoyl) piperidine (16) is reacted with an appropriate 4-fluorophenylacetylation reagent to give 4- [1 -Oxo-1 - (2,3-15 di methoxy in il) methyl] -N-2- (4-f-lorophenyl-1 -oxo-ethyl) piperidine (4). For example, 4- (2,3-dimethoxybenzoyl) piperidine (16) is contacted with an appropriate 4-fluorophenylacetylation reagent, such as 4-fluorophenylacetyl chloride, in a suitable solvent, such as toluene or aqueous toluene, in the presence of an eliminating agent Suitable basic, such as hydroxides (eg, sodium hydroxide, potassium hydroxide) and organic amine bases (eg, diethylamine and diisopropylethylamine), at a temperature range of from about -1 5 ° C to about room temperature during a period of time that varies from approximately 30 minutes to 5 hours. The 4- [1 -oxo-1 - (2,3- m¡¡? ¡y ^^ tlltBí. dimethoxy in yl) methyl] -N-2- (4-f luorof in yl-1 -oxo-ethyl) piperidine (4) can be recovered from the reaction zone by extractive methods as are known in the art. In Scheme J, step b, 4-piperidinecarboxylic acid (13) is reacted with an appropriate 4-fluorophenylacetylation reagent to give N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21). For example, 4-piperidinecarboxylic acid (13) is contacted with an appropriate 4-fluorophenylacetylation reagent, such as 4-fluorophenylacetyl chloride, in the presence of a suitable basic scavenger, such as hydroxides (eg, sodium hydroxide or sodium hydroxide). potassium) and carbonates (eg, potassium carbonate and sodium carbonate), in a suitable aqueous medium, such as water or mixtures of water and acetone, at a temperature range of from about 0 ° C to 50 ° C for a period of time. period of time that varies from approximately 10 minutes to 5 hours. The N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) can be recovered from the reaction zone by extractive methods as are known in the art. In Scheme J, step c, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is reacted with N, O-dimethylhydroxylamino to give N- (4-f luorof in ilacetyl) -4- (N, O- dimethylhydroxyaminocarboxy) piperidine (22). For example, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is first contacted with a suitable reagent to form an activated form of N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21), such as 1.1. '-carbonyldiimidazole or oxalyl chloride. When 1, 1 '-carbonyldiimidazole is used, the suitable solvents are methylene chloride and the like and the reagents are typically contacted at room temperature for a period of time ranging from about 30 minutes to 5 hours. When oxalyl chloride is used, suitable solvents are toluene and the like, and are preferably contacted in the presence of a suitable catalyst, such as N, N-dimethylformamide. The reagents are typically contacted at a temperature range of from about 1 5 ° C to about 50 ° C for a period of time ranging from about 10 minutes to 12 hours. The activated form of N- (4-fluorophenylacetyl) -4-carboxylpiperidine is then contacted with N, O-dimethylhydroxylamine at room temperature for a period of time ranging from about 3 hours to 1 5 hours. Regardless of the reagent used, N- (4-f luorof in lacethyl) -4- (N, Od i methyl lhydroxyaminocarboxy) piperidine (22) can be recovered from the reaction zone by extractive methods as are known in the art and it can be purified by distillation. In Scheme J, step d, N- (4-fluorophenylacetyl) -4- (N, O-dimethylhydroxyaminocarboxy) piperidine (22) is reacted with litiated veratrola to give 4- [1 -oxo-1 - (2,3- dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4). For example, N- (4-fluorophenylacetyl) -4- (N, O-dimethylhydroxyaminocarboxy) piperidine (22) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range of from about -78 ° C. up to room temperature for a period of time ranging from 2 hours to 12 hours. 4- [1-Oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) can be recovered from the reaction zone by extractive methods such as they are known in the art and can be purified by chromatography. In Scheme J, step e, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is reacted with litiated veratrola to give 4- [1 -0X0-1 - (2, 3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4). For example, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range of from about -78 ° C to room temperature over a period of time. Time varying from approximately 2 hours to 12 hours. 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) can be recovered from the reaction zone by extractive methods as known in the art and can be purified by chromatography. In Scheme J, step f, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is reacted with lithium hydroxide to give N- (4-fluorophenylacetyl) -4-carboxylpiperidine, lithium salt (21 a). For example, N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) is contacted with lithium hydroxide monohydrate in a suitable aqueous solvent system, such as aqueous tetrahydrofuran, at a temperature range of from about 0 ° C to about 50 ° C for a period of time ranging from about 5 minutes to about 5 hours. N- (4-fluorophenylacetyl) -4-carboxylpiperidine, lithium salt (21 a) can be recovered from the reaction zone by methods as are known in the art, such as azeotropic distillation with toluene. In Scheme J, step g, N- (4-fluorophenylacetyl) -4-carboxylpiperidine, lithium salt (21 a) is reacted with litiated veratrola to give 4- [1-oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4). For example, N- (4-fluorophenylacetyl) -4-carboxylpiperidine, lithium salt (21 a) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range from about -25 ° C to about room temperature for a period of time ranging from about 1 5 minutes to about 1 2 hours. 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) can be recovered from the reaction zone by extractive methods as known in the art and can be purified by chromatography. 4- (2,3-Dimethoxybenzoyl) piperidine (16) for use in Scheme J, step a, may be prepared as described in U.S. Patent No. 5,169,096 or as described in Scheme L.

As stated previously, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) for use in Scheme I, step b, can be prepared as is described in U.S. Patent No. 5,169,096 or as described in Scheme K. Scheme K In Scheme K, step a, 4- (2,3-dimethoxybenzoyl) piperidine (16) is reacted with a 4-fluorophenylethyl alkylating agent of structure (2) to give 4- [1 -oxo-1 - (2) , 3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) using techniques and procedures well known to one of ordinary skill in the art. For example, 4- (2,3-dimethoxybenzoyl) piperidine (16) can be reacted with the 4-fluorophenylethyl alkylating agent of structure (2), wherein X is a suitable leaving group such as halide, methanesulfonate, and the like. similar, in the presence of a suitable base, such as potassium carbonate, optionally in the presence of a suitable catalyst such as sodium iodide or potassium iodide, in an organic solvent, such as acetonitrile or aqueous tetrahydrofuran. The reagents are typically stirred together at a temperature from about room temperature to the reflux temperature of the chosen solvent for a period of time ranging from about 2 hours to about 25 hours. The resultant 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) can be recovered from the reaction zone by extractive methods as are known in the art . In Scheme K, step b, 4-piperidinecarboxylic acid, ethyl ester (23) is reacted with p-fluoroacetophenone and sulfide to give ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24). For example, 4-piperidinecarboxylic acid, ethyl ester (23) is contacted with p-fluoroacetophenone and sulfide, in the presence of a catalytic amount of p-toluenesulfonic acid, in a suitable solvent, such as toluene, at a temperature sufficient to withdraw azeotropically water. The water is removed for a period of time ranging from about 3 hours to 7 hours. Ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24) can be recovered from the reaction zone by extractive methods as are known in the art and can be purified by distillation or chromatography. In Scheme K, step c, ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24) is reduced to give 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25). For example, ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24) is contacted with a reducing agent, such as borane complex »dimethylsulfide, in a suitable solvent, such as tetrahydrofuran at room temperature for a period of time which It varies from approximately 1 5 minutes to 3 hours. After cooling with methanol, 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) is recovered from the reaction zone by the concentration of the solvent and can be purified by distillation. In Scheme K, step d, ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24) is hydrolyzed to give 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane (26). For example, 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) is contacted with a suitable hydrolyzing agent, such as aqueous hydrochloric acid and / or aqueous acetic acid at reflux temperature for a period of Time varying from 30 minutes to 5 hours. 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane (26) can be recovered from the reaction zone by concentration of the solvent and can be purified by crystallization. In Scheme K, step e, 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane (26) is reacted with N, O-dimethylethylhydroxylamine to give 1- (4 '- (N, O-dimethylhydroxylaminocarboxy) piperidino) -2- (4'-fluorophenyl) ethane (27). For example, 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane (26) is contacted first with a suitable reagent to form an activated form of 1- (4-carboxypiperidine) -2- (4-fluorophenyl) Ethane (26), such as 1,1 '-carbonyldiimidazole or oxalyl chloride. When 1, 1 '-carbonyldiimidazole is used, suitable solvents are chloroform, methylene chloride and the like and the reagents are typically contacted at room temperature for a period of time ranging from about 30 minutes to 5 hours. When oxalyl chloride is used, the suitable solvents are toluene and the like, and are preferably contacted in the presence of a suitable catalyst, such as N, N-dimethylformamide. The reagents are typically contacted at a temperature range of from about 1 5 ° C to about 50 ° C for a period of time ranging from about 10 minutes to 12 hours. The activated form of 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane is then contacted with N, O-dimethylhydroxylamine at room temperature for a period of time ranging from about 3 hours to 15 hours. Regardless of the reagent used, 1- (4 '- (N, O-dimethylhydroxylaminocarboxy) piperidino) -2- (4'-fluorophenyl) ethane (27) can be recovered from the reaction zone by extractive methods as are known in the art and it can be purified by distillation.

In Scheme K, step f, 1 - (4 '- (N, O-dimethylhydroxylaminocarboxy) piperidino) -2- (4'-fluorophenyl) ethane (27) is reacted with litiated veratrola to give 4- [1 -oxo- 1 - (2,3-Di methoxy-enyl) methyl] -N-2- (4-f luorof in the lethyl) -piperidine (6). For example, 1 - (4 '- (N, O-dimethylhydroxylaminocarboxy) piperidino) -2- (4'-fluorophenyl) ethane (27) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range from -20 ° C to room temperature for a period of time ranging from 30 minutes to 8 hours. 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) can be recovered from the reaction zone by extractive methods as are known in the art. In Scheme K, step g, 4-piperidinecarboxylic acid, ethyl ester (23) is reacted with a 4-fluorophenylethyl alkylating agent of structure (2) to give 1- (4-carboethoxypiperidine) -2- (4- fluorophenyl) ethane (25) using techniques and procedures well known to someone of ordinary skill in the art. For example, 4-piperidinecarboxylic acid, ethyl ester (23) can be reacted with the 4-fluorophenylethyl alkylating agent of structure (2), wherein X is an leaving group such as halide, methanesulfonate, and the like, being Preferred methanesulfonate, in the presence of a suitable base, such as potassium carbonate, optionally in the presence of a suitable catalyst such as sodium iodide or potassium iodide, in a suitable organic solvent, such as acetonitrile or aqueous tetrahydrofuran. The reagents are typically stirred together at a temperature from about room temperature to the reflux temperature of the chosen solvent for a period of time ranging from about 12 hours to about 25 hours. The resulting 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) can be recovered from the reaction zone by extractive methods as are known in the art. In Scheme K, step h, 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) is reacted with lithium hydroxide to give 1- (4-carboxypiperidine) -2- (4-fluorophenyl) Ethane, lithium salt (25a). For example, 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) is contacted with lithium hydroxide monohydrate in a suitable aqueous solvent, such as aqueous tetrahydrofuran, at a temperature range of from about environment to about 80 ° C for a period of time ranging from about 1 hour to about 24 hours. 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) can be recovered from the reaction zone by methods as is known in the art, such as azeotropic distillation. In Scheme K, step i, 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) is reacted with litiated veratrola to give 4- [1 -oxo-1 - (2, 3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6). For example, 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) is contacted with lithiated veratrola in a suitable solvent, such as tetrahydrofuran, at a temperature range of from about -20. ° C to about 20 ° C for a period of time ranging from about 30 minutes to about 24 hours. 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) can be recovered from the reaction zone by extractive methods as are known in the art. As previously stated, 4- (2,3-dimethoxybenzoyl) piperidine (16) for use in Scheme J, step a, and for use in Scheme K, step a, may be prepared as described in US Patent No. 5, 169,096 or as described in Scheme L. Scheme L In Scheme L, step a, 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) is deprotected to give 4- (2,3-dimethoxybenzoyl) piperidine (16). For example, 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) is contacted with a suitable acid, such as trifiuoroacetic acid or aqueous hydrochloric acid, optionally in the presence of a suitable solvent, such as tetrahydrofuran at a temperature range of from room temperature to 60 ° C for a period of time ranging from about 30 minutes to 24 hours. 4- (2,3-Dimethoxybenzoyl) piperidine (16) can be recovered from the reaction zone by treatment with a suitable base, such as sodium hydroxide, followed by extractive methods as are known in the art. 4- (2,3-Dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) for use in Scheme L, step a, can be prepared as described in Scheme G. 4- [(Methoxymethyl mino) -carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) for use in Scheme L, step b, can be prepared as described in Scheme G, step b. As previously stated, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) for use in Scheme I, Step c, can be prepared as described in Scheme M.

Scheme M In Scheme M, step a, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) is reacted with a 4-10 fluorophenylacetylation reagent to give 4- [1-hydroxy-1] - (2,3-dimethoxyphenyl) methyl] - N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (20). For example, 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11) is contacted with a suitable 4-fluorophenylacetylation agent, such as 4-fluorophenylacetyl chloride, in the presence of a suitable base, such as sodium hydroxide, in a suitable solvent, such as methanol, toluene, toluene / methanol, aqueous toluene, methanol / acetic acid, methanol / acetic acid / toluene, or toluene / acetic acid at a temperature range of from 0 ° C to 50 ° C for a period of time varying from 15 minutes to 5 hours. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) can be recovered from the reaction zone by extractive methods as they are known in the art and can be purified by distillation. In Scheme M, step b, 4- [1 -oxo-1 - (2,3-25-dimethoxyphenyl) methyl] -N-2- (4-flurofen-1-oxo-ethyl) piperidine (4) is reduced to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20). For example, 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-flurofen-1-oxo-ethyl) piperidine (4) is contacted with a suitable reducing agent, such as sodium borohydride, optionally in the presence of a suitable catalyst, such as sodium hydroxide, in a suitable solvent, such as ethanol at room temperature for a period of time ranging from about 2 hours to 24 hours. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) is recovered from the reaction zone by extractive methods as known in the art and can be purified by chromatography. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) for use in scheme M, step a, can be prepared as described in Scheme F, steps c, e and f. 4- [1 -Oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) for use in Scheme M, step b, can be prepared as previously described in Scheme J. A preferred process for preparing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol is shown in Scheme N .

Scheme N In Scheme N, step a, 4-pyridinecarboxaldehyde (9) is reacted with litiated veratrola to give 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10) as previously described in Scheme F, stage d. In Scheme N, step b, the functionality of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine pyridine (10) is reduced to give 4- [1-hydroxy-1 - ( 2,3-dimethoxyphenyl) methyl] piperidine (11) as previously described in Scheme F, step e. In Scheme N, step c, 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11) is reacted with a 4-fluorophenylacetylation reagent to give 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (20) as previously described in Scheme M, step a. In Scheme N, step d, 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) is reduced to give a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) as previously described in Scheme I, step c. In Scheme N, step e, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is reacted with (2S, 3S) - (+) acid -di- (p-anisoyl) tartaric to give a mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S , 3S) - (+) - di- (p-anisoyl) tartaric (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3b) as previously described in Scheme B, step a. In Scheme N, step f, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) is separated from the mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) and (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3b) by filtration as previously described in Scheme B, stage b. In Scheme N, step g, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3a) is converted to (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) by the treatment with a suitable base as previously described in Scheme C, step b. The ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a) can optionally be improved by recrystallization as previously described in Scheme C, step a, before conversion to (R) -a- (2,3-d-methoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). The following examples present typical syntheses as described in Examples A to M. These examples are presented to illustrate the present invention. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; ° C refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; "nm" refers to nanomolar; "μM" refers to micromolar; "HPLC" refers to High Performance Liquid Chromatography; and "ee" refers to enantiomeric excess. Example 1 Scheme A, step a: (R) -a- (2,3-D-methoxyphenyl) -1-r2- (4-fluorophenyl) etl1-4-piperidinemethanol (3) A reactor maintained under nitrogen was charged with alcohol 4-fluorophenylethyl (2.6 kg, 1 8.6 mol) and 1 8 L of methylene chloride. The stirred solution was cooled to and maintained at 0-5 ° C while triethylamine 2.85 kg (28.2 mol) was added rather quickly. The reaction temperature was maintained at 0-5 ° C while methanesulfonyl chloride (2.5 kg, 21.8 mol) was added for 1 hour. The stirred reaction mixture was kept at 0-5 ° C for 1 hour, then was warmed to room temperature within about 2 hours. The reaction mixture was diluted with a solution of 0.5 kg of 33% hydrochloric acid in 1.0 L of water. The organic phase was separated and rinsed with a solution of 0.2 kg of 33% hydrochloric acid in 5 L of water. Both acid extracts were combined and extracted with 5 L of methylene chloride. Both organic phases were combined, rinsed with 2 x 15 L of water, then dried with sodium sulfate (2 kg). The drying agent was filtered off and rinsed with 2 x 5 L of methylene chloride. The majority of the solvent was boiled at atmospheric pressure, with the final quantity distilled at 35 ° C / 500 torr to give 4-fluorophenyl alcohol methanesulfonate (4.1 7 kg). A suitable reactor maintained under nitrogen was charged with (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) from Scheme F, steps a and b, Example 45 (3.7 kg, 14.7 mol, 95.5% ee) , then potassium carbonate (2.65 kg, 1 9.2 mole), sodium iodide (0.25 kg, 1.67 mole) and 60 L of acetonitrile were added. The stirred reaction mixture was heated slowly to 75 ° C for 1 5 hours. After cooling the reaction mixture to 50 ° C, it was diluted with 15 L of water. The solvent was distilled off below 50 ° C at 500 to 200 torr. The residue was cooled to 25 ° C and 25 L of water were added. The mixture was extracted with 2 x 35 L methylene chloride. The organic extracts were combined, rinsed with 2 x 35 L of water, then sodium sulfate (5 kg) and activated carbon (0.3 kg) were added. After stirring for 30 minutes, the drying agent and the activated carbon were separated by filtration and rinsed with 2 x 1.0 L methylene chloride. The solvent was distilled off below 40 ° C at 500 torr. The residue obtained was diluted with 30 L of isopropanol, then the stirred mixture was heated to 52 ° C to obtain complete solution. The stirred mixture was cooled slowly to room temperature for 1 7 hours, then cooled to 1 7CC. The solid that crystallized was filtered off, rinsed with 2 x 3 L cold isopropanol, then air dried to give the main compound (R) -a- (2,3-dimethoxyphenyl) -1 - [2- ( 4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (3.25 kg, 59% product, 98.5% ee). A suitable reactor maintained under nitrogen was charged with (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (3.25 kg), 6.8 L of ethanol and 34 L of toluene. The mixture was stirred until the solution was obtained, then silica gel (5 kg) was added. The mixture was stirred at 18 ° C for 2 hours. The silica gel was separated by filtration and rinsed twice with a mixture of 2 L of ethanol / 10 L of toluene. The filtrate was concentrated to a residue below 50 ° C at 500 to 200 torr. The residue was diluted with 5 L of isopropanol and the solvent was distilled off below 50 ° C at 200 torr. The residue obtained was diluted with 8.5 L of isopropanol. The stirred mixture was heated to 70-75 ° C until the complete solution was obtained. The stirred mixture was cooled to 60 ° C, then seed was reared with laboratory material having an optical purity of 99% ee. The stirred mixture was cooled slowly to 20 ° C for 20 hours. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) which crystallizes was filtered off, rinsed with 2 x 1 L cold isopropanol , then dried in a circulation oven below 40 ° C to give the main compound (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4 -piperidinemethanol (3) (2.75 kg, 85% recovery, ee> 99%). The following procedure can be used as an alternative for the purification of silica gel. A solution of approximately 1 g of (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) crude / 5 mL of toluene is rinsed successively with a solution of 0.125 g of sodium metabisulfite / 5 mL of water, a solution of 0.04 g of sodium metabisulfite / 1 .8 mL of water and 2. X 2.5 mL of saturated sodium chloride solution. Example 2 Scheme A, step b: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etn-4-piperidinemethanol (3) A solution of 4- [1 -oxo -1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) (1.5 g, 3.8 mmol) in tetrahydrofuran (10 mL) is treated with (+) - ß-chlorodiisopinocanphenylborane (6.0 g, 1 8 mmol). The resulting solution is stirred for 60 hours at room temperature. The reaction mixture is treated with acetaldehyde (1 mL) and stirred overnight. The mixture is treated with NaOH (2 N) and extracted in toluene. The organic extract is rinsed with H2O, dried, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography (SiO2, 3: 1 EtOAc / toluene) gives the main compound (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (0.6 g, 40% product, 90: 1 0 (R: S) Example 3 Scheme A, step c: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethyl 1- 4-piperidinemethanol (3) A mixture of 4- [1 -oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) piperidine (6) hydrochloride salt (212 g, 0.52 mol ), Aqueous NaOH (1 N, 1 L) and methylene chloride (2 L) was stirred at room temperature for 30 minutes, the phases were separated and the aqueous layer was extracted with methylene chloride (1 L). The combined extracts were rinsed with brine (1.5 L) and dried (MgSO) The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr) to a residue which was dissolved in anhydrous tetrahydrofuran (400 mL). The resulting solution was added to a solution of 4- [1-h id roxi-1 - (2,3-d imethoxy in il) methyl] -N-2- (4-f-1-chlorophenyl-1-oxo-ethyl) piperidin α-β-chlorodiisopinocamphenylborane ((+) - lpc2BCl, 500 g, 1.56 mol) in tetrahydrofuran (860 mL) and the mixture was stirred at room temperature for 3 days. Water (210 mL) followed by 30% H2O2 (260 mL) was added to the solution for 1.5 hours at 10 ° C. The resulting mixture was extracted with methylene chloride (2 L). The organic layer was rinsed with 10% NaHSO 3 (1 L), 5% NaOH (1 L) and brine (1 L) and dried (MgSO). The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr) to a residue which was divided into two portions. Each portion was purified by flash chromatography (SiO2, 10 cm x 15 cm, eluted with 2 L of hexane, 3 L of 1: 4 EtOAc: hexane, 4 L of 1: 1 EtOAc: hexane and 4 L of 1:19 MeOH : EtOAc). The desired fractions (TLC, Rf 0.28, 1:19 MeOH: EtOAc) were combined and concentrated (35 ° C / 20 torr) to give the main compound (5) as a white solid [(R) - enriched, 130 g, 67% product, 82% ee]; m.p. = 105-108 ° C. IR (KBr) 3558, 3422, 3141, 2962, 2942, 2833, 2804, 1600, 1584, 1510, 1478, 1430, 1302, 1266, 1222, 1081, 1041, 1006, 836, 792, 755 cm-1; 1 H NMR (CDCl 3) d 6.7-7.2 (m, 7H, aryl), 4.63 (d, 1H, J =8. 5 Hz, CHO), 3.87 (s, 6H, OCH3's), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.5 (m, 3H), 1.8-2.1 (m, 3H) ), 1.7 (m, 1H), 1.2-1.6 (m, 3H). 13C NMR (CDCI3) d 161.3 (d, JF-c = 242.3 Hz), 152.4, 146.5, 136.4, 136.0, 130.0, 123.9, 119.3, 115.0 (d, JF-c = 10.5 Hz), 111.4, 74.5, 60.9, 55.7, 53.7, 42.8, 32.9, 28.8, 28.7; 19 F NMR (CDCl 3) d -118.1; MS (Cl, CH4) m / z (Intensity reagent) 374 (MH +, 65%), 356 (68), 364 (27), 342 (6), 322 (8), 264 (100), 236 (7 ); [a] D20 + 10.3 ° (c 1.04, CHCl3); Anal Cale for C22H28FNO3 (373.5): C, 70.75; H, 7.56; N, 3. 75. Found: C, 70.53; H, 7.73; N, 3.63. Example 4 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-Dimethoxy-enyl) -1-f2- (4-f luorof in il) ethyl-1-4-piperidine methanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') To a stirred suspension of a- (2,3-dimethoxyphenyl) -1 - [2- (4- fluorophenyl) ethyl] -4-piperidinemethanol (5) (16.5 g, 44 mmol) in 2-butanone (100 mL) was added (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (19.3 g 44 mmol). The mixture was heated to reflux and another 50 mL of 2-butanone was added. The resulting clear solution was allowed to cool to room temperature while stirring and after the addition of seed crystals [obtained from tetrahydrofuran, using equimolar amounts of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a '. 3a "or 3a"')] a precipitate formed. After three hours the precipitate was collected, rinsed with 2-butanone and dried to give material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (13.2 g, 37%, 87% ee). The recrystallization of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - acid di- (p-anisoyl) tartaric (3a) of 270 mL of 2-butanone gave (R) -a- (2,3-dimethoxy in il) -1 - [2- (4-f luorof in yl) ethyl] -4-piperid ina methanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') salt diastereomerically pure. (1 0.1 g, 28% product). Example 5 Scheme B, stage av stage b, and Scheme C stage a: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethip-4-piperidinemethanol, acid salt (2S, 3S ) - (+) - di- (p-anisoyl) tartaric (3a ') A 1 00 mL glass round bottom flask was charged with a- (2,3-dimethoxyphenyl) -1- [2- (4- fluorophenyl) ethyl] -4-piperidinemethanol (5) (3.41 g, 9.1 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3.98 g, 9.5 mmol) and ethyl methyl acetone (31 mL). The mixture was heated to reflux until the solution became homogeneous. The resulting yellow solution 5 was cooled to room temperature over a period of 1-1.5 hours and allowed to crystallize. Nucleation of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) occurred at approximately 30-35 ° C. Mix was then cooled to 0-5 ° C and kept at this temperature for 2.5 hours. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) was isolated by filtration in a sintered quartz glass funnel and rinsed with 9 mL of ethyl acetone methyl refrigerated. The wet cake was dried in a vacuum oven at 65 ° C to a constant weight to give 3.27 g of material enriched in (R) -a- (2, 3-di methoxy-enyl) -1- [2- (4- f luorof in yl) ethyl] -4-piperid ina methanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) in a product of 41.3% of 90.7% of ee of the product. In a round bottom flask glass of 1 00 mL the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (3.1 g, 3.9 mmol) was suspended in ethyl methyl acetone (62 mL). The mixture was heated to reflux (78.8 ° C) and the resulting homogeneous solution was cooled to room temperature. environment for a period of 1 0-1 5 minutes. Following the ^^^^^^^ and ^^^^^^ j ^^^^^ crystallization of (R) -a- (2, 3-di methoxy in il) -1 - [2- (4-f luorof in il) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a '), the mixture was cooled to 0-5 ° C and maintained at that temperature for 1 -1 .5 hours. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) purified tartaric (3a ') was then isolated by filtration in a sintered glass funnel and rinsed with 10 mL of ethyl methyl acetone. The wet cake was dried in a vacuum oven at 65 ° C to a constant weight to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified (2.62 g, 35.9% product, 97.1% ee). Example 6 Scheme B, stage a and stage b. and Scheme C, step a: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etiN-4-p, piperidylmethanol. (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') A three-necked round bottom flask was charged with a- (2,3-dimethoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (36.6 g, 98 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (42.9 g, 103 mmol) and ethyl methyl acetone (330 mL). The mixture was heated to reflux for about 20 minutes. When the internal temperature was 45 ° C, the almost homogeneous solution began to crystallize. When reflux was achieved, the solution was not homogeneous. The flask was isolated to allow a slow cooling. After two hours the solution had cooled to 50 ° C and again it was homogeneous. The seeds of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ', 3a ", or 3a"') were added and the resulting mixture was allowed to cool to ambient temperatures. Before the isolation the mixture was cooled in an ice bath. The product was isolated by filtration through a sintered quartz glass funnel. The filter cake was rinsed with cold ethyl methyl acetone (50 mL) and dried by suction. The pass product of material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3a) was 26.8 g with 92.5% ee. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) was suspended in ethyl methyl acetone (520 mL) and the mixture was heated to reflux for about 1.5 minutes. The homogeneous solution was allowed to cool to ambient temperatures. After stirring overnight, the seed crystals of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ', 3a "or 3a"') was added and the mixture was stirred at ambient temperatures for 24 hours. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) purified tartaric (3a ') was isolated by filtration through a sintered glass funnel. The filter cake was rinsed with ethyl methyl acetone (50 mL) and dried in a vacuum oven to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl ] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') purified as a white solid (14.8 g, 99% ee). Example 7 Scheme B, step a and step b, and Scheme C step a: (R) -a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etip-4-piperidinemethanol, acid salt (2S , 3S) - (+) - di- (p-anysol) tartaric (3a ") A reactor coated with 1 L was charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol (5) (41 .8 g, 0.1 1 mol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (49.9 g, 0.12 mol) and acetone ethyl methyl (375 mL) The mixture was stirred for one hour at 30 ° C, during which time the solution initially became homogeneous and then crystallized.The mixture was heated to 58-60 ° C for about one hour and The mixture was allowed to cool at 5 ° C for about 1 1 hours and the material enriched in (R) -a- (2)., 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) was isolated by filtration in a sintered glass funnel. The filter cake was rinsed with cold ethyl methyl acetone (100 mL) to give material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (34.5 g, 86% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (33.8 g, 43 mmol) was suspended in ethyl methyl acetone (675 mL) and digested at 51 ° C for about two hours. The mixture was allowed to cool to 4 ° C for about 7.5 hours. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) purified tartaric (3a ') was isolated by filtration in a sintered quartz glass funnel, rinsed with cold ethyl ethyl acetone (1000 mL) and dried by suction to give (R) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, purified (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') salt (30.8 g, 87% ee). (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) purified tartaric (3a ') (29.5 g, 37 mmol) and ethyl methyl acetone (590 mL) were charged to a 1 L coated reactor and the mixture was heated to reflux. A homogeneous yellow solution was obtained which was cooled for approximately one hour at 51 ° C. After one hour at 51 ° C, the seed crystals of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ', 3a ", or 3a"') were added to induce crystallization. After 1.5 hours at 51 ° C the mixture was cooled to 6 ° C overnight. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) tartaric (3a ",) purified was isolated by filtration in a sintered glass funnel, rinsed with ethyl methyl acetone (70 mL), dried by suction and dried overnight in a vacuum oven to give (R) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt ( 3a ") (1 5.6 g, 99% ee).

Example 8 Scheme B, step a and step b: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etyl-4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoiDtartaric (3a) a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (39.6 g, 106 mmol) was dissolved in Ethyl methyl acetone (300 mL) at 45 ° C in a Camile® controlled 1 L coated reactor The solution was cooled to 30 ° C and (2S, 3S) - (+) - di- (p-) acid was added. anisoyl) tartaric (46.6 g, 11.1 mmol) An additional ethyl methyl acetone rinse (60 mL) was added with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid. (2S, 3S) - (+) - di- (p-anisoyl) tartaric was immediately soluble at 30 ° C and the coated temperature gradually moved to 20 ° C. When the internal temperature reached 24 ° C crystallization and nucleation occurred The mixture was then allowed to cool to 0 ° C for 5 hours and then maintained at 0 ° C before isolation.The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) was isolated by filtration in a sintered glass funnel . The filter cake was rinsed with ethyl methyl acetone (75 mL) to give the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) after drying in a vacuum oven overnight (48 g, 79% ee).

Example 9 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2.3-Dimethoxyf in il) -1 -f2- (4-f luorof in il) etn-4-piperid ina goal nol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') A 100 mL round glass bottom flask was charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (2.06 g, 5.5 mmol) and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (2.4 g , 5.7 mmol) and methanol (1.7 mL). The mixture was heated to reflux and dissolved. The transparent homogeneous solution was then allowed to cool to room temperature with crystallization of the material enriched in (R) -a- (2,3-d-methoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperid ina nol goal, salt of (2S, 3S) - (+) - di- (p-anysol) tartaric acid (3a) occurring very quickly. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) was then isolated by filtration in a quartz sintered glass funnel and the wet cake was rinsed with cold methanol (10 mL) to give the material enriched in (R) -a- (2). , 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (2.21 g , 88.4% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (2.1 g, 2.7 mmol) was recrystallized from methanol (21 mL) at reflux. The reflux solution was cooled to room temperature and then cooled in an ice bath at 0-5 ° C. Isolation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ') purified by filtration in a quartz sintered glass funnel gave 1.86 g, 44% product, > 99% of us Example 1 0 Scheme B, step a and step b, and Scheme C step a: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etin-4-piperidinemethanol, acid salt ( 2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') A 1 00 mL glass round bottom flask was charged with a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (2.14 g, 5.7 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (2.5 g, 6.0 mmol) and methanol to 90%, 10% water (9.5 mL). The mixture was heated to reflux and dissolved. The transparent homogenous solution was then allowed to cool to room temperature with crystallization of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) occurring very quickly. The pulp was heated to dissolve some of the diastereomeric salt until the mixture was thin. The mixture was allowed to cool slowly to room temperatures. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) was isolated by filtration in a sintered quartz glass funnel and the wet cake was rinsed with 90% cold methanol, 10% water (8 mL) to give the material enriched in R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt tartaric (3a) (2.4 g, 52% product, 90% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (2.26 g, 2.9 mmol) was recrystallized from 90% methanol, 10% water (23 mL) at reflux. The solution was cooled to room temperature and then cooled in an ice bath at 0-5 ° C. Nucleation and crystallization started at 45 ° C. Isolation by filtration in a quartz sintered glass funnel gave (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') purified (1.93 g, 44.0% product, >99% ee). Example 1 1 Scheme B, step a and step b, v Scheme C step a: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etip-4-pyridylamine, salt of (2S.3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') A 100 mL round glass bottom flask was charged with a- (2,3-dimethoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (2.3 g, 6.2 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (2.69 g, 6.4 mmol) and Ethanol (10 mL). The mixture was heated to reflux and dissolved. The clear homogenous solution was then cooled to room temperature with crystallization of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) occurring very rapidly. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) then isolated by filtration in a quartz sintered glass funnel and the wet cake was rinsed with cold ethanol (11 mL) to give material enriched in (R) -a- (2.3 -dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (2.65 g, 53 % of product, 89% of ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (2.36 g, 3.0 mmol) was recrystallized from ethanol (108 mL) at reflux. The reflux solution was cooled to room temperature and then cooled in an ice bath at 0-5 ° C. Isolation by filtration in a quartz sintered glass funnel gave (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') (1.68 g, 38% product, 96% ee). Example 12 Scheme B. stage a and stage b, and Scheme C stage a: (R) -a- (2,3-dimethoxyphene) -1-r2- (4-fluorophenyl) etin-4-piperidine methanol, salt of (2S.3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') A 100 mL round glass bottom flask was charged with a- (2,3-dimethoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (2.02 g, 5.4 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (2.5 g, 6 mmol) and Ethanol (1 3 mL). The mixture was heated to reflux and dissolved. The clear homogenous solution was then cooled to room temperature with crystallization of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) occurring very rapidly. The coarse mixture was heated to dissolve most of the crystals and then allowed to cool slowly to room temperature. Filtering in a quartz sintered glass funnel and rinsing the wet cake with ethanol (10 mL) gave the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4- fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (2.1 3 g, 49% product, 92% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (1.96 g, 2.4 mmol) was recrystallized from ethanol (58 mL). The reflux solution was cooled to room temperature and then cooled in an ice bath at 0-5 ° C. Isolation while filtering in a quartz sintered glass funnel gave (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') (1.73 g, 43% product, > 99% ee). Example 13 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etin-4-piperidinemethanol, acid salt (2S .3S) - (+) - di- (p-anisoyl) tartaric (3a ') a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) ( 53.9 g, 144 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (63.0 g, 1 50 mmol) and methanol (563 mL) were charged in a 1 L coated reactor controlled Camile®. The mixture was heated to reflux to prepare a homogeneous solution. The mixture was refluxed for about one hour before cooling to 25 ° C for 3.5 hours. On the road of 25 ° C, when the internal temperature was 48 ° C, very rapid crystallization occurred (monitored with a fiber optic probe). When the internal temperature reached room temperature, there was a crust on the surface that does not shake. The mixture was heated to 62 ° C to thin the mixture. The thin mixture was digested at 62 ° C for 3 hours and then cooled to 4 ° C / hour for 4 hours thereafter at 8 ° C / hour at 0 ° C. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) was isolated by filtration in a quartz sintered glass funnel to give 58.6 g, 94% ee after drying. The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (45.5 g) was dissolved at reflux in methanol (500 mL). The mixture was refluxed for thirty minutes and then cooled to 4 ° C / hour for 5 hours and finally 8 ° C / hour at 0 ° C. The mixture was kept at 0 ° C overnight before isolating (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S) , 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified by filtration through a quartz sintered glass funnel. The filter cake was rinsed with cold methanol (75 mL) and dried in a vacuum oven to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified (37.8 g, >99% ee). Example 14 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-Di methoxy in il) -1 -f2- (4-f luorof in íl) etH4 -piperidinameta nol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') In a 1 00 mL glass round bottom flask, a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (3.21 g, 8.6 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (2.17 g, 5.2 mmol) and acetic acid (0.35 g, 5.8 mmol) were mixed in ethyl acetone methyl (29 mL). The mixture became homogeneous after heating to 50 ° C. The solution was then cooled to room temperature and reared with crystals of (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S) , 3S) - (+) - di- (p-anisoyl) tartaric (3a) purified. After 5 days, the mixture was cooled in an ice bath and isolated by filtration in a sintered quartz glass funnel to give the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1- [ 2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (2.76 g, 39.6% product, 92% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (2.62 g, 3.3 mmol) was charged in a 1000 mL round glass flask with ethyl methyl acetone (52 mL). The mixture was heated to reflux. The diastereomeric salt did not enter solution and additional ethyl methyl acetone (600 mL) was added at reflux until the crystals dissolved completely. Once dissolved, the solution was concentrated by evaporating 350 mL of ethyl methyl acetone in the rotary evaporator. The yellow solution was raised seed with (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) acid -di- (p-anisoyl) tartaric (3a ') purified and then wet in an ice bath. The crystallization occurred after approximately 2 hours of cooling. The mixture was filtered on a sintered quartz glass funnel, and rinsed with 10 mL of ethyl methyl acetone to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified (0.98 g, 15% product,> 99% ee). Example 1 5 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2.3-Dimethoxy-en-yl) -1-f2- (4-fluorophenyl) ethyl-1-4-piperidine metaol, (2S.3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') A 1 00 mL glass round bottom flask was charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (3.0 g, 8 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (1.71 g) , 4.1 mmol), acetic acid (0.29 g, 4.8 mmol) and methanol (1 2 mL). The mixture was heated to reflux (65 ° C) and the resulting homogeneous solution was cooled to room temperature for about 2.5 hours. Nucleation occurred followed by rapid crystallization. The mixture was digested at 45 ° C and then cooled to room temperature. Before being isolated, the mixture was cooled in an ice bath and then filtered in a sintered quartz glass funnel. The wet cake was rinsed with cold methanol (6 mL) and dried to give the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) as white needles (1.64 g, 25.4% product, 95% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (1.53 g, 2 mmol) was recrystallized from methanol (18 mL) in a 1 00 mL glass round bottom flask. After cooling, the mixture was heated to 40 ° C to digest the crystal for 1 hour. The mixture was cooled in an ice bath before filtration in a sintered quartz glass funnel to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') acid salt purified (1.45 g, 24.1% of the product,> 99% ee). Example 16 Scheme B, stage av stage b, and Scheme C stage a: (R) -a- (2,3-Dimethoxyf in il) -1 -f2- (4-f luorof in il) etiH-4-piper of methanol, (2S.3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') A 1 00 mL round bottom flask was charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (2.87 g, 7.7 mmol), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3.35 g, 8 mmol), and methanol (31 mL). The mixture was heated to reflux to provide a homogeneous solution which was cooled to 50 ° C and allowed to crystallize. Once the crystallization appears complete, the concentrated sulfuric acid (5 drops) is added and the mixture is digested at 50 ° C for about 2 hours. The mixture was cooled to ambient temperatures, then cooled in a cold water bath before isolation of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a). The product was isolated as a white solid by filtration in a sintered quartz glass funnel. The filter cake was rinsed with cold methanol (10 mL) to give the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (3.1 g, 89% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (3.0 g) was dissolved in methanol (35 mL) at reflux. The mixture was allowed to cool slowly to room temperature. Nucleation and crystallization occurred at 48 ° C. The mixture was cooled in an ice bath before being isolated by filtration in a sintered quartz glass funnel to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') purified as a white solid (2.8 g, 97.6% ee). Example 17 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-D¡methoxyphenol) -1-f2- (4-fluorophenyl) etn-4-piperidinemethanol , salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) A reactor lined with straight walls of controlled drainage bottom Camile® of 1 L was fitted with a glass head containing a stainless steel thermocouple, a nitrogen bubbler, a fiber optic probe, a stirrer and a water addition tube. The water addition tube was inserted above the level of the liquid and the water was allowed to run down the wall in a dropwise manner. A piston pump provided constant, slow flow. The agitator was a 4-blade impeller, tilted 45 ° for pumping the flow down. The vessel was charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (72.8 g), (2S, 3S) - (+) - acid di- (p-anisoyl) tartaric (45.1 g), and 50% acetic acid (300 g). The mixture was stirred at 350 rpm at a coating set point of 57 ° C. The contents were heated to complete dissolution at 53 ° C in 10 minutes. After 0.5 hours, the solution at 55 ° C was reared with 94% ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a 'or 3a ") One hour later, the addition of75 g of deionized water was initiated at a rate of 0.14 mL / After the addition of approximately 2/3 of water, the rate of addition was increased to 0.23 mL / min, the addition required 7.9 hours, after 1.5 hours, the mixture was cooled from 57 ° C to 35 °. C at 0.15 ° C / minute The mixture was stirred at 35 ° C for 1 1 hours before isolation.The contents were drained into a beaker and immediately separated in a fritted glass funnel by suction filtration. mother 283 g was a light pale yellow.The wet cake was rinsed in the funnel with 1 12 g of 40% HOAc (20 ° C) .The combined stock solution and rinse weighed 437 g.The wet cake, 53.5 g , was transferred a vessel and dried in a ventilation field for 72.22 g of white crystals. Correcting for aggregate seed crystal, the gravimetric product of material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S , 3S) - (+) - di- (p-anisoyl) tartaric (3a) was 91.7%. Through HPLC, the crystal product contained 50.4% by weight of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid and 47.1% by weight of a- (2,3-dimethoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol. By chiral HPLC, the ratio of% area of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to (S) -a - (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) was 94.3%: 5.7% or 88.6% ee. The stock solution plus the rinse solution contained 1.56% by weight of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid and 8.82% by weight of a- (2,3-dimethoxyphenyl). -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol. By chiral HPLC, the ratio of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to (S) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) was 1.1.1%: 88.9%. The mass liability was 94% for a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (assuming a 100% analysis of raw material). The standard molar responsibility of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) :( S) -a- (2,3- dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) was 50.7: 49.3. Example 1 8 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-Dimethoxyf in il) -1 - [2- (4-f luorof in il) ethyl1-4- piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol (5) recovered from the racemisation of the stock solutions of Example 38 (39.5 g, 0.1 mol) and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (46.6 g, 0.1 mol ) were dissolved in methanol (400 mL) under reflux in a 1 L round bottom flask. The clear solution was filtered by suction to remove any insoluble sodium sulfate and allowed to cool slowly to room temperature. At 40 ° C crystallization occurred. The mixture was cooled in an ice bath and then isolated by filtration, rinsed with chilled methanol (50 mL) and dried to a constant weight (46.5 g, 55%, 87.5% ee). The material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (45.38 g) was dissolved in methanol (460 mL) under reflux, allowed to cool and isolated by filtration. The white solid was rinsed with chilled methanol (50 mL) then dried to constant weight to give (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol , salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified (40.58 g, 49.6% product, 98.6% ee). Example 19 Scheme B, step a and step b, v Scheme C step a: (R) -a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) et.p.-4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ") In a 500 mL round bottom flask equipped with cold water condenser, heating mantle, magnetic stirrer and a line of nitrogen, a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (1 7.68 g, 47 mmol; recovered from the racemisation of stock solutions of Example 37), (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (20.79 g, 50 mmol) and methanol (197 mL) were combined and heated to Reflux. The solution was crystallized at 55 ° C while cooling to room temperature. The mixture was refrigerated in an ice bath at 0 ° C. The crystals were filtered by suction and rinsed with methanol (25 mL) before being dried at a constant weight in a vacuum oven. The isolation of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidynametol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (15.22 g) was made in 40.6% product (maximum product is 50%) and had an optical purity of 79.9%. The dried crystals were then recrystallized. In a 500 mL round glass flask, the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (15.0 g) was combined with methanol (195 mL). The mixture was heated to reflux and cooled slowly to room temperature, crystallization occurred at about 50 ° C. The mixture was refrigerated in an ice bath for 30 minutes and then filtered by suction. The crystals were rinsed with methanol (20-25 mL) before being dried in a vacuum oven at a constant weight. Isolation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ') purified (12.94 g) was in 35% product (based on the product of the first crystallization) and had an optical purity of 96.5%. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) tartaric (3a ') purified was still lower than the desired purity of > 99% so a second recrystallization was done. 96.5% ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - purified di- (p-anisoyl) tartaric (3a ') (12.75 g) was combined with methanol (200 mL) and heated to reflux. The solution was cooled to room temperature and crystallized. The mixture was refrigerated in an ice bath for 30 minutes and then filtered by suction through a sintered quartz glass funnel. Isolation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ") purified twice recrystallized (10.53 g) was in a 28.9% product (based on the product of the second crystallization) having an optical purity of 98.9% Example 20 Scheme B, stage a and stage b, and Scheme C step a: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etip-4-p-peridynametanol, acid salt (2S.3S) - (+ ) -di- (p-anisoyl) tartaric (3a ') In a suitable reactor, maintained under an argon atmosphere, p-anisic acid (39.5 kg, 260 mol) is mixed with approximately 51 kg of xylenes.1 Chloride is added. oxalyl (27.7 kg) while maintaining the temperature below about 60 ° C. The mixture is heated between 50-60 ° C for about 1 hour until a homogeneous solution is formed.The mixture is heated to about 100 ° C and any remaining oxalyl chloride is removed by distillation The mixture is then cooled to 60-70 ° C. In a second suitable reactor. , (2S, 3S) - (-) tartaric acid (12.7 kg, 85 mol) is mixed with approximately 45 kg of xylenes2. The hot solution (above 70 ° C) of p-anisoyl chloride is added and the mixture is heated to about 35 ° C for about 3 hours. The mixture is then cooled to approximately 60 ° C. Approximately 13 kg of oxalyl chloride is added and the mixture is heated to about 65 ° C for at least 1 hour. The reaction mixture may be heated to about 70 ° C to partially dissolve the anhydride 3. The mixture is then kept at this temperature for about 1 hour. The crystallization is completed by cooling the mixture to about -1 0 ° C for about 1 hour before isolating the anhydride by filtration. The wet cake is rinsed with approximately 38 kg of cold xylenes to typically provide 22.36 kg (13-20% xylenes) of anhydride (70-91% product) 4. A suitable reactor is charged with anhydride (28 kg, 60 mol) as a wet cake of xylenes, acetone (78 kg) and 26 kg of water. The mixture is heated to reflux (60 ° C) for about 2 hours. To the mixture (at about 60 ° C) about 1 90 kg of water are added, causing the precipitation of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid. The acetone is removed by distillation until the temperature of the mixture reaches approximately 80 ° C. The mixture is cooled to about 5 ° C and the product is isolated by filtration. The reactor and the transfer lines are rinsed with approximately 38 kg of water. The wet cake is rinsed with about 1 70 kg of water to typically provide 23-33 kg (with 5-30% solvent) of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (64). -1 04% product) .5 The product was dried at approximately 70-80 ° C (vacuum) .6 A suitable reactor is charged with a- (2,3-dimethoxyphenyl) -1- [2- (4- fluorophenyl) ethyl] -4-piperidinemethanol (5) (40.0 kg, 1 07 mol) as a wet cake of isopropanol and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (46.8 kg, 1 12 mol). Approximately 285 kg of methanol is added and the mixture is heated to about 65 ° C. The mixture is cooled to below 5 ° C for at least 1 hour and the material enriched in (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (85-90% ee) is recovered by filtration. The wet cake is rinsed with approximately 28 kg of methanol to typically provide 48-49 kg of material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (45-50% product) 7. In a suitable reactor the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) acid is charged. (+) - di- (p-anisoyl) tartaric (3a) and approximately 383 kg of methanol.8 The mixture is heated to about 65 ° C. The mixture is cooled to below 5 ° C for at least 1 hour and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a ') purified is isolated by filtration.9 The filter cake is rinsed with approximately 43 kg of cold methanol to typically provide 37.4 to 39.3 kg of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) salt ) tartaric (3a ') purified (90-95% of product) as a wet methanol cake.9 1 Stock solutions of anhydride filler from pre-fillers contain p-anisoyl chloride and anhydride and can be recycled. The exact amount of p-anisic acid used for each charge is determined following an analysis of the stock solutions. 2 The amount of xylenes used to mix tartaric acid is reduced when using a filler that uses stock solution of anhydride filtration from previous fillers according to comment 1. The amount of xylenes added is adjusted to maintain the anhydride concentration in the crystallization step. 3 The mixture can be reared seed with anhydride to aid crystallization. 4 The products are determined by HPLC analysis and loss in drying.

The products are determined in combination with loss in drying and HPLC analysis. 6 The product of other charges can be combined to dry. 7 The weights of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) -di- (p-anisoyl) tartaric (3a) are based on HPLC analysis. % Ee is determined by chiral HPLC analysis. 8 The dry weight of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (3a) is used as the base amount of methanol to be added. 9 The products are determined by HPLC analysis. The% ee is determined by a chiral HPLC method. Example 21 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3- Dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethyl 1-4-piperidinemethanol, acid salt (2S.3S) - (+) - di- (p-anisoyl) tartaric (3a ') In a suitable reactor, maintained under an argon atmosphere, p-anisic acid (361 kg, 2376 mol) is mixed with about 385 kg of xylenes1. Oxalyl chloride (approximately 329 kg) is added while maintaining the temperature below about 60 ° C. The mixture is heated between 50-60 ° C for about 1 hour until a homogeneous solution is formed. The mixture is heated to about 100 ° C and any remaining oxalyl chloride is removed by distillation. The mixture is then cooled to 60-70 ° C. In a second suitable reactor. , (2S, 3S) - (-) tartaric acid (1 7 kg, 783 mol) is mixed with approximately 340 kg of xylenes2. Hot solution 20 (above 70 ° C) of p-anisoyl chloride is added and the mixture is heated to about 135 ° C for about 3 hours or until evolution of hydrogen chloride is stopped. The mixture is cooled slowly to about 60 ° C. Approximately 1 55 kg of oxalyl chloride is added and the mixture is heated to about 65 ° C for at least 1 hour. The I '' i rmí r -j-t-jj-lft '• • ~ ¿y-¡> ~ > . Y . > *. -.- -. . . . . . . ... .. .:. ... .Y ? k -. . j &ran? iac and ...

The reaction mixture can be heated to about 70 ° C to partially dissolve the anhydride 3. The mixture is then kept at this temperature for about 1 hour. The crystallization is completed by cooling the mixture to about -10 ° C. The mixture is maintained at about -1 0 ° C for about 1 hour before isolating the anhydride by filtration. The wet cake is rinsed with approximately 290 kg of cold xylenes to typically provide 200-330 kg of anhydride as a wet cake containing about 1 3-20% xylenes (70-96% product) 4. A suitable reactor is charged with anhydride (256 kg, 549 mol) as a wet cake of xylenes, acetone (71.0 kg) and about 240 kg of water. The mixture is heated to reflux (60 ° C) for about 2 hours. Approximately 1740 kg of water is added to the mixture at approximately 60 ° C, causing the precipitation of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid. The acetone is removed by distillation until the temperature of the mixture reaches approximately 80 ° C. The mixture is cooled to about 5 ° C and the product is isolated by filtration. The reactor and the transfer lines are rinsed with approximately 350 kg of water. The wet cake is rinsed with about 1550 kg of water to typically provide 210-302 kg of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid as a wet cake containing 5-30% of solvent (64-104% of product) .5 The product of six charges was combined and dried at 70-80 ° C (vacuum).

A suitable reactor is charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (40.0 kg, 1 07 mol) as a wet cake of isopropanol and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (46.8 kg, 1 12 mol). Approximately 285 kg of methanol is added and the mixture is heated to about 65 ° C. The mixture is cooled to below 5 ° C and the material enriched in (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (85- 90% ee) is recovered by filtration. The wet cake is rinsed with about 10 kg of methanol to typically provide 48-49 kg of material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (45-50% product) 6. In a suitable reactor, the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) acid is charged. (+) - di- (p-anisoyl) tartaric (3a) and approximately 380 kg of methanol.7 The mixture is heated to about 65 ° C. The mixture is cooled to below 5 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) - purified di- (p-anisoyl) tartaric (3a ') is isolated by filtration.8 The filter cake is rinsed with approximately 40 kg of cold methanol to typically provide 37.4 to 39.3 kg of (R) -a - (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') ) purified (90-95% product, 98-1 00% ee) as a wet methanol cake.9 1 Stock solutions of anhydride filler from pre-charges contain p-anisoyl chloride and anhydride and can be recycled. The exact amount of p-anisic acid used for each charge is determined following an analysis of the stock solutions. 2 The amount of xylenes used to mix tartaric acid is reduced when using a filler that uses stock solution of anhydride filtration from previous fillers according to comment 1. The amount of xylenes added is adjusted to maintain the anhydride concentration in the crystallization step. 3 The mixture can be reared seed with anhydride to aid crystallization. 4 The products are determined by HPLC analysis and loss in drying.

The products are determined in combination with loss in drying and HPLC analysis. 6 The weights of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) - (+) -di- (p-anisoyl) tartaric (3a) are based on HPLC analysis. The% ee is determined by a chiral HPLC method. 7 (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol recovered from the filtrates resulting from the conversion of (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) in (R) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in Scheme B, stage c (R) -a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol recovered from the filtrates resulting from the recrystallization of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol in Scheme B, step c, as a wet isopropanol cake can also be charged to the reactor with (2S.3S) - (+) - di- (p-anisoyl) tartaric acid in a molar ratio from 1 to 1. The recovered (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol typically has an enantiomeric excess of 95% in (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol. The dry weight of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (or equivalent, adjusted for (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol is used as the base amount of methanol 8 Methanol can be recovered from the filtrates of both crystallizations by resolution by for reuse in this reaction step 9 The products are determined by HPLC analysis The% ee is determined by a chiral HPLC method.

Example 22 Scheme B, stage a and stage b, and Scheme C stage a: (R) -a- (2,3-Di methoxy in i D-1 -f2- (4-f luorof in il) et-n-4 -piperidinemethanol, (2S.3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') In a suitable reactor, maintained under an argon atmosphere, p-anisic acid (361 kg, 2.37 kmol) with approximately 385 kg of xylenes.1 Oxalyl chloride (approximately 330 kg) is added while maintaining the temperature at about 60 ° C. The mixture is maintained at about 60 ° C for about 1 hour until a solution is formed. The mixture is heated to about 100 ° C and any remaining oxalyl chloride is removed by atmospheric distillation.The mixture is then cooled to about 70 ° C. In a suitable second reactor, (2S, 3S) - (-) acid Tartaric (1 17 kg, 0.78 kmol) is mixed with approximately 340 kg of xylenes.2 The p-anisoyl chloride solution is added to the mixture and the mixture is heated to approx. Te 1 35 ° C for about 3 hours or until evolution of hydrogen chloride stops. The mixture is cooled to approximately 60 ° C. Approximately 1 55 kg of oxalyl chloride is added and the mixture is heated to about 65 ° C for at least 1 hour. The mixture is heated to about 70 ° C to partially dissolve the anhydride. The mixture is then kept at this temperature for about 1 hour.3 The crystallization is completed by cooling the mixture to about -10 ° C. The mixture is then cooled and the wet cake is rinsed with approximately 290 kg of cold xylenes to typically provide 280 kg (approximately 1.7% xylenes) of anhydride (approximately 80% product) 4. A suitable reactor is charged with anhydride (256 kg, 639 mol) as a wet cake of xylenes, acetone (710 kg) and 240 kg of water. The mixture is heated to reflux (60 ° C) for at least 2 hours. Approximately 1740 kg of water is added to the mixture at approximately 60 ° C. The acetone is removed by atmospheric distillation until the temperature of the mixture reaches approximately 80 ° C. The mixture is cooled to approximately 5 ° C. The mixture is filtered using approximately 350 kg of water to rinse the reactor. The wet cake is rinsed with about 1550 kg of water to typically provide about 250 kg (with about 5-30% solvent) of acid (2S), 3S) - (+) - di- (p-anisoyl) tartaric (approximately 80% product) .5 (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid of 6 charges was combined and dried under vacuum at 70 ° C. A suitable reactor is charged with a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (40.0 kg, 107 mol) as a wet cake of isopropanol and acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric (46.8 kg, 1 12 mol). Approximately 285 kg of methanol is added and the mixture is heated to about 65 ° C. The mixture is cooled to below 5 ° C and the material enriched in (R) -a- (2,3-di methoxy in il) -1 - [2- (4-f luorof in yl) ethyl] -4 -piperid i na meta nol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a) (about 85-90% ee) is recovered by filtration. The wet cake is rinsed with about 10 kg of methanol (about 5 ° C) to typically provide about 40 kg of material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4- fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) (approximately 47% product) 7.8. The filtrate contains mainly (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3b) .7 In a suitable reactor the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- is charged. piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a) and approximately 380 kg of methanol.6,9 The mixture is heated to about 65 ° C. The mixture is cooled to approximately 5 ° C. The mixture is filtered and the filter cake is rinsed with about 40 kg of cold methanol to typically provide about 38 kg of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl ] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') purified (approximately 90-95% product, approximately 98-1 00% ee) as a wet cake of methanol.10 The filtrate contains mainly a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+ ) -di- (p-anisoyl) tartaric (essentially 3a and 3b) 7. The stock solutions of the final filtration of previous fillers contain p-anisoyl chloride and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid and can be recycled. The exact amount of p-anisic acid used for each charge is determined following an analysis of the stock solutions by HPLC analysis. 2 The amount of xylenes used to mix the tartaric acid is reduced if a load using mother liquors of previous fillers of the final filtrate is used (see comment 1). The amount of xylenes added is adjusted to maintain the anhydride concentration in the crystallization step. 3 The mixture can be reared seed with anhydride to aid crystallization. 4 The products are determined by HPLC analysis and loss in drying.

The products are determined in combination with loss in drying and HPLC analysis. Methanol recovered by distillation of the filtrates of both crystallizations by resolution (Scheme B, step b) can be used in this stage of the process. 7 The filtrates are stored at approximately 5 ° C for use in Scheme C, step a. 8 The weights of the material enriched in (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) acid -di- (p-anisoyl) tartaric are based on HPLC analysis. The% ee is determined by a chiral HPLC method. 9 (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) which is recovered by distillation to about 14 to 30% by weight of solution followed by crystallization and filtration of the filtrates of Scheme B, step c and the final recrystallization of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol ( 3) as a wet isopropanol cake, can also be charged to the reactor with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid in a molar ratio of 1 to 1. The recovered (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) typically has an enantiomeric excess of about 95%. The dry weight of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric (3a) (or equivalent, adjusted for (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) recovered) is used as the basis for the amount of methanol to be added. 10 The products are determined by HPLC analysis. The% ee is determined by a chiral HPLC method.

EXAMPLE 23 Scheme C, step b: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethyl-1-4-piperidinemethanol (3) (R) -a- (2,3- Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') (10.1 g) is stirred with 100 mL of 6.5 N of ammonium and 1 00 mL of toluene for 2 hours at room temperature. The toluene layer was separated and the water layer was extracted twice with 50 mL of toluene. The combined toluene layers were rinsed with 30 mL of 10% KOH solution and 30 mL of brine, dried over sodium sulfate, filtered and evaporated to give the main compound (R) -a- (2,3-dimethoxyphenyl) - 1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as a white solid (> 99% ee); [a] 578 + 23.8 ° (c = 0.5 MeOH). Example 24 Scheme C, step b: (R) -a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etyl-4-piperidinemethanol (3) (R) -a- (2,3- Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a 'or 3a ") (9.1 kg, 8.0 kg dry weight) was suspended in toluene (20.1 kg) with stirring in a 50 L round bottom reactor. The aqueous potassium carbonate (13.7 kg of a 12.8% by weight solution) was added for about 60 minutes between 1 8-38 ° C. The mixture was heated within the range of 40-45 ° C with stirring for about 30 minutes.The stirring was stopped and the phases were allowed to separate.The temperature remained in the range of 40 minutes. -45 ° C for decanting The phases were decanted and the aqueous phase (approximately 1 8.5 kg) was allowed to cool in the preparation for acid recovery (2S, 3S) - (+) - di- (p-anisoyl) tartaric1. The toluene solution was extracted with additional aqueous potassium carbonate (4 kg of 2.5% by weight solution). Stirring was continued for about 1 hour in the range of 40-45 ° C. The phases were allowed to settle and the aqueous phase was decanted within the temperature range of 40-45 ° C. The aqueous phase (approximately 4.4 kg) was discarded. If it is required to remove residual (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid, the toluene solution can be extracted with additional aqueous potassium carbonate (4 kg of a 12.5% by weight solution). Stirring was continued for about 1 hour within the temperature range of 40-45 ° C. The phases were allowed to settle and the aqueous phase was decanted within the temperature range of 40-45 ° C. The aqueous phase was discarded. The toluene phase (approximately 23.6 kg) was analyzed for% by weight of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) ( typical range 12-16% by weight) and% by weight of acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (typical range 0.2% by weight not detectable by 0.04% by weight) before of additional processing. The toluene phase (23.6 kg, containing approximately 3.5 kg of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3)) was added either by loading or continuously to a rotary evaporator of 20 L to maintain its own operating volume. The solvent was removed to <40 ° C and 35-65 mm Hg, until the feed is gone and the amount of solvent taken up was decreased. 2-Propanol (10.5 kg) was added and the solvent was removed above to < 40 ° C and approximately 35 mm Hg to azeotropically remove the remaining toluene. 2-Propanol (7.5 kg) was added and the 20 L vessel was heated under nitrogen to about 75 ° C to dissolve (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). The solution was filtered by polishing through a 0.2 μm filter while transferring to a 50 L crystallizer. The crystallizer was stirred under a nitrogen blanket while cooling to < 0.2 ° C / m at room temperature. Three charges of the rotary evaporation of 20 L were combined for a crystallizer charge of 50 L. (R) -a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) was recrystallized by heating the 50 L flask for a thin mixture at about 62 ° C and cooling to < 10 ° C in > 6 hours. The crystals of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) were isolated by vacuum filtration in a ceramic funnel of 35.56 centimeters diameter with a propylene filter cloth, particle retention 0.5 μm. The wet cake was rinsed with approximately 2.6 kg of cold filtered 2-propanol (0.2 μm), transferred to a drying vessel, and dried in a vacuum oven at 32-36 ° C and 35-65 mm Hg. to constant weight. The dried crystals (drying loss = 8-13%) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) were large, white, and in triangular shape, weighing approximately 9.5 kg (90% of isolated product). 1 The aqueous phase of the initial stirring was diluted with 2-propanol (6.9 kg). Hydrochloric acid (5% by weight, 19.9 kg) was added to the well-stirred aqueous solution of the potassium salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid for about 1.5 hours . The temperature of the mixture was kept below about 30 ° C during this addition. The precipitated (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid was isolated by filtration. The filter cake was rinsed with approximately 16 kg of water and dried by suction. The recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (6-1 6 kg) was analyzed for residual anisic acid (typically not detected) and a loss in drying was obtained (35-82). %). Example 25 Scheme C, step b: (R) -a- (2,3-Dimethoxy-phenyl) -1-p2- (4-fluorophenyl) etn-4-piperidinemethanol (3) (R) -a- ( 2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ') Example 1 8 (40.58 g, 98.6% ee) was suspended in toluene (206 mL) and neutralized with 12.8% aqueous potassium carbonate (61 g). The phases were stirred at 60 ° C for about 30 minutes. The phases were separated and the organic phase was extracted twice with 12.8% potassium carbonate (30 g and 14 g). The toluene was removed on the rotary evaporator. The residual solid was dissolved in 2-propanol, concentrated on rotary evaporation and then dissolved in 2-propanol (28 mL) and crystallized. The mixture was cooled in an ice bath before filtration. (R) -a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) was isolated in 16.2 g of product (99.8% ee, 1 02% of analysis). The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) of (S) -a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in Example 38 in the initial toluene was 32.5%.

EXAMPLE 26 Scheme C, step b: (R) -a- (2,3-D-methoxyphenyl) -1-r2- (4-fluorophenyl) ethyl-1-4-piperidinemethanol (3) In a glass round-bottomed flask of 500 mL equipped with a heating mantle, cold water condenser, magnetic stirrer and a nitrogen line, 98.8% ee of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (3a ") of Example 1 9 (1 0.41 g, 1 3.2 mmol) was suspended in toluene (54 mL) To the suspension was added an aqueous solution of 12.8% by weight of potassium carbonate (15.6 g) The phases were stirred at 60 ° C for 45 minutes and then separated. the second time with more of the carbonate solution (4.2 g) .The phases were again stirred at 60 ° C for 30 minutes before being separated.The upper organic phase was analyzed and found to contain 9.5% by weight (4.57 g, 12.2 mmol) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ) ethyl] -4-piperidinemethanol (3). The solution was stripped to an oil and then dissolved in 2-propanol. The solution was then concentrated to a white residue. The residue was dissolved in 2-propanol (10.6 g) to give a 30% by weight solution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidinemethanol (3). The solution was heated to reflux, cooled to room temperature and allowed to crystallize. The crystals were digested at 60 ° C for 45 minutes. The mixture was then cooled to room temperature, cooled in an ice bath and filtered by suction. The wet cake was rinsed with 4-6 mL of wet 2-propanol. Analysis of stock solutions showed 2.2 wt% (0.26 g) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). The isolation of the crystals gave 83.1% of product (based on the weight of salt (R) -diastereomeric used) and the product had an optical purity of 99.9%. Example 27 Scheme C, step b: (R) -a- (2l3-dimethoxyphenyl) -1-r2- (4-fluorophenyl) et.n-4-piperidinemethanol (3) A mixture of (R) -a- (2) , 3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') (as a wet cake of methanol, 98-100% ee) of Example 20 (8.9 kg, 11.1.2 mol) in toluene (20 kg) is prepared in a suitable reactor at about 25 ° C. The salt is neutralized by the addition of approximately 14 kg of an aqueous 3% potassium carbonate solution 1. The mixture is heated to about 40 ° C and the phases are separated. The aqueous phase is transferred to a separate reactor and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is recovered from phase.2 The toluene solution containing (R) -a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) was extracted with about 4 kg of a 13% aqueous potassium carbonate solution, and the aqueous phase is discarded . The toluene solution is concentrated by vacuum distillation.4 Approximately 11 kg of isopropanol is added to the mixture and the mixture is heated to about 40 ° C and the residual isopropanol and toluene is removed by vacuum distillation. dissolve in about 8 kg of isopropanol at about 70 ° C and the solution is filtered by clarification, using approximately 0.2 kg of isopropanol as a rinse. The filtered solution is heated to about 62 ° C, then cooled to about 10 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is isolated by filtration.5 The filter cake is rinsed with approximately 3 kg of isopropanol and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidine methanol (3) is dried at about 30 ° C under vacuum. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically 10 kg (91% product) as determined by HPLC analysis. 1 The 13% aqueous potassium carbonate solution is prepared by dissolving approximately 2.3 kg of anhydrous potassium carbonate in . 7 kg of water. 2 The aqueous solution is diluted with approximately 10 kg of isopropanol and then made acidic by adding approximately 19 kg of a hydrochloric acid solution to approximately 5% (prepared by diluting approximately 3.4 kg of 32% aqueous hydrochloric acid with approximately 15.6 g. kg of water). The precipitated (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is isolated by filtration. The wet cake is rinsed with approximately 19 kg of water. The recovered solid typically weighs 10 kg, with a typical loss in drying of 35-82%. This mixture is analyzed for the presence of p-anisic acid by HPLC. 3 The range of concentrations of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in toluene obtained were 1 1. 16% by weight as determined by HPLC analysis. (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid varied from 0.2% undetectable, as determined by HPLC analysis, and the enantiomeric excess varied from 98-99% as determined by the Chiral HPLC analysis. 4 The distillation is continued until no additional solvent is condensed. 5 The organic phases of 3-fold isopropanol are combined in a suitable reactor and processed as a single charge.

Example 28 Scheme C, step b: (R) -a- (2,3-dimethoxyphenyl) -1-r2- (4-fluorophenyl) ethyl 1-4-piperidinemethanol (3) A mixture of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid salt (3a ') (as wet methanol cake, 98-100% ee) of Example 21 (29.5 kg, 37.2 mol) in toluene (74 kg) is prepared in a suitable reactor at about 50 ° C. The salt is neutralized by the addition of approximately 59 kg of an aqueous 3% potassium carbonate solution 1. The mixture is maintained at about 50 ° C and the phases are separated. The aqueous phase is transferred to a separate reactor and (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is recovered from phase.2 the toluene solution containing (R) -a- ( 2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is mixed at about 50 ° C with about 13 kg of a 3% aqueous potassium carbonate solution, and the aqueous phase is discarded. The toluene solution containing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is mixed at about 50 ° C with about 30 kg of water and the aqueous phase is discarded. The toluene solution is filtered, using approximately 35.4 kg of isopropanol mixed with 8.9 kg of water as a rinse. The solvent is exchanged from toluene to isopropanol and water by distillation by removing approximately 245 kg of solvent. After each of the first four increments of 49 kg of distillate, another 35.4 kg of isopropanol and 8.9 kg of water are added to the solution for a total of 141.6 kg of isopropanol and 35.6 kg of water. Approximately 9.3 kg of water is added to the solution while maintaining the temperature at or above 70 ° C. The solution is then cooled to below 0 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is isolated by filtration . The filter cake is rinsed with approximately 9.1 kg of isopropanol. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically 12.3 kg (89% product was determined by HPLC analysis ). (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) remaining in filtrate 3 can be recovered and returned to Scheme B, step a, to improve its enantiomeric excess4. A suitable container is loaded with approximately 0.6 kg (dry basis) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (as a wet cake of isopropanol / water). Approximately 3.6 kg of methanol is added to dissolve (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) .5 the solution is filtered. A mixture of seed crystals is formed by joining with the rapid mixing of the continuous additions of the methanol solution and about 57 kg of water at a constant ratio in a suitable inert vessel. Approximately 0.2 kg of isopropanol is used to level the addition of methanol solution and approximately 33 kg of water is used to level the seed crystals in the container.6 The mixture is maintained at 1 to 20 ° C. In a separate inserted container, approximately 0.9 kg (dry basis) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (as a wet isopropranol cake / water) are dissolved in approximately 54 kg of isopropanol. The solution is stirred and heated to dissolve (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3). and then it is maintained at 15 to 20 ° C. The isopropanol solution is filtered in the seed crystal mixture. In a separate inserted container, approximately 0.8 kg (dry basis) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) are dissolved in approximately 39.1 kg of isopropanol and 9.7 kg of water. The solution is stirred and heated to dissolve (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and then maintained at about 65 ° C. . The isopropanol solution is filtered in the seed crystal mixture while the mixture is maintained at 1 to 25 ° C. Approximately 6.5 kg of isopropanol is used as a rinse. Approximately 58.2 kg of water is added to the mixture while maintaining the temperature at 1 to 25 ° C. The mixture is cooled to 0 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is isolated by filtration. The filter cake is rinsed with approximately 18 kg of water and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is dried to approximately 70 ° C vacuum. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 1 1 .4 kg (93% product as it is determined by HPLC analysis). (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) remaining in the filtrate 7 can be recovered and returned to Scheme B, step a, for improve its enantiomeric purity.8 1 The 13% aqueous potassium carbonate solution is prepared by dissolving approximately 9.2 kg of anhydrous potassium carbonate in 62.8 kg of water. 2 Approximately 21 kg of the aqueous solution is diluted with approximately 10 kg of isopropanol and then made acidic by adding approximately 19 kg of a hydrochloric acid solution to approximately 5% (prepared by diluting approximately 3.4 kg of 32% aqueous hydrochloric acid) with approximately 1 5.6 kg of water). The precipitated (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is isolated by filtration. The wet cake is rinsed with approximately 19 kg of water. The recovered solid typically weighs 10 kg, with a typical drying loss of 35-82%. This mixture is analyzed for the presence of p-anisic acid by HPLC analysis. 3 This filtrate can be combined with the filtrate from the final recrystallization of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to recover (R ) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to be recycled. 4 (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) remaining in the filtrate can be recovered by concentrating the solution while adding isopropanol ( as necessary) to maintain the boiling point below 90 ° C and then cool to about 0 ° C and isolate by filtration. The filter cake is rinsed with isopropanol. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 1.0 kg when the filtrates from this stage of the procedure, Scheme B, step c, and filtering the final recrystallization from (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) combine (41% product as determined by HPLC analysis with an enantiomeric excess of 95% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as determined by chiral HPLC analysis 5 A portion of methanol can be reserved and used as a flow after filtration. 6 If more water is mixed with the methanol solution, the amount of flow is reduced in such a way that the total water mixed with the methanol solution does not change. 7 Isopropanol filtrate from the isolation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3), from the basic hydrolysis of the diastereomeric salt , can be combined with the final recrystallization filtrate to recover (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol (3) to recycle. 8 (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) remaining in the filtrate can be recovered by concentrating the solution while adding isopropanol ( as necessary) to maintain the boiling point below 90 ° C and then cool to about 0 ° C and isolate by filtration. The filter cake is rinsed with isopropanol. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 1.0 kg when the isopropanol filtrate of the insulation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) from the basic hydrolysis of the diastereomeric salt is combined with the filtrate from the recrystallization final (41% product as determined by HPLC analysis with a 95% enantiomeric excess of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as determined by HPLC analysis.) Example 29 Scheme C, step b: (R) -a- (2,3-D-methoxyphenyl) -1 - [2- (4-fluorophenyl) etiN-4-piperidinemethanol (3) (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, salt of (2S, 3S) - (+) - di- ( p-anisoyl) tartaric (3a ') (100 kg, 126 mol) as a wet cake of methanol (98-100% ee, of Example 22) and toluene (250 kg) are charged to a suitable reactor and the mixture is mixed. heat to approx imadamente 50 ° C. Approximately 1 95 kg of an aqueous 3% potassium carbonate solution 1 is added and the phases are separated.2 The toluene solution containing (R) -a- (2,3-dimethoxyphenyl) -1- [2 - (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is extracted at about 50 ° C with about 50 kg of a 3% aqueous potassium carbonate solution and the aqueous phase is discarded. The toluene solution is extracted at approximately 50 ° C with approximately 1000 kg of water and the aqueous phase is discarded. The organic phase is filtered. A mixture of approximately 120 kg of isopropanol and approximately 30 kg of water are used as a filter rinse. The solvent is exchanged from toluene to isopropanol and water by the addition in a portion of isopropanol and water for a total of 480 kg of isopropanol and 120 kg of water. Approximately 30 kg of water is added to the mixture while maintaining the temperature at approximately 65 ° C. The solution is cooled to about 0 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is isolated by filtration. The filter cake is rinsed with approximately 20 kg of cold isopropanol. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 42 kg (89% product as determined by HPLC analysis) .3 A suitable vessel is loaded with approximately 2.0 kg (dry basis) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ( 3) (like a moist isopropranol / water cake). Approximately 12.2 kg of methanol are added6 and the solution is filtered. A mixture of seed crystals is formed by continuously feeding at a constant rate both the solution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as approximately 300 kg of water to a suitable container7. The mixture of seed crystals is maintained at approximately 1 5 ° C (solution A). Approximately 3.1 kg (dry basis) of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) (as a wet cake of isopropanol / water ) and approximately 1 80 kg of isopropanol are charged to a separate vessel (solution B). The solution is heated to above about 25 ° C and maintained at approximately 20 ° C. Solution B is filtered in the mixture of seed crystals (solution A), forming the solution C. Approximately 35.6 kg (dry basis) of (R) -a- (2,3-dimethoxyf in yl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3 ) (such as a wet isopropanol / water cake), approximately 35 kg of isopropanol and approximately 22 kg of water are charged to a separate vessel (solution D). The mixture is heated to about 65 ° C. This solution (solution D) is filtered in solution C while maintaining the temperature at about 25 ° C. Approximately 22 kg of isopropanol is used as a rinse. Approximately 138 kg of water is added to the mixture while maintaining the temperature at approximately 1 to 25 ° C. The mixture is cooled to about 0 ° C and (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is isolated by filtration. The filter cake is rinsed with approximately 80 kg of water. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is dried at about 70 ° C under vacuum. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 38.7 kg (95% product as determined by HPLC analysis) .8 1 The aqueous 3% potassium carbonate solution is prepared by dissolving approximately 32 kg of anhydrous potassium carbonate in 214 kg of water. 2 A suitable reactor is charged with the initial aqueous potassium carbonate solution containing (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid, potassium salt (61.8 kg) (see comment 4) ). Approximately 186 kg of water and hydrochloric acid (106 kg, 32%) are then added and the addition line is leveled with approximately 9 kg of water. The mixture is allowed to degas for at least 1 hour and the pH of the solution is measured to confirm that pH # 2 (see comment 5). Acetone (62 kg) is added to the mixture and the mixture is heated to about 70 ° C. The pH is then measured again to ensure a pH # 2 (see comment 5). The mixture is then cooled to about 70 ° C and held there for about 2 hours before cooling to about 1 5 ° C. The recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid is collected by filtration. The wet cake is rinsed with approximately 185 kg of water to provide approximately 45 kg of recovered (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid (80% product as determined by HPLC analysis) . 3 The filtrate from this step can be combined with that from the final crystallization of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to recover (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to recycle to Scheme B, step a. 4 Aqueous solutions of multiple loads can be combined for processing. The weight% of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid in solution is typically about 12% by weight, as determined by HPLC analysis. 5 The additional hydrochloric acid can be added as necessary to achieve the desired pH. 6 A portion of methanol can be reserved and used as a flow after filtration. 7 A portion of the water (typically 30 kg) is reserved and used to level the seed crystals to the container. 8 (R) -a- (2,3-dimethoxyf in yl) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3) remaining in the filtrate of this step and the filtration of the isolation of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) from the basic hydrolysis of the diastereomeric salt can be recovered by concentrating the solution while adding isopropanol (as needed) to maintain the boiling point at about 90 ° C, followed by cooling to about 0 ° C and asylating by filtration. The filter cake is rinsed with isopropanol. The product of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is typically about 1.0 kg when the filtrates of this stage and filtering the insulation of (R) -a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) from the basic hydrolysis of the diastereomeric salt (41% product as determined by HPLC analysis with an enantiomeric excess of 95%). % (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as determined by chiral HPLC analysis). Example 30 Scheme C. stage c: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etyl-4-piperidinemethanol (5) The mother liquors (filtered) from a second recrystallization of material enriched in ( R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S, 3S) - (+) - di- (p-anisoyl) acid salt tartaric (3a) in Scheme C, step a, were concentrated to a foam in the rotary evaporator. The residue (3.6 g, 4.6 mmol) is mixed in ethanol (4.25 g) and water (5.4 g). To this mixture is added dropwise a solution of potassium carbonate (0.8 g, 4 mmol) in water (5.4 mL). The mixture is stirred for about 30 minutes, a white crystalline mixture was obtained which was digested at 50 ° C for 1 hour before cooling and isolating the white solid by filtration. The solid filter cake was rinsed with chilled 2-propanol (1.6 mL). The isolated product was dried at a constant weight to give 1.4 g, 98% analysis and 83% product. Chiral HPLC confirmed this to be a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) etl] -4-piperidinemethanol (5). The aqueous methanol filtrate was added to the solution of 32% HCl (1 mL) in water (7.2 mL) and (2S.3S) - (+) - di- (p-anisoyl) tartaric acid was isolated by filtration and dried at constant weight, 1.5 g, 92% analysis, 79% recovery. Example 31 Scheme C, step c: a- (2l3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etin-4-piperidinemethanol (5) A sample of 287.18 g of resolution stock solution and rinsing solutions from Scheme B , step b, 1 were charged to a 1 L coated drainage bottom reactor with 46 g of tetrahydrofuran and 125 g of 50% sodium hydroxide, and the mixture was heated to 40 ° C. The basic aqueous phase of 391 .7 was removed. The organic phase was rinsed with 30 g brine, and the aqueous phase of 45.86 g was removed. The organic phase of 45.66 g2 was charged to a 100 Ml coated drainage bottom reactor with 22.5 g of water and 14.76 g of sulfuric acid. The mixture was heated to reflux overnight. Analysis by chiral HPLC indicated that the mixture was racemic. The mixture was cooled to 20 ° C and diluted with 44 g of toluene, 24 g of 50% sodium hydroxide, and 10 g of water. The aqueous phase 68.8 g was removed. The organic phase was rinsed with 1 5 g of water, and 16 g of aqueous phase was removed. The organic phase was heated to remove 32.2 g of distillate at an internal temperature of 1 1 5 ° C, then cooled to 70 ° C, raised seed, and cooled to 0 ° C. The solid was collected by filtration and rinsed with 3 g of 2-propanol to give 9.35 g of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (62% of product). The stock solution was evaporated to a residue of 4.15 g (28% theory). 1 Crystallization using 30.0 g of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5), 8.0 g of acid (2S.3S) - ( +) - di- (p-anisoyl) tartaric acid, 81 g of acetic acid, 189 g of water, and 47 g of 30% aqueous acetic acid as a wash; 5.14% by weight (15 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol isomers by HPLC analysis. 2 Containing 1 3.7 g of isomers of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol by HPLC analysis. Example 32 Scheme D, step a: (S) -a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etiN-4-piperidinemethanol (3c) A portion of the resolution stock solution (filtered) from Scheme B, stage b, (465.44 g) was concentrated at 0.67 g / mL1. The concentrated solution was added dropwise, during 1 -1.5 hours, to a stirred suspension of toluene (590 mL), water (304 mL) and potassium carbonate of solid (44.34 g, 0.32 mol). The phases were stirred for 15 minutes at 50-60 ° C. Two phases were formed and separated by the use of a 2 L separatory funnel. The aqueous phase was decanted and analyzed for (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl ] -4-piperidinemethanol (3c) residual. HPLC analysis showed 1.3% by weight of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution (8.7 g) . The aqueous phase was extracted a second time with toluene (290 mL). The phases were stirred at 60 ° C for a half hour and then separated2. The analysis of the aqueous phase twice extracted showed 0.42% in _JLH_. weight of (S) -a- (2,3-D-methoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) and 8.65% by weight (56.6 g) of acid (2S) , 3S) - (+) - di- (p-anisoyl) tartaric in solution. The two higher organic phases were combined and analyzed for (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) 3. The organic phase was concentrated to an oil by evaporating the toluene in vacuo. The residual oil was dissolved with 2-propanol and evaporated a second time to remove residual toluene. Assuming that 84.7 g of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) were in the organic phase, the concentrated oil was dissolved in 2-propanol (350 mL) until a solution of 30% by weight was achieved. The solution was then heated to reflux and then cooled slowly and allowed to crystallize. The mixture was refrigerated at 0-5 ° C in an ice bath before suction filtration through a sintered quartz glass funnel. The wet cake was rinsed with chilled 2-propanol (100 mL) and then dried at a constant weight. Isolation of the mixture gave 55.6 g of white crystals of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in a product at 66.8 %. The mother liquors of the filtration showed 9.0% by weight (24.2) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution . A second crop of crystals obtained from the stock solutions gave 8.7 g of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c). The total product of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) recovered was 68.7%. 1 Analysis of the solution showed about 44% by weight of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3b in solution. Units are based on the calculated weight of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution (201 g, 0.25 mol) 2 The aqueous phase of the recovery of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol was added dropwise to a solution of dilute acid consisting of 32% HCL (73.1 3 g, 0.64 mol) and water (400 mL) The addition was initially slow to avoid the precipitation of the acid (2S, 3S) - (+) - di- (p-an) As the crystals are formed, the rate of addition could increase.The white crystals were formed and digested at 50-60 ° C for one hour.The crystals were filtered by suction to through a quartz sintered glass funnel and rinsed with water a (200 mL) The isolated crystals were dried in a vacuum oven at 60 ° C until a constant weight was achieved (73.58 g). Isolation of acid (2S, 3S) - (+) - di- (p-anisoyl) tartaric was in 69% product. HPLC analysis showed 9.5% by weight (84.7 g) of (S) -a- (2,3-d-imethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethane nol (3c) in solution. Example 33 Scheme D, step b: a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etn-4-piperidinemethanol (5) In a 100 mL round glass bottom flask equipped with a cold water condenser, magnetic stirrer and a nitrogen line, (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) ( 4.82 g, 13 mmol), methanol (18 mL), water (6 mL) and 37% HCl (5.46 g, 55 mmol) were combined and heated to reflux (76 ° C). The reaction solution was sampled periodically to verify the conversion of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) to a- (2) , 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). After 24 hours at reflux the reaction was complete. The solution was cooled to room temperature and then neutralized with 50% NaOH (4.2 g). After stirring the phases for 10 minutes the methanol was removed by rotary evaporation. Toluene (29 mL) was added to the residue with mixing, the phases were allowed to separate and the organic phase was decanted and stripped to a solid. The phase cut did not go very well due to the formation of an emulsion. The white residue obtained from the concentration of the toluene phase was analyzed. The analysis showed only 1 0.4% a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). Example 34 Scheme D, steps a and b: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etH-4-piperidinemethanol (5) A portion of the resolution methanol stock in Scheme B , step b, was concentrated to a solid (185.6 g of salt). The residue was dissolved in methanol at a concentration of 0.67 g / mL. The methanol solution was then added dropwise to a stirred suspension of toluene (464 g), water (280 g) and potassium carbonate (40.86 g, 0.3 mol). The phases were stirred for half an hour at 50 ° C and then allowed to separate. The lower aqueous phases were extracted a second time with toluene (250 mL). The two organic phases were combined and concentrated in rotary evaporation to a solid. The solid (82 g, 0.22 mol of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) by analysis) was then dissolved in isopropanol (382 mL) and water (1 27 mL). To the solution, 37% HCl (1.38 g, 1.4 mmol) was added. The solution was heated to reflux for a total of 17 hours. The solution was cooled to room temperature and neutralized with 50% NaOH (1 12.8 g, 1.41 mol). The addition was made slowly to control the exotherm. The phases were stirred for 10 minutes before the isopropanol was removed on the rotary evaporator. Toluene (500 mL) was added to the residue. The phases were stirred for 10 minutes before separating. The lower aqueous phase was extracted a second time with toluene (200 mL). The organic phases were then combined and concentrated in rotary evaporation until about 30% by weight of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5%) was reached. ). The mixture was heated to reflux and slowly cooled to 40 ° C where seed was bred. The solution was crystallized and cooled to room temperature. The mixture was refrigerated in an ice bath for half an hour before being filtered by suction through a sintered quartz glass funnel. The wet cake was rinsed with 50 mL of refrigerated isopropanol and then dried at a constant weight. Isolation of the mixture gave 19.96 g of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (23.6% product, 95% analysis). The stock solution contained 3.3% (4.22 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). Example 35 Scheme D, step b: a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etyl-4-piperidinemethanol (5) In a 250 mL round-bottomed glass flask equipped with a stirrer magnetic, cold water condenser and a nitrogen line, 97.5% pure (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) (10.49 g, 28 mmol), water (13 mL), glyme (40 mL), and 37% HCl (1.86 g, 140 mmol) were combined and heated to reflux. The solution was analyzed initially and showed 14.4% by weight (1 0.39 g) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution. The clear homogenous solution was heated for 4-5 hours. Analysis of the reaction solution at the end of the racemization showed an optical purity of 1.1% of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidinemethanol (3c). The solution was cooled to room temperature and neutralized with 50% NaOH (11.25 g, 140 mmol). The solution was cooled before the base was added to help control the exotherm produced during the addition. The reaction mixture was stirred for 5-10 minutes. The glyme was removed by rotary evaporation. To the residue, toluene (53 mL) was added. The phases were stirred and heated to 70 ° C. The phases were separated at 60 ° C. The lower aqueous phase was removed and extracted a second time with toluene (27 mL). The phases were heated and stirred for 1 5 minutes before separating. The organic phases were combined and analyzed at 9.5% by weight (8.2 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in solution. Essentially no product was left in the aqueous phase. The organic solution was stripped to a solid in the rotary evaporator. The residue was dissolved in 2-propanol (15 g) to give a 35% solution of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) . The solution was heated to reflux and cooled to room temperature. The solution was crystallized, the mixture was heated and the crystals were digested at 45-50 ° C for 30 minutes. The mixture was then cooled to room temperature and then refrigerated in an ice bath for 30 minutes. The crystals were filtered by suction through a sintered quartz glass funnel. The wet cake was rinsed with 1 7 mL of 2-propanol before being dried in a vacuum oven at 60 ° C. The stock solution showed 2.6% by weight (0.66 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in solution. The isolation of the crystals of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) were made in 69.7% of product based on the initial amount of ( S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) used. In analysis of the crystals was >100% and showed an optical purity of 1.2% of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c). Example 36 Scheme D, step b: a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) et pi-4-piperidinemethanol (5) In a glass round bottom flask of 250 mL of 1 neck equipped with a cold water condenser, magnetic stirrer, and a nitrogen line, 97.5% (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl ] -4-piperidinemethanol (3c) (10.4 g, 28 mmol), water (16 mL), glyme (37 mL) and 98% H2SO4 (9.75 g, 97 mmol) were combined and heated to reflux. The homogeneous solution was initially analyzed. The analysis showed 1 5.5% by weight (10.38 g) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution. After 5 hours at reflux, an analysis of the solution showed 3.9% (8.97 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) . The reaction mixture was cooled to room temperature and neutralized with 50% NaOH (15.59 g). Additional water (1 5 mL) is needed to dissolve the sodium sulfate salt formed. The glyme was removed from the reaction mixture by rotary evaporation. Toluene (53 mL) was added to the residue. Two phases were formed and stirred while heating at 70 ° C. The phases were cooled to 60 ° C and separated. The lower aqueous phase was extracted a second time with toluene (26 mL). The two organic extractions were combined and analyzed. There was 11.1% by weight (8.84 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in solution. The solution was stripped to a solid and then dissolved in 2-propanol (20 g) to 30 wt% solution of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] - 4-piperidinemethanol (5). The solution was heated to reflux, cooled and allowed to crystallize. The crystals were digested at 50 ° C for 30 minutes before being cooled to about 0 ° C in an ice bath. The crystals were isolated through a quartz sintered glass funnel with 10 mL of 2-propanol. The wet cake was dried in a vacuum oven at a constant weight. The analysis of the stock solutions showed 4.4% by weight (1.1 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in solution . Isolation of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) was made in 76.6% product giving 98.7% pure white crystals. Example 37 Scheme D, step b: a- (2,3-Dimethoxyphenyl) -1-γ2- (4-fluorophenyl) etH-4-piperidinemethanol (5) In a 500 ml round glass beaker of 1 ml neck equipped with a cold water condenser, magnetic stirrer, and a nitrogen line, 97.5% (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- pure piperidinemethanol (3c) (20.43 g, 55 mmol), tetrahydrofuran (71.5 mL), water (35 mL), and sulfuric acid (19.27 g, 196 mmol) were combined. The solution was analyzed initially and showed 14.7% by weight (20.4 g) of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) in solution. The solution was heated to reflux for 12 hours. The solution was cooled to room temperature and refrigerated in an ice bath for neutralization. Slowly 50% NaOH (30.1 g, 0.38 mol) was added to the reaction solution. The addition was exothermic. The tetrahydrofuran was then removed by rotary evaporation. The residue was dissolved in toluene (72 mL). Excess water (30 mL) was added to the mixture to help keep the sodium salt dissolved. The phases were stirred and heated at 70 ° C for 30 minutes. The phases were separated and the lower aqueous phase was extracted a second time with toluene (37 mL). The organic phases were combined and analyzed. The phase cut must be done in hot to ensure that a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol (5) remains in solution and the sulfate salt of sodium remains dissolved in the aqueous phase. Analysis of the higher organic phases showed 1 6.8% by weight (1 9.6 g) of a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in solution. No residual product was left in the aqueous phase after the second extraction. The toluene solution was stripped to a white solid by rotary evaporation. The solid residue was dissolved in 2-propanol (25.5 g) to give 30% by weight of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol solution (5). The solution was heated to reflux and cooled slowly to room temperature. The solution was crystallized and refrigerated in an ice bath for 30 minutes. The isolation of the mixture was done by suction filtration. The wet cake was rinsed with 1 5 mL of refrigerated 2-propanol and then dried at a constant weight. Analysis of stock solutions showed 9.0% by weight (5.71 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). The solution was then concentrated in the roto-vap at half its original weight and crystallized. The crystals were cooled in an ice bath and filtered by suction through a sintered quartz glass funnel. Analysis of the stock solution of the second harvest showed 40% by weight (1.1 g) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ( 5) in solution. The two crystal collections were combined and dried at a constant weight. Isolation of the mixture gave 1 00% pure a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) crystals in 87.4% product having an optical purity of 16.3% (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c). Considering the weight left in the mother solution, the product was increased to 92.8%. Example 38 Scheme D, stages a and b: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etin-4-piperidinemethanol (5) The concentrated resolution mother liquors of Scheme B, stage b, (302.3 g, analyzed 38.5% by weight of diastereomeric salt (1 16 g, 147 mmol of salt) were concentrated in the rotary evaporator to a solution which was approximately 0.67 g / mL This solution was added dropwise to a suspension of toluene ( 250 mL), water (175 mL) and potassium carbonate (25.58 g, 0.185 mol) The mixture was stirred for approximately 30 minutes at 40 ° C. (The organic phase contained 14.1% by weight, 49.8 g of (S) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) by analysis The aqueous phase contained 1.3% by weight, 5 g of (S) α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c) by analysis) The toluene was removed by evaporation to give a white solid (60 g). This residue was dissolved in tetrahydrofuran (1 74 mL), water (75 mL) and sulfuric acid (47.6 g, 0.48 mol). (The pale yellow solution was analyzed, 14.8% by weight, 50.3 g of (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3c)) .

The mixture was refluxed for 32 hours. After 16 hours, an additional portion (6.5 g, 66 mmol) of sulfuric acid was added. The reaction mixture was cooled to room temperature and carefully neutralized with 50% aqueous sodium hydroxide (87.92 g, 1.1 mol). The tetrahydrofuran was removed by vacuum distillation on the rotary evaporator, toluene (1 75 mL) and water (55 mL) were added and the mixture was stirred at 60-70 ° C for about 30 minutes. The phases were decanted at 60 ° C and the aqueous phase was extracted a second time with toluene (80 mL). The toluene phases were combined and concentrated in the rotary evaporator to remove water. The solution was analyzed (29.7%, 43.2 g of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5), heated to reflux and cooled slowly. breed seed at 50 ° C. The mixture was digested at 50 ° C before cooling to 0-5 ° C before isolation by filtration.The filter cake was rinsed with cooled toluene (30 mL) and dried at a constant weight to obtain a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (40.25 g, 81%, 97.5% analysis) 1 The aqueous phase which contained (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid was added dropwise to a solution of 32% HCl (42.57 g, 0.37 mol) and water (243 mL) at 40 ° C. The (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid was precipitated as a white solid, the solution was cooled to room temperature overnight and an ice bath for 45 minutes before isolation by filtration. The recovered solid was rinsed with cold water, filtered by suction and finished It was dried at a constant weight in a vacuum oven to give 47.55 g of product (77% recovery). Example 39 Scheme D, stages a and b: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etH-4-piperidinemethanol (5) A suitable reactor is charged with resolution filtrates from Scheme B, stage b. Example 21 containing about 88.7 kg of diastereomeric salts. The mixture is concentrated to approximately 46% by distillation as determined by HPLC analysis. Approximately 220 kg of toluene and 150 kg of 13% aqueous potassium carbonate are added to the concentrated filtrates. The temperature of the solution is controlled at about 50 ° C and the phases are separated. The organic phase is retained and the aqueous phase is discarded.2 The organic solution is concentrated by distillation until no more distillate is collected. Approximately 1 30 kg of tetrahydrofuran is added to the reactor to dissolve the distillation residue. Approximately 60 kg of water and approximately 39 kg of sulfuric acid (98%) are added to the reactor. The solution is heated to reflux (about 75 ° C) for about 18 hours or until the enantiomeric excess of the mixture is less than 4% as determined by chelal HPLC analysis. The solution is cooled to below 40 ° C while approximately 62 kg of 50% sodium hydroxide is added to neutralize the sulfuric acid. The pH of the solution is checked to ensure it is # 7. about 1 1 3 kg of solvent are removed by distillation before approximately 125 kg of toluene is added. After about 1 70 kg of solvent are distilled and approximately 65 kg of toluene are added to complete solvent exchange in toluene; resulting in a concentration of α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) of 20-30% as determined by HPLC analysis. The solution is then maintained at about 70 ° C. The salts dissolve by adding approximately 355 kg of water and then separating the phases3. The aqueous phase is discarded. The solution is cooled to below -10 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration4. The wet cake is rinsed with about 5 kg of cold isopropanol to typically provide about 31 kg of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (74 % of product as determined by HPLC analysis). 1 The 1 3% potassium carbonate solution is prepared by dissolving approximately 20 kg of potassium carbonate in 130 kg of water. 2 The aqueous phase can be extracted twice more with approximately 65 kg of toluene each to improve recovery. All the organic phases are combined and the organic phase is discarded. The organic phase can be dried by azeotropic distillation [toluene, isopropanol, and water] after phase separation. 4 a- (2, 3-D¡methoxyf in l) -1 - [2- (4-f luorofenyl) ethyl] -4-pyrifine meta-nol (5) can be recovered from the filtrates ( 228 kg) by concentrating them in vacuo to approximately 11% by weight (see comment 1) and then acidifying at approximately 25 ° C with approximately 3.4 equivalents of 1 N HCl (50 kg). The organic phase is discarded and the aqueous phase is neutralized with NaOH. a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is extracted into toluene (85 kg) and the aqueous phase is discarded. The toluene solution is concentrated by distillation to approximately 25-30% by weight as determined by HPLC analysis. The solution is cooled below -1 0 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration. The wet cake is rinsed with about 5 kg of cold isopropanol to typically provide about 2.3 kg of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) as determined by chiral HPLC analysis.

Example 40 Scheme D, avb steps: a- (2,3-dimethoxyphenyl) -1-f2- (4-f luorof eniPetilM-piperidinemethanol (5) A suitable reactor is charged with resolution filtrates from Scheme B, step b and filtrates of recrystallization from Scheme C, step a, of Example 22 containing about 277 kg of diastereomeric salts (0.35 kmol) .The mixture is concentrated under vacuum at about 25 ° C. Approximately 1600 kg of toluene and 1 1 10 kg of carbonate of aqueous potassium at 1 3% 1 are added.The mixture is maintained at about 50 ° C and the phases are separated.The aqueous phase is retained2 and contains (2S, 3S) - (+) - di- (p-anisoyl) acid The organic solution is concentrated by distillation, tetrahydrofuran (940 kg) is added by the addition of approximately 450 kg of water and sulfuric acid (98%, 274 kg, 2.74 kmol) .The mixture is heated to reflux (approximately 75 °). C) for approximately 18 hours or until the enantiomeric excess of the mixture is less than 4% com or is determined by chiral HPLC analysis. The solution is cooled to approximately 25 ° C while approximately 50% sodium hydroxide solution (444 kg, 5.56 kmol) and approximately 1080 kg of toluene are added. The mixture is then heated to about 50 ° C. The phases are separated and the aqueous phase is discarded. The solvent is removed by atmospheric distillation until the temperature reaches approximately 105 ° C. The mixture is then cooled to about 70 ° C. Approximately 276 kg of water is added and the phases are separated. The aqueous phase is discarded. The toluene is removed by atmospheric distillation until the temperature reaches approximately 110 ° C3. The solution is cooled to approximately -10 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration4. The wet cake is rinsed with about 220 kg of cold toluene to typically provide about 1 00 kg of a- (2,3-di methoxy-enyl) -1- [2- (4-f luorof in yl) ethyl] -4- piperidinemethanol (5) (77% product as determined by HPLC analysis). 1 The 13% potassium carbonate solution is prepared by dissolving approximately 144 kg of potassium carbonate in 966 kg of water. 2 The aqueous phase can be extracted twice more with approximately 65 kg of toluene each to improve recovery. All organic phases are combined for the recovery of (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid. 3 The concentration of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is estimated by mass balance. Toluene can be added again to obtain a concentration of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) between 15-30% if necessary (determined by HPLC analysis). 4 a- (2,3-Dimethoxyphenyl) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (5) can be recovered from the filtrates by concentrating them in vacuo to approximately 1 1% by weight ( determined by HPLC analysis) and then acidified at approximately 25 ° C with 1 N hydrochloric acid. The organic phase is discarded and the aqueous phase is neutralized with sodium hydroxide solution. a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is extracted into toluene (85 kg) and the aqueous phase is discarded. The toluene solution is concentrated by atmospheric distillation to approximately 25-30% by weight (determined by HPLC analysis). The solution is cooled to about -10 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration. The wet cake is rinsed with cold isopropanol to provide additional a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (determined by HPLC analysis).

Example 41 Scheme E, step a: a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etin-4-piperidinemethanol, butyrate ester (5a) Add butyryl chloride (140 mL, 1.34 mol) to a solution of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (100 g, 0.27 mol), triethylamine (75 mL, 54 g , 0.54 mol), and dimethylamine pyridine (1.64 g, 0.01 mol) in chloroform (1.8 g) for 10 min under nitrogen. Stir the resulting solution under reflux for 16 hours. Cool to room temperature and rinse with 5% aqueous sodium carbonate (MgSO). Filter the mixture and concentrate the filtrate (35 ° C / 20 torr), and purify the residue by flash chromatography (SiO2, 1 0 cm x 1 5 cm, eluted with hexane (2 L), 1: 4 EtOAc: hexane (4 L), and 1: 2 EtOAc: hexane (4L)). Combine the desired fractions and concentrate (35 ° C / 20 torr) to give a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5a) Example 42 Scheme E, stage bv step c: (R) -a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etn-4-p-peridinemethanol (3) A suspension of 20 g of Candida cylindracea lipase (Sigma: 665 units / mg solid, 4780 units / mg protein) in 400 mL of distilled water was stirred at room temperature for 30 minutes. The solution was centrifuged at 12000 g for 20 minutes. The supernatant was collected and (NH 4) 2 SO 4 (140 g) was added in portions with stirring. The mixture was stirred for 2 hours and then centrifuged (12000 g, 20 minutes). The supernatant was discarded and the solution of the precipitate in 30 mL of distilled water was dialyzed against distilled water overnight. The dialyzed solution was used in additional experiments. To a solution of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5a) (2.77 g, 6.2 mmol) in t-BuOMe (1 0 mL), Baker silica (8.3 g, 40 μ) was added. After evaporation of the ether, the silica was transferred to 180 mL of 0.1 M phosphate buffer (pH 7.0) and then 25 mL of partially purified lipase (1 00 g crude = 230 mL of a solution) was added. The suspension was stirred at 45 ° C for 4 days. The reaction was stopped by filtering the reaction mixture. Both the filtrate and the silica were extracted with ethyl acetate (300 mL). The organic layer was dried over MgSO, evaporated in vacuo to give a residue, which was purified by column chromatography (60 g of Baker silica (40 μ), EtOAc / heptane = 3: 1). (Rf 0.45 for (S) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5b) and 0.06 for (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3)). After the ester is eluted, the eluent is changed to MeOH / EtOAc = 3: 7 to recover (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidinemethanol (3) as a yellow oil (1.08 g, 46%, 98% ee). Recrystallization twice from EtOAc / heptane gave (R) -a- (2,3-dimethoxy-phenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as a white crystalline compound (770 mg , 33%, 99% ee); m.p. = 114-116 ° C; [a] D = 14.3 (C = 1; CHCl3). 1 H NMR (CDCl 3) d 1.2-1.6 (m, 3 H), 1.7 (m, 1 H), 1.9-2.0 (m, 3H), 2.35 (brd, 1H), 2.5 (m, 2H), 2.8 (m, 2H), 2.93 (brd, 1H), 3.07 (brd, 1H), 3.88 (s, 6H), 4.63 ( d, 1H), 6.34 (dd, 1H, J = 1.5, 8.1 Hz), 6.89 (dd, 1H, J = 1.5, 7.8 Hz), 6.94 (dd, 2H, J = 8.8, J = 8.8 Hz), 7.05 (dd, 1H, J = 9, 7.9 Hz); 7.13 (dd, 2H, J = 5.4, 8.7 Hz). 19 F NMR (CDCl 3, 282.2 MHz) d 118.5 (brs, proton coupling is not resolved); IR (KBr) 3150, 1430, 1222 crn "1; MS: m / e (relative intensity): 402 (23), 374 (100), 356 (62), 264 (60) Anal.Cal, for C22H28FNO3 ( MW 373.5): C, 70.75; H, 7.56; N, 3.75; Found: C, 70.47; H, 7.84; N, 3.86, Example 43 Scheme E. Step a: a- (2,3-Dimethoxyphenyl) -1- f2- (4-fluorophenyl) ethyl-1-4-piperidinemethanol, butyrate ester (5a) Butyryl chloride (140 mL, 1.34 mol) was added to a solution of (R) -enrichment-to- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (100 g, 0.27 mol), triethylamine (75 mL, 54 g, 0.54 mol), and dimethylaminopyridine (1.64 g, 0.01 mol) in chloroform (1.8 L) for 10 minutes under nitrogen atmosphere The resulting solution was stirred under reflux for 16 hours After cooling to room temperature, the solution was rinsed with 5% aqueous sodium carbonate (3 x 2 L), saturated sodium bicarbonate (2 L), brine (2 L) and dried (MgSO) The mixture was filtered and the filtrate was concentrated (35 ° C / 20 torr) to a residue. or which was purified by flash chromatography (SiO2, 10 cm x 15 cm, eluted with hexane (2 L), 1: 4 EtOAc: hexane ((4L), and 1: 2 EtOAc: hexane (4 L)). The desired fractions (TLC, Rf 0.45, 1.1 EtOAc: hexane) were combined and concentrated (35 ° C / 20 torr) to give (R) -enrichment-a- (2,3-dimethoxyphenyl) -1- [2- ( 4-fluorophenyl) ethyl] -4-piperidinemethanol (5a) as an oil (116 g, 82% ee, 98% product). IR (pure) 3069, 3040, 2941, 2877, 2803, 1735, 1643, 1601, 1588, 1510, 1482, 1374, 1268, 1221, 1180, 1089, 1005, 827, 752 cm'1. 1 H NMR (CDCl 3) d 6.8-7.2 (m, 7 H, aryl), 5.85 (d, 1 H, J = 7.5 Hz, CHO), 3.91 (s, 3 H, OCH 3), 3.85 (s, 3 H, OCH 3), 3.0 (m, 2H), 2.8 (m, 2H), 2.5 (m, 2H), 2.30 (t, 2H, J = 7.5 Hz, CH2CO), 1.9 (m, 1H), 1.8 (m, 2H), 1.6 ( m, 2H), 1.5 (m, 4), 0.90 (t, 3H, J-7.5 Hz, CH3); 13 C NMR (CDCl 3) d 172, 161.3 (d, JF-c = 243.0 Hz), 152.4, 146.4, 133.6, 130.0 (d, JF.C = 8.0 Hz), 123.9, 118.6, 115.1, (d, JF. = 21.3 Hz), 111.3, 73.6, 60.4, 55.6, 53.4, 40.9, 36.4, 32.7, 27.8, 18.4, 13.7; 19 F NMR (CDCl 3, 282.2 MHz) d -117.9; MS (Cl, CH4) m / z (Reverse Intensity) 444 (MH +, 57%), 424 (35), 356 (100), 334 (98); [a] D20 + 4.8 ° (c 1.03, CHCl3); Anal cale for C 26 H 34 FNO 40.3 H2O (448.9): C, 69.55; H, 7.77; N, 3.12; Found: C, 69.49; H, 7.90; N, 2.94 Example 44 Scheme E, stage bv stage c: (R) -a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethyl 1-4-piperidinemethanol (3) Silica gel (Science MS, 230-400 mesh, 21.5 g) was added to a solution of (R) -enrichment-a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, butyrate ester (5a) (72 g, 0.16 mol, 82% ee) in t-BuOMe (320 mL). The resulting mixture was concentrated (35 ° C / 20 torr) to give a light yellow powder. A mixture of the powder, partially purified Candida cylindracea lipase (1 7.1 g, equivalent to 522 g of crude Sigma enzyme) in phosphate buffer (0.1 M, pH 7, 5.2 L) was stirred at 45 ° C for 4 days. EtOAc (4 L) was added and the mixture was stirred at room temperature for 1 hour. The solid material was removed by filtration, and the two phases in the filtrate were separated. Both the solid and the aqueous layer were extracted with EtOAc (2 L). The combined organic solutions were concentrated (35 ° C / 20 torr) to a residue that was purified by flash chromatography (SiO2, 10 cm x 1.5 cm, eluted with 1: 1 EtOAc, hexane (8 L) and 1: 19 EtOAc: MeOH (8L)). The desired fractions (TLC, Rf 0.16, acetone) were combined and concentrated (35 ° C / 20 torr) to a residue which was dissolved in methylene chloride (800 mL). The solution was rinsed with 0.5 N NaOH (2 x 600 mL), brine (600 mL) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr) to give a solid which was recrystallized from cyclohexane (2 L) to give (R) -a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) as a white solid (31 g, 52% product, 99.9% ee); m. p. 1 1 3-1 14 ° C, [a] D20 + 14.0 ° (c 0.49, CHCI3). Anal cale for C 22 H 28 FNO 3 (373.5): C, 70.75; H, 7.56; N, 3.75; Found: C, 70.62; H, 7.60; N, 3.61.

Example 45 Scheme F, stages a and b: (R) -a- (2,3-dimethoxyphenyl) piperidine (1) A reactor maintained under argon was charged with (+) - β-chlorodiisopinocamphenylborane (18.2 kg, 56.7 mol) and 4 L of tetrahydrofuran. This stirred mixture was cooled and maintained below -10 ° C while adding a solution of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1 -1-dimethylethyl ester (7) (1 5.0 kg, 39.8 mol, 1 3.03 kg of theory) in 4 L of tetrahydrofuran for a period of 2 hours. The stirred mixture was kept below -10 ° C for 20 hours, then below -5 ° C for 20 hours, then below + 5 ° C for 30 hours, and finally maintained at 15 ° C for 4 hours. days. The reaction mixture was diluted with 1 1 L of tetrahydrofuran, followed by the addition of a solution of diethanolamine (6 kg, 57.1 mol) in 18 L of tetrahydrofuran while maintaining the reaction temperature below 20 ° C. The reaction mixture was transferred to a larger reactor and 19 L of tetrahydrofuran was distilled off at atmospheric pressure. The mixture was diluted with 30 L of water and the remaining tetrahydrofuran was distilled off below 45 ° C to 300 torr. A solution of 5 kg of 33% hydrochloric acid in 40 L of water was added for 5 minutes while maintaining a reaction temperature of 1 5 ° C. The reaction mixture was extracted with 75 L of heptane. The organic phase was separated and extracted successively with a solution of 2.2 kg of 33% hydrochloric acid in 20 L of water, followed by a solution of 0.55 kg of 33% hydrochloric acid in 5 L of water. The acid extracts were combined and diluted with a mixture of 20% sodium hydroxide (23.9 kg, 1 19.5 mol) and 5 L of water. The basic aqueous solution was stirred for 1 7 hours at room temperature while the product crystallized. The stirred mixture was cooled and maintained at 5 ° C for 1 hour, then the product was filtered off and rinsed with 3 L of water. After drying at room temperature, the amount obtained was 6.45 kg (72.9% ee). 6.45 kg was added to a solution of 43 L of acetone and 86 L of water. The stirred mixture was refluxed for 30 minutes, then cooled slowly to room temperature for 20 hours. After cooling to 3 ° C, the product was filtered off, rinsed with 2 x 3 L of water, then air-dried at 40 ° C to give 4.6 kg (93% ee). 4.6 kg were added to a solution of 1 1 L of acetone and 22 L of water. The stirred mixture was refluxed for 30 minutes, then cooled slowly to room temperature for 20 hours. After cooling to 3 ° C, the product was filtered off, rinsed with 2 x 2 L of water, then air-dried at 40 ° C to give (R) -a- (2,3-dimethoxyphenyl) methyl] piperidine (1) (34% product, 95.5% ee).

EXAMPLE 46 Scheme F. Step a: (R) -4- (1-Hydroxy-1- (2,3-dimethoxy-phenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) 1, 2: 3,5-Di -O-isopropylidine-D-xylofuranose (70.66 g, 0.30 mol) is treated with H2SO4 (0.1 M, 300 mL) After stirring, the xylose dissolves slowly.After 30 minutes, the reaction is cooled with NH4OH ( pH 9.0) and half of the water is removed under reduced pressure.The aqueous layer is diluted with brine (100 mL) and extracted with ethyl acetate (3x200 mL) .One treatment provides an oil.The distillation of Kugeirohr provides 1, 2-0-isopropylidine-D-xylofuranose (40 g, 68.5%) M bp 120-135 ° C / 0.4 mm Hg. 1, 2-O-lsopropylidin-D-xylofuranose (8.35 g, 43.9 mmol) is dissolved in pyridine (50 mL), the resulting solution is cooled to 0 ° C and treated with tosyl chloride (10.0 g, 52.5 mmol) and dimethylaminopyridine (0.5 g), after reacting for 16 hrs at 0 ° C, the solution cool with water (50 mL) and dilute with tolue no (50 mL) The organic phase is separated, dried, filtered and concentrated under reduced pressure < 40 ° C (pyridine is still present in the organic phase). The oil is dissolved in ethyl acetate (1 00 mL), extracted with 1.0% acetic acid, rinsed with water, then extracted with NaHCO3 (saturated). The organic phase is dried, filtered and concentrated under reduced pressure to leave a white solid. The solid was dissolved in ethyl acetate (50 mL) with heating, diluted with hexane (50 mL), filtered through the Celite7 filter aid and cooled to 0 ° C to provide 1,2-O-isopropylidine-5- (p-toluenesulfonyl) -D-xylofuranosa as white crystals (10.1 g, 67% product); m.p. 137-8 ° C. 1, 2-O-lsopropi lid ina-5- (p-toluenesulfonyl) -D-xylofuranosa (1 0.0 g, 29 mmol) is added to a NaOMe solution at 0 ° C (prepared from 1.3 g, 56 mmol, Na was added to 50 mL of MeOH). The reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with ammonium chloride (saturated, 20 mL), then concentrated under reduced pressure to remove MeOH. The mixture is diluted with water (30 mL), and extracted with ethyl acetate (4x50 mL). The combined organic extracts are extracted with brine, dried, filtered and concentrated under reduced pressure to leave an oil. The distillation of Kugeirohr provides 3,5-anhydro-1,2-O-isopropylidynaxylfuranose as a clear oil (4.1 g, 82% product); b.p. 55-70 ° C / 0.5 mm Hg. 3,5-Anhydro-1, 2-O-isopropylidinaxilofuranose (4.0 g, 23 mmol) was dissolved in ether and treated with portion drop with solid LiA 1 H (1.76 g, 46 mmol). After the addition is complete, the reaction mixture is refluxed for 16 hours. The reaction is cooled by slow addition of acetone (4 mL), followed by 1.0% acetic acid / water (35 mL). The mixture is diluted with ethyl acetate (50 mL) and treated with the filter aid. After stirring for 30 minutes, the suspension is centrifuged; the supernatant is filtered through the filter aid and the phases are separated. The aqueous phase is neutralized with NaHCO3, then NaCl is saturated. The mixture is extracted with EtOAc (2x50 mL). The pellets of the centrifugal tubes are resuspended in 50% of a mixture of H2O / EtOAc (100 mL). After stirring for 30 minutes, the mixture was re-centrifuged. The supernatant was filtered and the phases separated. The aqueous phase is combined with the original aqueous phase and extracted with ethyl acetate (50 mL). The combined organic phases are rinsed with brine, filtered and concentrated under reduced pressure to leave an oil. The distillation of Kugeirohr provides 5-deoxy-1,2-O-isopropylidine-D-xylofuranose as a solid (3.05 g, 76% product); m. p. 70-72 ° C. A tetrahydrofuran solution of 9-BBN (0.5 M, 45 mL, 22. 5 mmol) is treated with a solution of 5-deoxy-1,2-O-isopropylidine-D-xylofuranose (3.90 g, 22.4 mmol, 1 5 mL of tetrahydrofuran) and stirred at room temperature for 2 hours, then at reflux for 1 hour to complete the formation of 9-O- (1, 2-isopropylidine-5-deoxy-aD-xylofuranosyl) -9-borabicyclo [3.3.1] nonane. The solution is cooled to room temperature and transferred, via cannula, into a flask containing solid KH (2.0 g, 49 mmol). The reaction mixture is heated until mixed. After stirring for 4 hours, the reaction mixture is allowed to stand under argon overnight. The clear solution (0.35 mM in borohydride reagent) is used as it is for the reduction of 4- (2,3-d-imethoxybenzoi I) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7). A solution of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) (1.0 g, 2.9 mmol) in tetrahydrofuran (5 mL) is cooled to -40 ° C and it is treated with a solution at -40 ° C of the borohydride reagent (10 mL, 0.35 M, 3.5 mmol). The reaction mixture is heated to -15 ° C and allowed to react at this temperature for 1 8 hours. The reaction is cooled with MeOH, followed by NH 4 Cl (saturated). The product is extracted in toluene. After a normal preparation, the residue is chromatographed instantaneously to provide (R) -4- (1-hydroxy-1- (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (8) (0.64 g, 63%, 80% ee) Example 47 Scheme F, step c: 4-f 1 -Hydroxy-1 - (2,3-dimethoxyphenyl) methylpiperidine i To a 50 mL flask equipped with nitrogen bubbler 0.1 9 g (0.54 mmol) of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) and 10 mL of tetrahydrofuran were added, this solution was cooled to 0 ° C, then 0.1 g (2.6 mmol) of small sodium borohydride pellets were added.The reaction mixture was stirred one hour at 0 ° C and then for 5 days at room temperature.The reaction mixture was poured into 50 mL of tetrahydrofuran and 1.0 mL of water in a separatory funnel The tetrahydrofuran solution was then rinsed with brine (3 x 15 mL) and dried over magnesium sulfate. It was evaporated and then evaporated to leave 0.22 g of a colorless oil. The crude intermediate of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, 1-dimethylethyl ester was purified by column chromatography (silica gel, 20% ethyl acetate in toluene as eluent) to give the main compound (11) as a colorless oil after removal of the solvent (0.15 g, 79%). Cool the intermediate of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, 1-dimethylethyl ester at 0 ° C, treat with trifluoroacetic acid (-1.0 mL) and stir at room temperature for 1 hour. Concentrate in vacuo, dissolve the residue in water (~30 mL), rinse with hexane (~ 2 x 10 mL) and treat with solid sodium hydroxide (-1 .8 g). Extract the resulting aqueous solution with methylene chloride (3 x 20 mL). Combine the organic extracts, rinse with brine (-20 mL), dry (MgSO) and concentrate in vacuo. Dissolve the resulting residue in ethanol (-10 mL), cool to 0 ° C, treat with anhydrous hydrogen chloride gas until acidic, dilute with ether (-1.0 mL) and stir for 1 hour. Collect the resulting solid by filtration to give 4- [1-Hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11) Example 48 Scheme F, step d: 4-f 1 -Hydroxy-1 - (2 , 3-dimethoxyphenyl) methoxypyridine LlO A 2L round bottom flask, equipped with a mechanical stirrer, nitrogen bubbler, addition funnel and thermocouple, was charged with 58.52 g (0.42 mol) of veratrola and 350 mL of tetrahydrofuran. The resulting solution was cooled to -14 ° C. The addition funnel was charged with 160 mL of 2.5 M n-butyllithium solution (400 mmol) in hexanes. The butyllithium was added to the reaction vessel for 1 5 minutes while maintaining the temperature of the reaction mixture between -1 0 and -1 5 ° C. A white solid begins to precipitate in the reaction vessel near the end of the addition of butyllithium. The reaction mixture was heated to room temperature. The mixture of litiated veratrola was difficult to shake, so it was diluted with 1 00 mL of additional tetrahydrofuran. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen before cooling to 2 ° C with an ice bath. The addition funnel was charged with a solution of 40.45 g (0.38 mol) of 4-pyridiniumcarboxaldehyde (9) in 200 mL of tetrahydrofuran. The 4-pyridiniumcarboxaldehyde solution was added to the reaction vessel for 1 hour, while keeping the temperature of the reaction mixture below 1 0 ° C. The reaction mixture was allowed to warm to room temperature and stir for 3.5 hours. The reaction mixture was cooled to 1 ° C and wetted with 285.78 g of 20% aqueous sodium chloride for 7 minutes. The temperature of the reaction mixture increased to 8 ° C during cooling. The cooled solution was allowed to stir for 5 minutes. The mixture was transferred to a separatory funnel and the phases separated. The aqueous phase weighed 277.54 g. The organic phase was rinsed with 286.73 g of 20% aqueous sodium chloride. The aqueous phase weighed 296.98 g; the organic phase weighed 853.65 g and contained 9.2% of the main compound (10) (85% product). In a separate experiment, it was found that the main compound (10) can be isolated as a solid. After the extractions, the organic phase was dried over anhydrous magnesium sulfate, filtered through a medium sintered glass funnel, and evaporated to dryness using a rotary evaporator and vacuum oven overnight at room temperature. The crude yellow solid 14.77 g was mixed in 200 mL of mixed heptanes and heated to 70 ° C. Ethyl acetate was added in increments of 25 mL until the solid almost dissolved; 200 mL of ethyl acetate were required. The solution was cooled to room temperature while stirring with a magnetic stir bar. The solution was stored in a freezer at -5 ° C overnight. The solid was isolated by vacuum filtration of the reaction mixture through a medium sintered glass funnel. The solid was rinsed with 50 mL of mixed heptanes and dried overnight in a vacuum oven at room temperature to give the main compound (10) as a pale yellow solid (10.90 g); m.p. 126-128 ° C. 1 H NMR (CDCl 3) d 8.42 (d, 2 H, J = 5.5 Hz, aromatic), 7.32 (d, 2 H, J = 5.5 Hz, aromatic); 7.08-6.86 (m, 3H, aromatic), 5.97 (d, 1 H, J = 5.5 Hz, ArCH), 4.41 (d, 1 H, J = 5.5 Hz, OH), 3.85 (s, 3H, OCH3), 3.62 (s, 3H, OCH3); 13C NMR (CDCI3) d 1 53.5, 1 52.7, 149.5, 146.4, 1 36.4, 124.3, 121.3, 1 19.9, 1 12.6, 70.9, 60.5, 55.8. Example 48a Scheme F, step d: 4-H-Hydroxy-1 - (2,3-dimethoxyphenyl) methylpyridine In a 2 L flask, 72 g of verratrole was dissolved in 300 g of toluene and 1 55.3 g of butyl lithium in toluene were added at temperatures from -10 ° C to above 30 ° C. The mixture was stirred for 1-4 hours at room temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 180 mL of toluene were added at about room temperature. The reaction mixture was stirred for 30 minutes to 5 hours. The solution was then cooled to approximately 5 ° C and wetted with 200 mL of water. The solution was then heated to 40-85 ° C and subsequently cooled to -5 ° C. The product was collected by filtration and rinsed with 60 g of water and 60 g of toluene. The product was approximately 80 g of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10). Example 48b Scheme F, step d: 4-f 1-Hydroxy-1 - (2,3-dimethoxyphenyl) methylpyridine (10) In a 2 L flask, 72 g of verratrola were dissolved in 300 g of tetrahydrofuran and 155.3 g of butyllithium in toluene were added at temperatures from -1 0 ° C to above 30 ° C. The mixture was stirred for 1-4 hours at room temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 1 80 mL of toluene were added at about room temperature. The reaction mixture was stirred for 30 minutes to 5 hours. The solution was then cooled to approximately 5 ° C and wetted with 200 mL of water. The phases were separated and the organic phase was diluted to remove the tetrahydrofuran. The residue was taken in toluene at -5 ° C. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10) was collected by filtration and rinsed with 60 g of toluene. Example 48c Scheme F, step d: 4-ri-Hydroxy-1 - (2,3-dimethoxyphenyl) metippyridine (Ifii) In a 2 L flask, 48 g of verratrola were dissolved in 200 g of toluene and 138 g of solution of Butyl lithium (15% in hexane) were added at temperatures from 4 ° C to 6 ° C. The mixture was stirred for one hour at about 5 ° C and 3 hours at room temperature, then 26.7 g of 4-pyridinecarboxaldehyde (9%). ) in 120 g of toluene were added at about room temperature The reaction mixture was stirred for about 4.5 hours The solution was then cooled to about 5 ° C and it was wetted with 133 mL of water.The mixture was then heated to about 80 ° C. The organic layer was separated and rinsed with 67 mL of water and separated The residual water was removed by azeotropic distillation The solution was then cooled to -1 5 ° C to -5 ° C. The product was collected by filtration and rinsed with 27 g of cold toluene.The product was 50 g of 4- [ 1 -Hydroxy-1 - (2, 3-dimethoxyphenyl) methyl] pyridine (10) (81% product) Example 48d Scheme F, step d: 4-f 1-Hydroxy-1 - (2,3-dimethoxy-phenyl) methyropyridine (101 A flask round bottom, three-necked, 2 L, equipped with a mechanical stirring blade, thermocouple, nitrogen bubbler, and addition funnel, was charged with 70.51 g (0.51 mol) of verratrola and 469.94 g of tetrahydrofuran. The resulting funnel was cooled to -14 [deg.] C. The addition funnel was charged with 125.50 g (0.1 8 mol) of a 24.6% solution of butyllithium in hexanes.The butyllithium solution was added to the reaction vessel for 3 min. keep the temperature of the reaction mixture between -13 and -16 ° C. The reaction mixture was heated to 0 ° C. for 1 hour and then warmed to room temperature for 3.3 h. The reaction mixture was cooled to -13 ° C. C. The addition funnel was charged with a solution of 39.59 g (0.37 moL) of 4-pyridinecarboxaldehyde in 1 77.15 g of tetrahydrofuran. The aldehyde solution was added to the reaction vessel for 1.3 h, while maintaining the temperature of the reaction mixture between -9 and 14 ° C. The reaction mixture was allowed to stir for 1 h at 10 ° C and then was heated to 0 ° C over the course of one hour. The reaction mixture was cooled with 201.58 g of city water. The temperature of the reaction mixture was maintained at less than 10 ° C during the addition of water. After stirring for 10 min, the cooled solution was diluted with 322.51 g of toluene. The aqueous phase was removed. The organic phase was rinsed with 100.83 g of city water. The organic layer was concentrated by atmospheric distillation. When the distillate temperature reached 87 ° C, an additional 86.06 g of toluene was added. Distillation stopped when the temperature of the distillate reached 101 ° C; The distillate harvested weighed 812.36 g. The reaction mixture was cooled slowly to -1 5 ° C. The product was isolated by vacuum filtration, rinsed with 44.32 g of cold toluene, and dried in a vacuum oven at room temperature overnight to provide 66.94 g (74% product) of the main compound as a pale yellow solid; 1 H NMR (CDCl 3) d 8.42 (d, 2 H, J = 5.5 Hz, aromatic), 7.32 (d, 2 H, J = 5.5 Hz, aromatic); 7.08-6.86 (m, 3H, aromatic), 5.97 (d, 1 H, J = 5.5 Hz), 4.41 (d, 1 H, J = 5.5 Hz), 3.85 (s, 3H, OCH3), 3.62 (s, 3H, OCH3); 13C NMR (CDCI3) d 153.5, 1 52.7, 149.5, 146.4, 136.4, 124.3, 121.3, 1 19.9, 1 12.6, 70.9, 60.5, 55.8. Example 49 Scheme F, step d: 4-f 1-Hydroxy-1 - (2,3-dimethoxyphenyl) metippyridine (101 A suitable reactor, maintained under an inert atmosphere is charged with veratrola (36 kg, 261 mol) and approximately 240 kg of tetrahydrofuran, n-Butyllithium (63 kg, 242 mol, 24.6% in n-hexane) is added while maintaining the temperature at about 0 ° C. The addition line is leveled with approximately 5 kg of tetrahydrofuran. maintained at about 0 ° C for at least 1 hour, then heated to about 25 ° C and held there for about 3 hours In a second suitable vessel, 4-pyridinecarboxaldehyde (9) (20 kg, 1 87 mol) was mix with approximately 90 kg of tetrahydrofuran.The solution of 4-pyridinecarboxaldehyde / tetrahydrofuran is added to the initial vernal mixture to maintain the temperature at about -10 ° C. The reaction mixture is maintained at about -1.5 ° C during the minus 1 hour, then warm up At about 0 ° C for about a period of 1 hour. Water (approximately 100 kg) is added to the reaction mixture while maintaining the temperature at about 10 ° C. Toluene (approximately 160 kg) is added and the phases separated. The organic phase is rinsed with approximately 50 kg of water and the phases are separated. The concentration of product in the organic phase is adjusted to approximately 20% by weight by atmospheric distillation, the optimum tetrahydrofuran range is approximately 10 to 20% by weight as determined by GC analysis. The solution is cooled to less than about -15 ° C and 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine is collected by filtration. The wet cake is rinsed with about 20 kg of cold toluene to give the main compound (10) (30 kg, 70% product). Example 50a Scheme F, step e: 4-ri-Hydroxy-1 - (2,3-dimethoxyphenyl) methypiperidine (1 1) 4- [1-Hydroxy-1 - (2,3-dimethoxyphenyl) methyl] pyridine (10) (10.1 g, 41 mmol) are dissolved in 100 mL of methanol and hydrogenated using 5% rhodium in carbon catalyst. At the conclusion of the reaction, the catalyst is removed by filtration. The filtrate weighed 1 1 1 .51 g. The reactor and the catalyst cake were rinsed with methanol. The combined rinses weighed 1 70.27 g and contained 7.6% of the main compound (11). Example 50b Scheme F, step e: 4-f1-H -droxy-1- (2,3-dimethoxyphenyl) metipiperidine (111 A 1 L Parr reactor was charged with 12.43 g (0.051 mol) of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine (10), 5.74 g of 5% rhodium in carbon catalyst and 237 g of methanol The solution was heated to 40 ° C and treated with 100 psi of hydrogen for 5.5 h When the reaction was complete, the solution was filtered and the catalyst was rinsed with 108 g of methanol which was The weight of the filtered solution was 310.45 g.The methanol solution was analyzed for the main compound using high pressure liquid chromatography.The methanol solution was found to contain 3.7% main compound by weight. to 11.5 g (90% of product) of main compound A sample of a methanol solution of the main compound was evaporated to dryness using a rotary evaporator and vacuum oven at room temperature The main compound was isolated as a white solid: 1H NMR (CDCl 3) d 7.06-6.82 (m, 3H, arom. attic), 4.61 (d, 1H, J = 7.8 Hz); 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.09 (d, 1H, J = 12.2 Hz), 2.97 (d, 1H, J = 12.2 Hz), 2.58-2.41 (m, 4H) , 2.01-1.97 (m, 1H), 1.75-1.72 (m, 1H), 1.30-1.17 (m, 3H); 13C NMR (CDCI3) d 152.5, 146.6, 136.6, 123.9, 119.7, 111.4, 74.3, 60.9, 55.7, 46.4, 43.3, 29.9, 29.7. Example 51a Scheme F, step e: 4-f1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl-piperidine (111) A suitable inert reactor is charged with 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl ] pyridine (10) (13.6 kg, 55.5 mol) as a wet cake of toluene and 5% rhodium in carbon catalyst (2.7 kg, 50% moisture with water) as a wet cake of water at approximately 25 ° C Approximately 1 90 kg of methanol is added and the reactor is pressurized to about 1 00 psig with hydrogen for about 4-12 hours at about 50 ° C. The catalyst is removed by filtration and the reactor and catalyst are rinsed with about 7 hours. kg of methanol Deionized water is used as a final rinse of the wet catalyst cake, the reactor rinse filtrate and the filtrate of the reaction mixture are combined.The concentration of 4- [1-hydroxy-1 - ( 2,3-dimethoxyphenyl) methyl] piperidine (1 1) is about 7% by weight, providing about 1 3 kg ( 90% average product) of the main compound (11). Example 51 b Scheme F, step e: 4-f 1 -Hydroxy-1 - (2,3-dimethoxyphenyl) metipiperidine (11) In a suitable inert reactor, 1 18 kg (481 mol) of 4- [1 - hydroxy-1 - (2,3-dimethoxyphenyl) methyl] pyridine (10) as a wet cake of toluene and 23.6 kg of 5% rhodium in carbon catalyst at 25 ° C. 850 kg of methanol and 29 kg of glacial acetic acid are then added to the mixture. The reactor is then pressurized to approximately 100 psi with hydrogen for about 4-12 hours1 at 40 ° C. The catalyst was removed by filtration and the reactor and the catalyst were rinsed with 1 50 kg of methanol2. The rinse filtrate from the reactor and the filtrate from the reaction mixture were combined. The concentration of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (1 1) is typically about 10% by weight, providing about 16 kg of 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] piperidine (11) (96% of product) 3. 1 HPLC analysis of the reaction mixture is used to determine that the reaction conversion is at least 98%. 2 To increase safety, deionized water can be used as a final rinse of the wet catalyst cake. 3 The weight percent of 4- [1-hydroxy-1- (2,3-d-methoxyphenyl) methyl] piperidine (11) and the product are based on HPLC analysis. Example 52 Scheme F, step f: (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) Add p-toluic acid (0.5 mol) to 1 00 mL of SOCI2 and stir overnight at room temperature. Evaporate the excess of SOCI2 to give p-toluyl chloride. Add (2R, 3R) - (+) - tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 1 70 ° C for one hour. Allow the mixture to cool to 100 ° C and add 200 mL of toluene. Cool the mixture to room temperature and add another 1 00 mL of toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL of acetone and 20 mL of water for two hours. Then add 200 mL of water and evaporate the acetone. Add another 200 mL of water and collect the precipitate, rinse with water and dry. Refill the product in 200 mL of toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL of hot toluene and dry to give (2R, 3R) - (-) - di- (p-toluoyl) -tartaric acid. Dissolve 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) (1.1 g, 43.8 mmol) and 17.0 g (40.1 mmol) of (2R, 3R) - ( -) - di- (p-toluoyl) -tartaric acid in 400 mL of refluxing isopropanol. Allow the mixture to cool to room temperature. Collect the precipitate, rinse with isopropanol and dry to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid salt . Recrystallize (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid salt of 250 mL of ispropranol. Stir (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid salt (7 g) with 10 mL of concentrated ammonium and 20 mL of MeOH. After 2 hours, add 30 mL of H2O and evaporate the MeOH / ammonium. Then add another 30 mL of H2O, collect the precipitate, rinse with water and dry to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) which will typically have an ee of 85%. Acidify the aqueous layer with 1 N HCl and collect the precipitate and dry to recover the acid (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid.

Example 53 Scheme F, step f: (R) -a- (2,3-Dimethoxyphenyl) -4-piperidinemethanol (1) Add p-anisic acid (77 g, 0.55 mol) to 100 mL of SOCI2 and stir overnight at room temperature. Evaporate the excess of SOCI2 to give p-anisoyl chloride. Add acid (2R.3R) - (+) - tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 1 70 ° C for one hour. Allow the mixture to cool to 100 ° C and add 200 mL of toluene. Cool the mixture to room temperature and add other 1 00 mL of toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL of acetone and 20 mL of water for two hours. Then add 200 mL of water and evaporate the acetone. Add another 200 mL of water and collect the precipitate, rinse with water and dry. Refill the product in 200 mL of toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL of hot toluene and dry to give (2R, 3R) - (-) - di- (p-anisoyl) -tartaric acid. Dissolve 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) (1.1 g, 43.8 mmol) and 17.0 g (40.1 mmol) of (2R, 3R) - ( -) - di- (p-anisoyl) -tartaric acid in 400 mL of refluxing isopropanol. Allow the mixture to cool to room temperature. Collect the precipitate, rinse with isopropanol and dry to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidimethylan, (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid salt . Recrystallize (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid salt of 250 mL of isopropanol.

Agitate (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol, (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid salt (7 g) with 10 mL of ammonium concentrate and 20 mL of MeOH. After 2 hours, add 30 mL of H2O and evaporate the MeOH / ammonium. Then add another 30 mL of H2O, collect the precipitate, rinse with water and dry to give (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol (1) (1.8 g,> 99% ee). Acidify the aqueous layer with 1 N HCl and collect the precipitate and dry to recover the acid (2R, 3R) - (-) - di- (p-anisoyl) tartaric acid. Example 54 Scheme F, step g: 4-f 1-Hydroxy-1 - (2,3-dimethoxyphenyl) methylpiperidine (111 A solution of 4- (2,3-dimethoxybenzoyl) pyridine (12) (2.1 g, 8.6 mmol ) in MeOH (10 mL) is treated with 5% Rh / alumina (0.72 g) The mixture is hydrogenated in a Parr shaker at 55 psig for 22 hours After filtration through the Celite 7 filter aid the filtrate is concentrated under reduced pressure to the main compound (11) as a solid (2.0 g, 92% product) Example 55 Scheme F, step q: 4-M -Hydrox-1 - (2,3 -methoxyphenyl) metipiperidine (111 4- (2,3-dimethoxybenzoyl) pyridine (12) (10.09 g, 42 mmol) was dissolved in 10 mL of methanol and hydrogenated using 5% rhodium in carbon catalyst. of the reaction, the catalyst was removed by filtration, the filtrate weighed 11.390 g, the catalyst cake and the reactor were rinsed with methanol, the combined rinses weighed 165.26 g, and a sample of the methanol solution was added. and evaporated to dry using a rotary evaporator and vacuum oven at room temperature. The main product (11) was isolated as a white solid; m.p. 171-173 ° C. 1 H NMR (CDCl 3) d 7.06-6.82 (m, 3 H, aromatic), 4.61 (d, 1 H, J = 7.8 Hz, ArCH); 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.09 (d, 1H, J = 12.2 Hz), 2.97 (d, 1H, J = 12.2 Hz), 2.58-2.41 (m, 4H) 2.01-1.97 (m, 1H); 1.75-1.72 (m, 1H), 1.30-1.17 (m, 3H). 13C NMR (CDCI3) d 152.5, 146.6, 136.6, 123.9, 119.7, 111.4, 74.3, 60.9, 55.7, 46.4, 43.3, 29.9, 29.7. Example 56 Scheme G, step a: 1,4-Piperidinedicarboxylic, 1- (1,1-dimethylethi ester (14) In a coated low drainage resin vessel, 500 mL suitable with a four-union head equipped with a mechanical stirrer , reflux condenser covered with a nitrogen bubbler, a thermocouple with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), 50% aqueous solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was heated to 50 ° C and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via a syringe in a portion (exothermic 6th) and the reaction was stirred for 1.25 hours. The reaction was cooled to 5 ° C and aqueous hydrochloric acid (15.0 g of 37%) was added, causing the product to precipitate. To the coarse mixture was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58 ° C) for 72 hours to give the main compound (14) as a white crystalline material ( 23.9 g, 91%); m. p. 150-1 51 ° C. 1 H NMR (CDCls) d 4.10 (m, 2H), 2.84 (t, 2H, J = 1 1 .7 Hz), 2.47 (m, 1 H), 1.90 (m, 2H), 1.62 ( m, 2H), 1.45 (s, 9H, (CH3) Si)); 13 C NMR (CDCl 3) d 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5 Example 57 Scheme G, step a: 1, 4-Piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide ( 1 M, 150 mL), and t-butanol (1 00 mL) at 0 ° C was added a solution of di-t-butyldicarbonate (30.0 g, 0.1 37 mol) in t-butanol (50 mL). it was stirred overnight at room temperature, the reaction was quenched by the addition of hydrochloric acid (3M, 75 mL) at 0 ° C and extracted with ether (3 x 200 mL) The combined organic extracts were dried (MgSO4) and concentrated in vacuo to provide the main compound (14) as a fluffy white solid (28.4 g, 99%), mp 149-150 ° C. Example 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1- (1) , 1 -dimethylethyl ester (14) A 3 L three neck flask containing 1.0 L (1 mole) of 1 N NaOH was cooled to 0 ° C. 4-piperidinecarboxylic acid (13) (108 g, 0.84 mole) and 500 mL of t-butanol was added They then added to the aqueous solution which was maintained at 0 ° C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in an addition funnel that equalizes the pressure and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5 ° C. After completing the addition, the reaction was allowed to warm to room temperature and then stirred for a further 22 hours. The nebulous reaction mixture was reduced to half its original volume using a rotary evaporator at 40 ° C. The resulting solution was cooled to 5 ° C in a 3 L flask, after 500 mL (1 .5 mol) of 3 N HCl were added to the cold solution over a period of 30 minutes. The resulting thick mixture was extracted with tetrahydrofuran (3 x 500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40 ° C) to give the main compound (14) as a white solid (189.5 g, 99% product). Example 59 Scheme G. Stage a: 1, 4-Piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) Solid di-t-butyldicarbonate (300 g, 1.37 mol) was added to a solution of 4-piperidinecarboxylic acid (1 3) (162 g, 1.25 mol) in aqueous NaOH (1 N, 1.5 L) and t-BuOH (1.5 L) at 4 ° C for 30 minutes The reaction mixture was stirred at ambient temperature for 18 hours The resulting solution was concentrated (40 ° C / 20 torr) to half its volume, aqueous HCl (3 N, 750 mL) was added to the concentrated solution at 4 ° C for 30 minutes. The resulting mixture was extracted with ethyl ester (3 x 2 L) .The combined ethereal solutions were dried (MgSO 4) .The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr) to give the main compound (14). after air drying (277 g, 97%), mp 145-147 ° C, 1 H NMR (CDCl 3) d 4.01 (d, 2 H, J = 12.0 Hz, CHN's), 2.83 (dd, 2 H, J = 12.0 Hz , CHN's), 2.5 (m, 1H, CH), 1.9 (m, 2H), 1.6 (m, 2H), 1.46 (s, 9H), 13C NMR (CDCI3) d 180.2, 1 54.7, 79.8, 43.0; 40.8; 28.4; 27.7; MS (Cl, CH4) m / z (Intensity reage) 230 (MH +, 32%), 174 (100), 156 (71), 130 (25); IR (KBr) 3451, 3208, 3002, 2974, 2932, 1734, 1661, 1452, 1431, 1393, 1369, 1283, 1170, 1159, 1035, 924, 862 cm'1; Anal Cale for CnH19NO4 (229.3): C, 57.62; H, 8.35; N, 6.11. Found: C, 57.68; H, 8.62; N, 6.00. Example 60: Scheme G, step a: 1,4-Pyridine-dicarboxylic acid, 1-M.1-dimethylethyl ester (14) To a solution of 4-piperidinecarboxylic acid (13) (700 g, 5.42 mol) in aqueous NaOH (1N, 6.5 L ) and t-butanol (6.5 L) at 0 ° C was added di-t-butyldicarbonate (1295.8 g, 5.94 mol) slowly over 30 minutes. The reaction mixture was stirred overnight at room temperature. The resulting solution was concentrated (48 ° C / 20 torr) to half its volume and cooled by the addition of HCl (10%, 2.6 L). The white solid that was precipitated was filtered off, rinsed with water (1 L) and air dried to give the main compound (14) (1 1 78 g, 1 00% product); m.p. 144-146 ° C. 1 H NMR (CDCl 3) d 4.1 (d, 2 H, J = 1 2.0 Hz), 2.91 (t, 2 H, J = 12.0 Hz), 2.5 (m, 1 H), 2.0 (m, 2 H), 1 .7 (m, 2H), 1.52 (s, 9H); Example 61 Scheme G, step a: 1, 4-Piperidinedicarboxylic acid, 1- (1,1-dimethylethyl ester (14) 4-piperidinecarboxylic acid) 10 kg, 77.4 mol) and 50 L of water were charged to a suitable vessel maintained under nitrogen . The stirred mixture was cooled to 5 ° C. 20% sodium hydroxide (1.7 kg, 85 mol) and 70 L of ethanol were charged while maintaining a reaction temperature of 5 ° C. A solution of di-t-butyl dicarbonate (1 7.8 kg, 81.6 mol) in 65 L of ethanol was charged to the stirred reaction mixture over a period of 15 minutes. The cooling was discontinued and the reaction mixture was stirred for a total of 22 hours. A total of 1 50 L of solvent is distilled in the reaction mixture below 50 ° C to 150 torr. The residue was diluted with 10 l of water and the stirred mixture was cooled to 5 ° C. The stirred mixture was diluted with 22 L of water and 33% of hydrochloric acid (1.0 kg). After stirring at 5 ° C for 2 hours, the product was filtered off, rinsed with 2 x 5 L, then dried below 40 ° C to 150 torr to give 16.5 kg, 93% product. Example 62 Scheme G. Stage b: 4-f (Methoxymethylamino) carbonyl1-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) A 3L Morton flask equipped with a mechanical stirrer and a gas outlet connected to a bubbler charged with 1 L of methylene chloride and 189 g (0.82 mol) of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14). The solution was stirred vigorously for one hour in order to dissolve all the solids, resulting in a slightly hazy, colorless solution. A mixture of 1,1 '-carbonyldiimidazole (147 g, 0.91 mol) in 250 mL of methylene chloride was added per portion droplet over a period of 15 minutes. Caution: a large volume of gas was included during the addition. After the addition was complete, the pale yellow reaction mixture was stirred for 4 hours after which most of the evolution of gas had ceased. N, O-dimethylhydroxylamine hydrochloride (88.5 g, 0.91 mol) was added to the reaction mixture which was then stirred for a further 24 hours at room temperature. The resulting mixture of yellow solution and cream colored solids was then rinsed sequentially with 1 N HCl (2 x 1.5 L), saturated sodium bicarbonate solution (1.5 L), and brine (1 L) and then dried over sodium sulfate. The solution was filtered and concentrated to give a pale green oil. The oil was distilled (185 ° C, 1 mm Hg) to give the main compound (1 5) which solidifies at room temperature (1 77 g, 84% product). Example 63: Scheme G, step b: 4-f (Methoxymethylamino) carbonn-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) 1,1'-carbonyldiimidazole (200 g, 1.23 mol) was added per drop. portion to a solution of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) (257 g, 1.12 mol) in methylene chloride under nitrogen at room temperature. After stirring for 2 hours, the solution was treated with N, O-dimethylhydroxylamine hydrochloride (120 g, 1.23 mol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was rinsed with aqueous hydrochloric acid (1N, 2 x 2L), saturated sodium bicarbonate (2L) and brine (2L). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated (30 ° C / 20 torr) to a residue that was distilled (150 ° C / 0.9 torr) to give the main compound (15) (276 g, 91%). IR (light) 2973, 2934, 1693, 1663, 1421, 1366, 1289, 1234, 1171, 1132, 1032, 998, 939, 870, 770 cm'1. H NMR (CDCl 3) d 4.1 (m, 2 H, CHN's), 3.70 (s, 3 H, OCH 3), 3.19 (s, 3 H, NCH 3), 2.8 (m, 3 H), 1.7 (m, 4 H, CH 2's), 1.47 (s, 9H, t-Bu); 13C NMR (CDCI3) d 175.6, 154.6, 79.4, 61.5, 43.3, 38.1, 32. 2, 28.3, 27.9; MS (Cl, CH4) m / z (Intensity reage) 273 (MH +, 20%), 217 (100), 199 (52), 173 (23); Anal Cale for C? 3H24N2O4 (272.3): C, 57.33; H, 8.88; N, 10.29. Found: C, 57.19; H, 9.14; N, 10.29.

Example 64 Scheme G. Stage b: 4-f (Methoxymethylamino) carbonip-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) To a solution of 1,4-piperidinedicarboxylic acid, 1-5 (1, 1 - dimethylethyl) ester (14) (27.85 g, 0.1206 mol) in methylene chloride (300 mL) under an atmosphere of dry nitrogen was added 1, 1'-carbodiimidazole (21.5 g, 0.133 mol) per drop of portion, with water cooling The resulting mixture was stirred for 2 hours at room temperature and then treated with N, O-dimethylhydroxylamine hydrochloride (12.9 g, 0.132 mol) per drop portion, with water cooling. The reaction mixture was stirred overnight at room temperature and then rinsed with hydrochloric acid (1 M, 2 x 200 mL), saturated aqueous sodium bicarbonate solution (200 mL) and brine (200 mL) and dried (MgSO 4). ). He The main compound (15) was isolated as a viscous colorless oil after concentration in vacuo and kugeirohr distillation (31.76 g, 97%); bp 155-160 ° C [oven temperature], 1 .75 mm Hg. Example 65 Scheme G, step b: 4-f (Methoxymethylamino) carbonyl1-1-20 piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) To a solution of 1,4-piperidinedicarboxylic acid, 1 - (1, 1 - dimethylethyl) ester (14) (11.5.5 g, 5.42 mol) in methylene chloride (1.5 L) under nitrogen was added carbodiimidazole (922.8 g, 5.69 mol) per portion drop. The resulting mixture was stirred for 2 hours. hours at room temperature, then hydrochloride of _ N, O-dimethylhydroxylamine (550 g, 5.64 mol) in one portion. The reaction mixture was stirred at room temperature for 18 hours, then aqueous HCl (5%, 2x4L), saturated NaHCO3 (2x4L) and brine solution (2x4L) were rinsed. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated (35 ° C / 50 torr) to give the main compound (1 5) as a thick oil which was then crystallized to a waxy white solid (1289.5 g, 87.4%); m.p. 68-70 ° C. IR (KBr) 3436, 2972, 2934, 1693, 1663, 1420, 1 233, 1 1 70, 1 1 32 cm'1. 1 H NMR (CDCl 3) d 4.1 (m, 2 H), 3.70 (s, 3 H, OCH 3), 3.1 9 (s, 3H, NCH3), 2.8 (m, 3H), 1.7 (m, 4H), 1.46 (s, 9H, t-Bu); 13 C NMR (CDCl 3) d 175.6, 1 54.6, 79.4, 61.5, 43.1, 38.1, 32.2, 28.4, 27.9; MS (Cl, CH4) m / z (Intensity reage) 273 (MH +, 8%), 21 7 (100), 1 99 (50), 1 71 (30); Anal Cale for C13H24N2O. Example 66: Scheme G, step b: 4-f (Methoxymethylamino) carbonyl-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) In a 250-mL four-necked flask equipped with a mechanical stirrer, a bubbler of nitrogen, an addition funnel of 125 mL with a stopper, and a thermocouple with a coupled thermocouple was placed 1, 1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g). The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g). The solution was added to the reaction mixture for a period of 2 minutes, causing a rapid evolution of CO2. The reaction mixture was allowed to stir at 28 ° C for 2 hours. A N, O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g). The imidazole / methylene chloride amide intermediate solution was added to the mixture of N, O-dimethylhydroxylamine hydrochloride and methylene chloride over a period of 20 minutes. The resulting mixture was allowed to stir at 28 ° C for 2 hours. To the reaction mixture was added sodium bicarbonate (4.3 g), and water (75 g). After stirring for 20 minutes at room temperature, the phases were allowed to remain and separated for 20 minutes. The phases were separated and toluene (1000 g) was added to the organic phase. The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath at 60 ° C) to give the crude main compound as a thick oil. The oil and heptane (25 g) were placed in a suitable 100 mL coated lower drainage resin vessel with a four union head equipped with a mechanical stirrer, a thermocouple with a thermocouple, a nitrogen bubbler, and a stopper . The mixture was heated to 60 ° C before allowing it to slowly cool to 10 ° C over a period of 2 hours. The solution was kept at 1 0 ° C for 1 hour (nucleation temperature) before cooling to 3 ° C and stirring overnight. The main compound was collected by suction filtration and rinsed with cold heptane (7 g, ~ 0 ° C). The wet cake was allowed to air dry for 24 hours to provide the main compound (1 5) as a white crystalline material (10.5 g, 89%); m. p. 69-71 ° C. 1 H NMR (CDCl 3) d 4.08 (m, 2H, CHN's), 3.66 (s, 3H, OCjHa), 3.1 3 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H , CH's), 1 .40 (s, 9H, t-Bu); 13C NMR (CDCI3) d 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36. 1, 28.5, 28.0; IR (KBr) 2973, 2935, 1694, 1663, 1421, 1 367, 1289, 1 1 33, 998, 870, 770 crn "1. In a 250 mL three-necked flask equipped with a mechanical stirrer, a bubbler nitrogen, and a septum was placed 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) (1 0.0 g, 0.037 mol) and n-heptane (40 g). it was brought to reflux, before the solution was filtered by polishing through a medium sintered glass funnel containing Celite 7 filter aid. The solution was then placed in another 250 mL three neck flask equipped with a mechanical stirrer. , a nitrogen bubbler and a stopper.The solution was cooled slowly to room temperature (23 ° C) for a period of 2 hours (core about 38 ° C.) The mixture was cooled to 0 ° C and the main compound was collected by suction filtration and rinsed with n-heptane (6 g, 0 ° C) The wet cake was allowed to air dry for 24 hours s to give (1 5) as a white crystalline material (9.4 g, 94%); m. p. 69-71 ° C. 1 H NMR (CDCl 3) d 4.14 (m, 2 H, CHN's), 3.72 (s, 3 H, OCH a), 3.1 9 (s, 3 H, -NCH 3), 2.82 (m, 3 H), 1.66 (m, 4 H , CH's), 1 .46 (s, 9H, t-Bu); 13 C NMR (CDCl 3) d 175.5, 154.6, 121.5, 79.4, 61.5, 43.2, 36.0, 28.4, 27.9; In a 250 mL three-necked flask equipped with a stir bar, a nitrogen bubbler, a thermocouple with a thermocouple and a stopper was placed 4- [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl. ester (15) (1 0.0 g, 0.037 mol) and heptanes (30 g). The solution was heated to 65 ° C and filtered by polishing through a medium sintered glass funnel containing Celite 7 filter aid. The solution was allowed to cool slowly, nucleation started at ~ 35 ° C. The mixture was allowed to stir at room temperature (23 ° C) overnight, then cooled to 0 ° C for 1 hour. The main compound was collected by suction filtration and dried under vacuum (29 Hg, 40 ° C) for 6 hours to give (15) as a white crystalline material (9.2 g, 92%); m.p. 69.5-71 ° C. Example 67: Scheme G, step b: 4-f (Methoxymethylamino) carbonyl-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) A suitable reactor maintained under nitrogen was charged with 7.6 kg of 1,1-carbodiimidazole and 1 5 L of methylene chloride. A solution of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) (10.5 kg, 45.8 mol) in 62 L of methylene chloride was added for 30 minutes while maintaining a reaction temperature of 20 ° C. After stirring the reaction temperature at room temperature for 2 hours, 0.1 kg of 1,1 '-carbonyldiimidazole were added. A solution of 4.55 kg of N, O-dimethylhydroxylamine hydrochloride in 32 L of methylene chloride was added to the mixture with stirring. The reaction mixture was stirred at 20 ° C for 24 hours, followed by the addition of 0.52 kg of N, O-dimethylhydroxylamine hydrochloride and 0.7 kg of 1,1'-carbonyldiimidazole. Stirring continued at 28 ° C for 48 hours. The stirred reaction mixture was diluted with a solution of sodium bicarbonate (4.5 kg, 53.6 mol) in 50 L of water. The organic phase was separated and rinsed with a solution of sodium chloride (7 kg) in 46 L of water. The organic phase was separated and dried with sodium sulfate (4 kg). The drying agent was filtered off and rinsed with 2 x 5 L of methylene chloride. The solvent was removed below 50 ° C to 500 torr. The residue was diluted with 5 L of heptane and the solvent was removed below 50 ° C to 500 torr. A total of 40 L of heptane was added and the stirred solution was heated to 70 ° C to obtain the solution. The stirred solution was cooled to room temperature for 18 hours, then cooled and kept at 10 ° C for 12 hours, then cooled to 0 ° C. The solid that was crystallized is filtered off, then dried at room temperature to give 11.1 kg (89% product). Example 68 Scheme GStep b: 4-f (Methoxymethylamino) carbonip-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) A suitable reactor maintained under nitrogen was charged with 1,4-piperidinedicarboxylic acid, 1 - (1, 1 - dimethylethyl) ester (14) (24.9 kg, 109 mol) and 1,1-carbodiimidazole (19.6 kg, 121 mol), about 206 kg of methylene chloride are added gradually and the solution is stirred for at least 1 hour to approximately 25 ° C1. The mixture is added to a second stirred reactor containing a mixture of N, O-dimethylhydroxylamine hydrochloride (12.0 kg, 123 mol) and about 12 kg of methylene chloride. The reaction mixture is stirred above 28 ° C for at least 4 hours2. The methylenes chloride is removed by distillation, then toluene is added. The toluene mixture was extracted with approximately 198 kg of a 5.5% by weight aqueous sodium bicarbonate solution and the mixture was stirred for at least 15 minutes.3. The organic and aqueous phases are separated and the aqueous phase is discarded. The toluene is removed by vacuum distillation leaving an oil. After approximately 63 kg of heptanes are added. The filtrate is cooled to -1 5 ° C. The solid is isolated by filtration and rinsed with approximately 25 kg of cold heptanes to typically provide 26.6 kg to 28.1 kg (dry weight basis) of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) (90-95% product).

This material can be used as a wet cake in Scheme C, step c.4 1 A sample can be removed and analyzed by GC to determine the conversion state. The reaction is complete if less than 3% area of 1,4-piperidinecarboxylic acid, 1- (1,1-dimethylethyl) ester (14) is detected. If necessary, the reaction time can be extended or 1, 1'-carbonyldiimidazole can be added to complete the reaction. The mixture can be sampled and analyzed by GC for 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester to determine the conversion. If necessary, the reaction time can be extended or more N, O-dimethylhydroxylamine hydrochloride can be added to complete the reaction. The reaction is complete if less than 5% area of imidazole ester is detected. 3 The aqueous sodium bicarbonate solution at 5.5% by weight is prepared by dissolving 1 1 kg of sodium bicarbonate in 187 kg of water. The stock solutions can be concentrated by vacuum distillation to obtain a second culture. The recrystallization is as described for the first crop. Example 69 Scheme G, step b: 4-f (Methoxymethylamino) carboniH-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) In a 100-mL three-necked flask equipped with a mechanical stirrer, an addition funnel 60 mL covered with a nitrogen bubbler, and a thermocouple with a thermocouple was placed 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) (3.0 g, 0.013 mol), N, N-dimethylformamide (-106 mL, 0.13 mmol) and toluene (45 g). The addition funnel was charged with a solution of oxalyl chloride (1.26 mL, 0.014 mol) and toluene (5 g). The oxalyl chloride / toluene solution was added at such a rate to maintain the smooth gas evolution (-10 min.). the internal reaction temperature reached 38 ° C during the addition. The reaction was stirred at room temperature for 40 minutes. A N, O-dimethylhydroxylamine hydrochloride (1.45 g, 0.015) was placed in a 250 mL four-necked flask equipped with a mechanical stirrer, a thermometer, a 125 mL addition funnel covered with a nitrogen sparger and a stopper. mol), water (25 g) and 50% by weight aqueous sodium hydroxide solution (2.32 g, 0.029 mol) resulting in the formation of a clear solution. The addition funnel was charged with the acid chloride / toluene solution and the solution was added over a period of 5 minutes at room temperature. The reaction was allowed to proceed overnight before the stirring stopped and the phases were separated. The organic phase was concentrated by rotary evaporation (28 Hg, bath at 58 ° C) to give the crude main compound as a thick clear liquid. Additional vacuum drying (0.05 mm Hg, 25 ° C) gave the crude main compound (2.4 g, 67%). The crude material was recrystallized from heptane (20 g) to give the main compound as a white crystalline material (2.3 g, 65%); m.p. 69-71 ° C. Example 70 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) A solution of n-BuLi (2.5 M, 452 mL) in exan was added to a solution of veratrola (149 g, 1.08 mol) between anhydrous tetrahydroflurane (1.2 L) for 10 minutes at -78 ° C under nitrogen. The resulting solution was stirred at 0 ° C for 1 hour and at room temperature for 4 hours. A solution of 4 - [(methoxymethylmethyl) carbon i I] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (275 g, 1.01 mole) in tetrahydrofuran (800 mL) was added to the reaction mixture at -65 ° C for 20 minutes. The mixture was warmed to room temperature, stirred for 1 8 hours and cooled with saturated ammonium chloride (1 L). After stirring for 1 hour the phases were separated and the aqueous part was extracted with ethyl ether (1 L). The combined organic solutions were rinsed with brine (2 L) and dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr) to a residue (41 3 g). The solution can be used directly in the scheme L stage a, Example 108. EXAMPLE 71 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) In a 250 mL four-necked flask equipped with a mechanical stirrer , a septum, a thermocouple with a thermocouple, and a nitrogen bubbler was placed veratrola (17.8 g, 0.129 mol) and 125 g of tetrahydrofuran. The solution was cooled to -20 ° C before 33.8 g (0.125 mol) of an exano solution was added to 23.3% by weight of n-butyllithium via syringe. The n-butyllithium / hexane solution was added at such a rate to maintain the internal reaction temperature below -10 ° C during the addition. The solution was then heated to 0 ° C and held there for 1 hour, during which time a white precipitate formed. The solution was then heated to 25 ° C and stirred for 2 hours, before cooling to -20 ° C. In a container of lower drainage resin, coated with a suitable 500 mL with a head of five unions equipped with a mechanical stirrer, a thermocouple, a reflux condenser covered with a nitrogen bubbler, a septum, and a stopper were placed 28.9 g (0.092 mol) of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) (28.9 g, 0.092 mol), 87% pure) and 80 g of tetrahydrofuran. the solution was cooled to -1 7 ° C and the cold litiated veratrole / tetrahydrofuran mixture was added through a cannula while keeping the internal reaction temperature below -10 ° C (addition of 1 5 minutes). The reaction mixture was then heated to 1 0 ° C and stirred for 3 hours. The solution can be used directly in Scheme L, step a, Example 1 09. Example 72 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) A a solution of verratrola (16.6 g, 0.020 mol) in tetrahydrofuran (1 30 mL) at -78 ° C was added n-butyllithium (50.5 mL, from a solution of 2.5 M in hexane, 0.126 mmol). The resulting mixture was allowed to warm to room temperature for 1 hour and then stirred at this temperature for 4 hours before being re-cooled to -78 ° C and treating the resulting mixture with a solution of 4 - [(methoxymethylamino) carbonyl] -1 acid. -piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) (30.71 g, 0.1 128 mol) in tetrahydrofuran (180 mL). The reaction mixture was allowed to slowly warm to room temperature overnight and was then cooled to 0 ° C and wetted by the addition of saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with ether (11 mL) and the combined organic extracts were rinsed with brine (220 mL), dried (MgSO) and concentrated a vacuum to give the main compound (7). Example 73 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) In a 500-mL four-necked flask equipped with a mechanical stirrer, a thermocouple with a thermocouple, a nitrogen bubbler and a septum were placed 17.8 g (0.129 mol) of verratrola and 125 g of tetrahydrofuran. The solution was cooled to -20 ° C before 48.9 mL (0.122 mol) of a 2.5 N solution of n-butyllithium / hexane were added via syringe, at such a rate, to keep the internal reaction temperature below -10 ° C. The solution was then heated to 0 ° C and held there for 1 hour, during which time a white precipitate formed. The solution was then heated to 25 ° C and stirred for 2 hours, before cooling to -20 ° C. In a container of lower drainage resin, coated with a suitable 500 mL with a suitable four-joint head with a mechanical stirrer, a thermocouple with a thermocouple, a septum, and a nitrogen bubbler, 25.0 g (0.092 mol) of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) and 80 g of tetrahydrofuran. The solution was cooled to -1 7 ° C and kept under a nitrogen atmosphere. The litiated veratrola / tetrahydrofuran mixture was added through a cannula under nitrogen pressure for a period of 30 minutes, keeping the internal reaction temperature below -10 ° C. The resulting clear orange solution was then heated to 0 ° C (2 hours) and finally to 25 ° C (16 hours). At room temperature, the reaction mixture was cooled with 32.5 g (0.61 mol) of ammonium chloride and 11.0 g of water. After stirring for 20 minutes the phases were allowed to remain for 20 minutes before separating. The organic phase was dried over 7.5 g of magnesium sulfate. Filtration and concentration by rotary evaporation (27 in Hg, bath at 35 °) provided 62.4 g of a crude solution of the main product (7) in tetrahydrofuran (46.2% by weight, 90% product). EXAMPLE 74 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1 -1-dimethylethyl ester (7) A 1 L flask equipped with mechanical stirrer, thermometer wall, and addition funnel that equals the pressure, was charged with 500 mL of tetrahydrofuran and 49 mL (0.38 mol) of verratrola under a nitrogen atmosphere. The solution was cooled to -1 5 ° C and 160 mL (2.5M; 0.42 mol) of b-butyllithium was placed in the addition funnel. The n-butyllithium solution was added to the reaction mixture over a period of 25 minutes while maintaining the reaction temperature below -1 0 ° C. After the addition was complete, the pale green solution was maintained at 0 ° C for one hour and then at room temperature for 2 hours resulting in a very thick mixture. A 3 L Morton flask containing 82.3 g (0.32 mol) of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) in 300 mL of tetrahydrofuran under nitrogen atmosphere was cooled to -15 ° C while the mixture of litiated veratrola is cooled to 0 ° C. The litiated veratrole mixture was added to the solution of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester over a period of 15 minutes while keeping the temperature below -10 ° C. . The resulting pale green mixture was stirred for a further 15 minutes at -1 5 ° C or after it was allowed to warm to room temperature, causing the reaction mixture to become clear. The reaction mixture was stirred for 20 hours at room temperature then cooled with 500 mL of saturated ammonium chloride solution. The aqueous phase was extracted with toluene (2 x 250 mL) which was then combined with the tetrahydrofuran solution. The organic solution was rinsed with brine (2 x 25 mL) and dried over sodium sulfate. The solution was filtered and then concentrated by rotary evaporator to give 140 g of an orange oil. The crude oil was rapidly passed through 350 g of silica gel using 20% ethylene acetate in toluene as eluent. The evaporation of the solvent then gave 88.9 g of an orange oil. The orange oil was then placed in a kugeirohr for three hours (80 ° C, 1 mm Hg) to remove most of the verratrola, giving the remaining main compound (7) in the container as an orange syrup (55.9 g, 50% ). Example 75 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1 -1-dimethylethyl ester (7) A suitable reactor maintained under nitrogen is charged with veratrola (5.53 kg, 39.8 mol) and 55 L of tetrahydrofuran. The stirred solution was cooled to and kept below -10 ° C while adding n-butyl lithium (1.1 g, 37.3 mol, 20% in hexanes) for 30 minutes. The mixture was allowed to warm to 0 ° C for 1 hour, then at 20 ° C for 2 hours. In a separate reactor maintained under nitrogen 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1 5) (10.9 kg, 40.0 mol) and tetrahydrofuran (45 L) and cool below - 10 ° C. The mixture was stirred and kept below -10 ° C while the verrale solution was added for 1.5 hours. The stirred mixture was slowly heated to room temperature for 1 7 hours. The stirred mixture was diluted with a solution of ammonium chloride (14.5 kg in 40 L of water), followed by 1 0 L of water and 15 L of toluene. The organic phase was separated and the aqueous phase was extracted with 2 x 20 L of toluene. The organic extracts were combined, rinsed with a solution of sodium chloride in 10 L of water, then dried with sodium sulfate (5 kg). The drying agent was filtered off and rinsed with 2 x 5 L of toluene. The filtrate was evaporated at 45 ° C / 300 torr, then the residual solvent was evaporated at 50X / 20 torr to give the main compound (7) (1 5.05 kg, theory 1. 3.96 kg (4.38% toluene). Example 76 Scheme G, step c: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1 -1-dimethylethyl ester (7) A suitable reactor maintained under nitrogen is charged with veratrola (12.5 kg, 90.0 mol) and approximately 87 kg of tetrahydrofuran The solution is cooled and maintained below -10 ° C while adding n-butyl lithium (22.9 kg, 83.3 mol, 23% solution in hexanes.) The mixture is heated to about 0 ° C for 1 hour, then At about 25 ° C for at least 2 hours, 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid is charged in a separate reactor maintained under nitrogen., 1,1-dimethylethyl ester (15) as a wet cake of heptanes (15.6 kg, 57.3 mol, dry weight basis) and approximately 66 kg of tetrahydrofuran. The mixture is cooled to below -10 ° C and the lithiated verrale solution is added at such a rate to maintain the temperature below -10 ° C. The mixture is heated to about 25 ° C for at least 6 hours.2 When completed, the main compound can be used in Scheme H, step a, Example 1 08 as the reaction solution. 1 The solution is sampled and analyzed by GC to determine the amount of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) present. 2 The solution is sampled and analyzed by GC to confirm the complete formation of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7). The reaction is completed if less than 3% area of 4 - [(methoxymethylamino) carbonyl] -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is detected. Example 77 Scheme G, step d: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) Litiated veratrola was prepared by adding 4.0 mL (10 mmol) of n-butyllithium to a solution of 1.2 mL (9.4 mmol) of verratrola in 25 mL of tetrahydrofuran at 0 ° C. The solution was stirred one hour at 0 ° C, 3 hours at room temperature, and then cooled again to 0 ° C. A solution of 1,4-piperidinedicarboxylic acid, 1- (1,1-dimethylethyl) ester (14) was dissolved in 40 mL of tetrahydrofuran in a 100 mL flask and cooled to -78 ° C, then 4.0 mL (10 mmol). of n-butyllithium were added. After 45 minutes, the litiated veratrola solution was added through a cannula. The white mixture was allowed to warm to room temperature. The reaction mixture was cooled with 25 mL of ammonium chloride solution after 16 hours. The organic phase is rinsed with brine (2 x 25 mL) and dried over magnesium sulfate. Filtration, followed by evaporation of the solvent gave 1.41 g of a red oil. Purification by column chromatography (silica gel, 20% ethyl acetate in toluene) gave the main compound (7) as an orange oil (0.40 g, 13% product). Example 78 Scheme G, step e: 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) In a 1 L four-necked flask equipped with a mechanical stirrer, a thermocouple with a thermocouple, a nitrogen bubbler, and a stopper were placed 33.0 g (0.12 mole) of 4- (2,3-dimethoxybenzoyl) piperidine (16), 21.5 g (0.27 mole) of a 50% by weight solution of aqueous sodium hydroxide, 330 g of 2B ethanol and 99.0 g of water. To the solution were added 29.7 g (0.14 mol) of di-t-butyl dicarbonate in one portion resulting in an exotherm of 16 ° C. The solution was clear until di-t-butyl dicarbonate was added. Within minutes a white precipitate formed. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The precipitated salts were removed by suction filtration through a sintered quartz glass funnel containing the Celite® filter aid and the solution was concentrated to provide a liquid containing a white residue. The crude material is taken in 250 g of water and 250 g of toluene and separated by phase. The aqueous phase was extracted with 150 g of additional toluene. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the main compound (7) (28.3 g, 90% product). 1 H NMR (CDCl 3) d 7.09-6.92 (m, 3H, aromatic), 4.04 (d, 1 H, J = 1 2.7 Hz); 3.86 (s, 3H, OCH3), 3.83 (s, 3H, -OCH3), 3.24-3.1 7 (m, 1 H), 2.80 (t, 2H, J = 1 1 .9Hz), 1.82 (dd, 2H, J = 12.9, 2.1 Hz), 1.59 (qd, 2H, J = 1 1 .7, 4.2 Hz), 1.42 (s, 9H, -Si (CH3) 3) 13C NMR (CDCl3) d 205.7, 1 54.6, 152.7, 147.0, 1 34.0, 1 24.2, 120.2, 1 1 5.0, 79.3, 61.6, 55.9, 48.0, 43.3, 28.3, 27.8.

Example 79 Scheme H, step a: 4- (2,3-dimethoxybenzoyl) pyridine (12) A 500 ml four-necked round bottom flask equipped with a reflux condenser, addition funnel, thermocouple, mechanical stirrer, and nitrogen sparger was charged with 23.55 g (1 71 mmol) of verratrola and 140 mL of tetrahydrofuran. The resulting solution was cooled to -77 ° C. In the addition funnel was placed 64 mL of a 2.5 M solution of n-butyllithium (160 mmol) in hexanes. The butyllithium was added to the reaction vessel for 11 minutes. The temperature of the reaction mixture at the conclusion of the addition was -70 ° C. The reaction mixture was allowed to warm to room temperature over 35 minutes. At 7.5 ° C, a solid precipitated in the flask. The reaction mixture was allowed to stir for 1 hour at room temperature before cooling to 2 ° C with an ice bath. A solution of 7.76 g (74.6 mmol) of 4-cyanopyridine (17) in 40 mL of tetrahydrofuran was placed in the addition funnel. The 4-cyanopyridine solution was added to the reaction vessel for 16 minutes while maintaining the temperature of the reaction mixture at less than 6 ° C. The color of the reaction mixture changed from yellow to purplish black as the first drops of the 4-cyanopyridine solution were added. The reaction mixture was warmed to room temperature and allowed to stir for 3 hours. The reaction mixture was cooled to 0 ° C and the addition funnel was charged with 1 30 mL of a 2.5 M solution of hydrochloric acid. The hydrochloric acid was added to the reaction vessel for 12 minutes while maintaining the temperature of the reaction mixture less than 30 ° C. The reaction mixture was allowed to warm at room temperature for 1 hour. The solution was concentrated by rotary evaporation to remove the tetrahydrofuran. The pH of the remaining aqueous solution was 1.1. The pH of the aqueous solution was adjusted to pH 1-1.5 by the addition of 50 mL of a 45% aqueous solution of potassium hydroxide. The color of the reaction mixture changed from purple to greenish black. The basic aqueous phase was extracted with 300 mL of toluene. A black insoluble oil was formed in the separating funnel at the interface of the aqueous and organic phases. The aqueous and organic phases are separated. The majority of the insoluble oil remains adhered to the walls of the separating funnel. The organic phase was dried over anhydrous magnesium sulfate, filtered through a sintered glass funnel and evaporated to dryness using a rotary evaporator and vacuum oven overnight at room temperature. The resulting black oil weighed 24.75 g. The product was dissolved in 100 mL of methanol; the solution weighed 98.35 g containing 9.4% of the main compound (12) 51% product). Example 80 Scheme H. Stage b: N-Methyl-N-methoxyisonicotinamide (19) 4-Pyridinecarboxylic acid (18) (17.0 g, 0.138 mol) is mixed with methylene chloride (200 mL) and treated with 1.1 min. -carbonyldiimidazole (25 g, 0.154 mol). After an induction period of 1 minute, the CO2 evolution begins and the solution becomes homogeneous. After stirring at room temperature for 2 hours, the solution is treated with N, O-dimethylhydroxylamine hydrochloride (20 g, 0.20 mol) and stirred at room temperature overnight. The reaction mixture was quenched with 1 N NaOH and the phases separated. After normal operation, the organic phase is concentrated to leave an oil. The kugeirohr distillation provided the main compound (1 9) as a clear liquid (14.34 g, 62% product); b. p. 120-135 ° C / 0.5 mm Hg. Example 81 Scheme H, step b: N-Methyl-N-methoxyisonicotinamide (1 9) A 2-L round bottom flask, equipped with a magnetic stir bar, reflux condenser and nitrogen bubbler, was charged sequentially with 84.30 g (0.69 mol) of 4-pyridinecarboxylic acid (18), 1000 mL of methylene chloride and 125.84 g (0.78 mol) of 1, 1'-carbonyldiimidazole. The evolution of carbon dioxide began after approximately one minute induction time. Approximately 1 5 minutes after the addition of 1, 1 '-carbonyldiimidazole, the solids in the reaction vessel have been dissolved. The reaction mixture was allowed to stir under nitrogen at room temperature for 2.5 hours. In a single portion, 100.45 g (1.03 mole) of N, O-dimethylhydroxylamine hydrochloride was added to the reaction vessel. The temperature of the reaction mixture was increased to the boiling point of methylene chloride. A white solid precipitated immediately after the addition of N, O-dimethylhydroxylamine hydrochloride. The reaction mixture was allowed to stir overnight at room temperature. The reaction was cooled with 500 mL of 1 M sodium hydroxide. The solid present in the reaction vessel dissolved. The two-phase system was allowed to stir for five minutes at room temperature. The reaction mixture was transferred to a separatory funnel and the phases separated. The methylene chloride layer was rinsed with 500 mL of additional 1 M sodium hydroxide. The methylene chloride layer was dried over anhydrous magnesium sulfate, filtered through a medium sintered glass funnel, and evaporated to dryness using a rotary evaporator and vacuum oven overnight at room temperature. The pale yellow residue weighed 103.83 g and purified by Kugeirohr distillation. The main product (19) was distilled between 100 and 1 10 ° C at 2.5 mm Hg. The distillate weighed 96.78 g corresponding to a product of 85%. 1 H NMR (CDCl 3) d 8.71 (d, 2 H, J = 6.0 Hz, aromatic), 7.52 (d, 2 H, J = 6.0 Hz, aromatic); 3.55 (s, 3H, OCH3), 3.37 (s, 3H, NCH3) 13C NMR (CDCl3) d 167.5, 149.8, 141.5, 121.9, 61.3, 33.0 Example 82 Scheme H, step c: 4- (2,3-dimethoxybenzoyl) pyridine (12) A solution of verratrola (8.04 g, 58.2 mmol) in tetrahydrofuran (50 mL) is treated with BuLi (26 mL, 2.5 M in hexane, 65 mmol) at -70 ° C. After the addition is complete, the reaction mixture is allowed to warm to room temperature and stir for 2 hours. The mixture is re-cooled to -70 ° C and treated with a solution of N-methyl-N-methoxyisonicotinamide (19) (9.1 5 g, 55.1 mol) in tetrahydrofuran (30 mL). The resulting mixture is allowed to warm slowly to room temperature over a period of one hour. When the reaction mixture reaches 0 ° C it becomes homogeneous. After 3 hours at room temperature, the reaction is cooled with 1.0% AcOH (aqueous, 100 mL). After stirring for 45 minutes, the tetrahydrofuran was removed under reduced pressure and the residue was diluted with toluene (150 mL). After neutralization with NHCO3, the phases are separated and the organic phase is subjected to normal operation to provide an oil. The Kugeirohr distillation provides the main compound (12) as a dark oil (12.77 g, 95% product); b. p. 130-1 50 ° C / 0.05 mm Hg. Example 83 Scheme H, step c: 4- (2,3-dimethoxybenzoyl) pyridine (12) A round bottom flask, four-necked 1 L, equipped with a reflux condenser, addition funnel, thermocouple, mechanical stirrer and Nitrogen bubbler was charged with 55.45 g (0.40 mol) of verratrola and 350 mL of tetrahydrofuran. The resulting solution was cooled to -78 ° C. In the addition funnel, 175 mL of a 2.5 M solution of n-butyllithium (0.44 mol) in hexanes were placed. The butyllithium was added to the reaction vessel for 20 minutes. The temperature of the reaction mixture was increased for 45 minutes. At 5 ° C, a white solid began to precipitate.

After stirring at room temperature for 2 hours, the reaction mixture was cooled to -79 ° C. A solution of 61.74 g (0.37 mol) of N-methyl-N-methoxyisonicotaminda (19) dissolved in 200 mL of tetrahydrofuran was placed in the addition funnel. The solution in the addition funnel was added to the reaction vessel for 18 minutes. The temperature of the reaction mixture was increased to -68 ° C during the addition. The reaction mixture was slowly warmed to room temperature and stirred overnight. After stirring overnight, almost all the solids in the reaction vessel have dissolved. The reaction mixture was cooled with 500 mL of 2.5 M hydrochloric acid. The resulting mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was concentrated using a rotary evaporator. The resulting solution was diluted with 500 mL of 2.5 M hydrochloric acid and transferred to a separatory funnel. The aqueous solution was extracted with 3 x 200 mL of toluene. The toluene extracts are discarded. The pH of the aqueous phase was 0.08. The pH of the aqueous phase was adjusted to 11.0 by the addition of 82 mL of 50% sodium hydroxide. The basic aqueous layer was extracted with 2 x 500 mL of toluene. The toluene extracts were combined and dried over anhydrous magnesium sulfate. The solution was filtered through a medium sintered glass funnel, and evaporated to dryness using a rotary evaporator and vacuum oven overnight at room temperature. The residue of roasted solid weighed 71.71 g. The curd product was mixed in 1 000 mL of mixed heptanes and heated to about 65 ° C. The solid was not completely soluble. The solution was cooled and 1 00 mL of linden acetate were added. The resulting mixture was heated to 55 ° C to dissolve the solid. The solution was cooled and kept at -5 ° C for 6 hours. The white solid was isolated by vacuum filtration of the reaction mixture through a medium sintered glass funnel, rinsed with 1 00 mL of mixed heptanes and dried overnight in a vacuum oven at room temperature to give the main compound (12) The dry solid weighed 61.62 g (68% product). 1 H NMR (CDCl 3) d 8.77 (d, 2 H, J = 5.8 Hz, aromatic), 7.58 (d, 2 H, J = 5.8 Hz, aromatic); 7.59-6.98 (m, 3H, aromatic), 3.91 (s, 3H, OCH3); 3.66 (s, 3H, OCH3) 13C NMR (CDCl3) d 195.4, 1 52.9, 150.5, 147.6, 144.3, 1 32.6, 124.2, 122.3, 1 20.9, 1 1 5.7, 61.5, 56.1. Example 84 Scheme H, step d: 4- (2,3-dimethoxybenzoyl) pyridine (12) A 250 ml three-necked round bottom flask equipped with a reflux condenser, an addition funnel, mechanical stirrer and nitrogen sparger was charged with 9.0 g (65 mmol) of verratrola, 6.0 g (49 mmol) of 4-pyridinecarboxylic acid (18) and 75 g of tetrahydrofuran. The reaction mixture was cooled to -12 ° C. In the addition funnel, 46 mL of a 2.5 M solution of 1 -butyllithium (1-150 mmol) in hexanes was placed. The butyllithium was added to the reaction vessel for 15 minutes. The temperature of the reaction mixture was increased to 0 ° C during the addition. The reaction mixture was heated to 29 ° C and allowed to stir for 9 hours under nitrogen. The reaction mixture was allowed to stir for a further 3 hours at 29 ° C. In HPLC analysis indicated 39.8% of the main product (1 2). Example 85 Scheme I, step a: a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) ethiH-4-piperidinemethanol (5) In a suitable 100 mL coated resin container with a head of four joints equipped with a mechanical stirrer, a thermocouple with a thermocouple, a condenser covered with a nitrogen bubbler and equalized pressure addition funnel of 60 mL was placed sodium bis (2-methoxyethoxy) aluminum hydride (10 mL of an 70% by weight in toluene) and toluene (15 g). The addition funnel was charged with 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) (10 g) in toluene (35 g). The solution of 4- [1 -oxo-1 - (2, 3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine / toluene was slowly added to the hydride / toluene solution at 25 ° C for a period of 10 minutes (resulting in a exotherm of 38 ° C). The reaction was stirred at room temperature for 1.5 hours (28 ° C). The reaction was quenched by the addition of 5% aqueous sodium hydroxide solution (6.96 g) causing the precipitation of a white granular solid. An additional 3 g of the 5% aqueous solution of sodium hydroxide was added and the mixture was stirred for 10 minutes, before allowing to stand and separate by phase for 30 minutes. The phases are separated and the aqueous phase is extracted with toluene (50 g) and the combined toluene phases are rinsed with a 5% aqueous sodium chloride solution. The phases are separated and the organic phase is concentrated by rotary evaporation (28 in Hg, bath at 58 ° C) to give the main compound (5) as a reddish-orange solution (30.65). 9) - Example 86a Scheme L, step a: a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) et pi-4-piperidinemethanol (5) In a 5-liter four-necked Morton flask equipped with a mechanical stirrer, a thermocouple with a thermocouple, a 1 L pressure equalization funnel with a stopper, and a reflux condenser covered with a nitrogen sparger was placed 4- [1 -oxo-1 - (2 , 3-d methoxyp eni l) methyl] -N-2- (4-f luorof in i I-1 -oxo-ethyl) piperidine (4) (635 g of a 29.9% solution in toluene, 89.8 g , 0.49 mol). The solution was cooled to -1 2 ° C and the addition funnel was charged with the borane / tetrahydrofuran solution (9.88 g of 9.0 M solution) in two portions. The borane / tetrahydrofuran solution was added to the solution of 4- [1-oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine / toluene during a period of time of 20 minutes resulting in an internal reaction temperature of 8 ° C. The reaction mixture was heated to 55 ° C for a period of one hour and kept there for 1.5 hours before the reaction mixture was cooled to 25 ° C and methanol (124 g) was added over a period of 5 hours. minutes (rapid gas evolution was observed first). After stirring for 20 minutes, diethyleneamine (133 g) was added in one portion causing a cloudy solution. The solution was then heated to 65 ° C and kept there for 2 hours. The reaction mixture was then allowed to cool to a temperature below 40 ° C before water (1216 g) and tetrahydrofuran (900 g) were added. The mixture was stirred for 20 minutes before the phases were allowed to stand and separate by phase (20 minutes). The phases are separated and the organic phase is stored as a wet solution containing the main compound (2.46 kg). The solution was concentrated and 14.96 g of crude a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) was placed in a 250 mL single neck flask. equipped with an agitator bar together with isopropranol (35 g). The mixture was heated to 70 ° C and filter by polishing through a medium sintered glass funnel. The solution was allowed to cool slowly to room temperature, at about 40 ° C, 50 mg of seed crystals of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 -piperidinemethanol (3) were added. The solution was then allowed to stir overnight and crystallize. The solution was cooled to 0CC before collecting the crystalline product in a sintered quartz glass funnel. The wet cake was rinsed with cold isopropanol (20 g, -5 ° C) and dried under vacuum (26 in Hg) at 50 ° C for 18 hours to give the main compound (5) as a white crystalline material (8.57 g). , 57%); m. p. 1 13-1 14 ° C. 1 H NMR (CDCb) d 7.15-6.63 (m, 7H, aromatic), 4.66-4.61 (m, 1H); 3.66 (s, 3H, -OCH3), 3.65 (s, 3H, -OCH3), 3.11 (d, 1H, J = 10.3 Hz), 2.96 (d, 1H, J = 11.0 Hz), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 3H), 2.11-1.91 (m, 3H), 1.67-1.65 (m, 1H), 1.53-1.20 (m, 3H); 13 C NMR (CDCl 3) d 163.0, 159.8, 152.5, 146.6, 136.4, 136. 1, 130.0, 129.9, 123.7, 119.7, 115.2, 114.9, 111.6, 96.2, 74.5, 60.8, 60.7, 55.8, 53.7, 42.8, 32.8, 28.7. Example 86b Scheme I. stage a: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) et pi-4-piperidinemethanol (5) In a 500 ml four-necked flask equipped with a stirrer mechanical, a thermocouple with a thermocouple, an equalized pressure addition funnel of 250 mL with a stopper, and a reflux condenser covered with a nitrogen bubbler were placed 67.1 g (10.0 g, 0.054 mol) of a 29.8% solution by weight of 4- [1-oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-f luorofenyl-1-oxo-ethyl) piperidine (4) (635 g of an 29.9% in toluene The solution was cooled to -11 ° C and the addition funnel was charged with 104 g of a borane / tetrahydrofuran 1.0 M solution. The borane / THF solution was added to the solution of 4- [1 -oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) / toluene for a period of time of 5 minutes resulting in a reaction temperature internal temperature of 2 ° C. The reaction mixture was heated to 55 ° C. over a period of for one hour and kept there for an additional 1.5 hours before the reaction mixture was cooled to 40 ° C and 1 3 g of methanol were added over a period of 5 minutes (rapid gas evolution was observed first). After stirring for 20 minutes, 14 g of diethyleneamine were added in one portion causing a cloudy solution. The solution was then heated to 65 ° C and kept there for 2 hours. The reaction mixture was then allowed to cool to a temperature below 35 ° C before 1 30 g of water and 130 g of tetrahydrofuran were added. The mixture was stirred for 20 minutes before the phases were allowed to stand and separate by phase (20 minutes). The phases are separated and the organic phase is stored as a wet solution containing the main compound (250.1 g). HPLC analysis indicated that the 250.1 g solution contained 1 7.9 g (93% product) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) raw. Into a 250 mL single neck flask equipped with a stir bar were placed 14.96 g of crude a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) and 35 g of isopropanol. The mixture was heated to 70 ° C and filtered by polishing through a medium sintered glass funnel. The solution was allowed to cool slowly to room temperature, at about 40 ° C, 50 mg of seeds of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol (3) were added. The solution was then allowed to stir overnight and crystallize. The solution was cooled to 0 ° C before collecting the crystalline product in a sintered quartz glass funnel. The wet cake was rinsed with 20 g of cold isopropanol (-5 ° C) and dried under vacuum (26 in Hg) at 50 ° C for 18 hours to provide 12.9 g (86%) of a- (2.3-). Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) as white crystalline material; m.p. 113-114 ° C. 1 H NMR (CDCl 3) d 7.15-6.63 (m, 7H, aromatic), 4.66-4.61 (m, 1H); 3.66 (s, 3H, -OCH3), 3.65 (s, 3H, -OCH3), 3.11 (d, 1H, J = 10.3 Hz), 2.96 (d, 1H, J = 11.0 Hz), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 3H), 2.11-1.91 (m, 3H), 1.67-1.65 (m, 1H), 1.53-1.20 (m, 3H); 13C NMR (CDCI3) d 163.0, 159.8, 152.5, 146.6, 136.4, 136.1, 130.0, 129.9, 123.7, 119.7, 115.2, 114.9, 111.6, 96.2, 74.5, 60.8, 60.7, 55.8, 53.7, 42.8, 32.8, 28.7. Example 87 Scheme I, step a: a- (2,3-dimethoxyphenyl) -1-f2- (4-fluorophenyl) etn-4-piperidinemethanol (5) To the toluene solution of 4- [1-oxo- 1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) of Scheme J, step a, Example 94 is added 1 M of borane solution (165 kg, 184 mol) in tetrahydrofuran maintaining the temperature below 25 ° C. The borane solution line was rinsed with approximately 16 kg of tetrahydrofuran. The solution is heated to about 60 ° C for at least 3 hours. The solution is cooled and methanol (21 kg) is added, keeping the temperature below 25 ° C. The solution is then heated to about 40 ° C for at least 30 minutes. To the solution of about 25 ° C diethylenetriamine (22.2 kg) is added and the solution is heated above 65 ° C for at least 3 hours. The solution is cooled to approximately 25 ° C and approximately 186 kg of tetrahydrofuran and approximately 204 kg of water are added. The phases are separated1. The organic phase is concentrated by vacuum distillation2. Two phase are formed when most of the tetrahydrofuran is removed. While maintaining the temperature at about 60 ° C, toluene (566 kg) is added and the phases are separated. The concentration of α- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in the organic phase is adjusted to 25-30% by vacuum distillation3. The solution is cooled to below -10 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration. The wet cake is rinsed with about 14 kg of cold sopropanol to typically provide 25.0 kg of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5). The weight% of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol in solution can be determined by HPLC analysis. 2 The organic phases of 3 turns until addition of water are combined in a suitable vector and processed as a single charge.

The weight% of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol is determined by HPLC analysis. Additional toluene may be added as necessary to adjust the concentration.

Example 88a Scheme I stage b: a- (2,3-dimethoxyphenyl) -1-r2- (4-fluorophenyl) etn-4-piperidinemethanol (5) A solution of 4- [1 -oxo-1 - (2) , 3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) (21.86 g, 58.8 mmol), in ethanol (400 mL) at 0 ° C was treated with boron sodium hydrate ( 4.45 g, 1 1 7.6 mmol). The resulting mixture was stirred overnight at room temperature and then collected at 0 ° C and cooled by the addition of a saturated aqueous solution of ammonium chloride (300 mL). The resulting mixture was concentrated in vacuo to remove a majority of ethanol and then extracted with methylene chloride (4 x 300 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue is then eluted through a silica pad (gradient; ethyl acetate to 9: 1 ethyl acetate: methanol) to provide a semi-solid foam. The residue was treated with excess acetic anhydride (20 mL) and pyridine (20 mL) and a catalytic amount of DMAP (~1.00 mg) in methylene chloride. After stirring for 2 days at room temperature and heating to reflux overnight, full consumption of the initial material was achieved. The corresponding acetate was isolated by rinsing the reaction mixture with water (50 mL), saturated aqueous sodium bicarbonate solution (2 x 50 mL), drying (MgSO) and chromatographing (ethyl acetate: methanol, 19: 1). The ethyl acetate was recovered by concentrating the reaction mixture in vacuo., dilution with methylene chloride (-500 mL), rinsing with water (2 x 50 mL), drying (MgSO) and concentration in vacuo. A solution of this material in tetrahydrofuran (500 mL) was then treated with excess lithium aluminum hydroxide (4.5 g) at 0 ° C. The resulting mixture was then allowed to warm to room temperature overnight. The reaction was cooled to 0 ° C by the addition of water (5 mL), dilute aqueous sodium hydroxide solution (1.0%, 10 mL) and an additional portion of water (10 mL). The mixture was allowed to warm to room temperature and stirred for 1 hour, dried (MgSO4), filtered through a silica plug with tetrahydrofuran (500 mL) and concentrated in vacuo. Purification was performed by recrystallization of cyclohexane to provide the main compound (5) as a white solid (16.6 g, 76%); m.p. 128-129 ° C. Example 88b Scheme I, step b: a- (2,3-Dimethoxyphenyl) -1-r2- (4-fluorophenyl) etin-4-piperidinemethanol (5) In a 25 mL single neck flask equipped with a stir bar magnetic and a reflux condenser covered with a nitrogen bubbler were placed 1.0 g (0.003 mol) of 4- [1-oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) ) -piperidine (6), 0.2 g (0.005 mol) of sodium borohydride and 6.0 g of ethanol (2B). The reaction mixture was heated to reflux and stirred overnight under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated by rotary evaporation to give a white slurry. To the white mud were added 30 g of toluene and 20 g of a 20% by weight aqueous solution of potassium carbonate. The mixture was stirred for 15 minutes and the phases separated. The organic phase was dried azeotropically and concentrated by atmospheric distillation to provide a 1 7% by weight solution. The solution was allowed to cool slowly and a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) crystallize. The product was collected by suction filtration, rinsed with toluene and dried under vacuum (30 in Hg) at 60 ° C for 8 hours to provide 0.81 g (81% product) of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) as a white crystalline material; m.p. 113-114 ° C. 1 H NMR (CDCl 3) d 7.15-6.63 (m, 7H, aromatic), 4.66-4.61 (m, 1H); 3.66 (s, 3H, -OCH3), 3.65 (s, 3H, -OCH3), 3.11 (d, 1H, J = 10.3 Hz), 2.96 (d, 1H, J = 11.0 Hz), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 3H), 2.11-1.91 (m, 3H), 1.67-1.65 (m, 1H), 1.53-1.20 (m, 3H); 13C NMR (CDCI3) d 163.0, 159.8, 152.5, 146.6, 136.4, 136.1, 130.0, 129.9, 123.7, 119.7, 115.2, 114.9, 111.6, 96.2, 74.5, 60.8, 60.7, 55.8, 53.7, 42.8, 32.8, 28.7. Example 89 Scheme I, step c: a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) etyl-4-piperidinemethanol (5) A 100 ml four-neck round bottom flask, equipped with a mechanical agitator, nitrogen bubbler, reflux condenser, addition funnel and thermocouple, was charged with 5.06 g (13.1 mmol) of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) and 25 mL of toluene. The resulting solution was cooled to -16 ° C. The addition funnel was charged with 30 mL of 1 M borane-tetrahydrofuran complex (30 mmol) in tetrahydrofuran. The borane-tetrahydrofuran complex was added to the reaction vessel for 7 minutes while maintaining the temperature of the reaction mixture between -8 and -17 ° C. The reaction mixture was heated to 55 ° C for a period of 1.5 hours and kept at this temperature for 2 hours. The reaction mixture was cooled to room temperature.

The addition funnel was charged with 3.33 g of methanol, which was added to the reaction vessel for 4 minutes. Rapid gas evolution was detected and the temperature of the reaction mixture increased to 29 ° C from 23 ° C during the addition. The reaction mixture was allowed to stir at room temperature for 30 minutes.

In a single portion, 3.55 g of diethylenetriamine were added to the reaction vessel. The reaction mixture became cloudy after the addition of diethylenetriamine. The reaction mixture was heated to 70 ° C and stirred at this temperature for 2 hours. The reaction mixture was cooled to 40 ° C and added to a solution containing 31.97 g of water and 23.93 g of tetrahydrofuran.

The solution was transferred to a separatory funnel and the phases separated. The organic phase weighed 81.83 g and contained 5.14% of the main compound (5). The solution was concentrated using a rotary evaporator and dried in a vacuum oven overnight at room temperature to give the main product (5) as a white solid. Example 90 Scheme I. stage c: a- (2,3-D-methoxyphenyl) -1-r2- (4-fluorophenyl) etH-4-piperidinemethanol (5) In a bottom drain resin vessel coated, 250 mL with a thermocouple with thermocouple and a suitable four-joint head with a mechanical stirrer, a 60 mL addition funnel, a reflux condenser covered with a nitrogen bubbler, and a stopper were placed on 95.1 g (0.041) mol) of a 16.7% by weight solution of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) in toluene of Example 1 13, Scheme M, step a. The addition funnel was charged with 8.8 mL (0.09 mol) of borane-dimethyl sulfide. The borane-dimethyl sulfide complex was added dropwise to 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine. (20) / toluene at 25 ° C for a period of 10 minutes. The reaction mixture was heated to 50 ° C (evolution of dimethyl sulfide was observed) and kept there under a nitrogen atmosphere for 3 hours. The mixture was then cooled to about 30 ° C and the addition funnel was charged with 0.7 g of methanol. The first third of methanol was added very slowly due to the rapid evolution of gas. The reaction mixture was then heated to 50 ° C and the addition funnel was charged with 1 1 .5 g (0.1 1 mol) of diethylenetriamine (DETA). DETA was added in one portion and the reaction mixture was heated to 65 ° C and stirred for 3 hours, before adding 49.2 g of water. The mixture was cooled to 55 ° C and the phases separated. The reflux condenser was replaced by a distillation head containing a receiver and the solution was heated. The solution was azeotropically dried and concentrated. The solution at 34.2% by weight of a- (2, 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) in toluene was allowed to cool slowly to room temperature overnight, before cooling to -20 ° C. The product was collected by suction filtration, rinsed with 8.2 g of cold isopropanol (5 ° C) and dried under vacuum (31 in Hg) at 70 ° C for 12 hours to provide 12.5 g (82%) of a- (2). , 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) as a white crystalline material; m.p. 113-114 ° C. 1 H NMR (CDCl 3) d 7.15-6.63 (m, 7H, aromatic), 4.66-4.61 (m, 1H); 3.66 (s, 3H, -OCH3), 3.65 (s, 3H, -OCH3), 3.11 (d, 1H, J = 10.3 Hz), 2.96 (d, 1H, J = 11.0 Hz), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 3H), 2.11-1.91 (m, 3H), 1.67-1.65 (m, 1H), 1.53-1.20 (m, 3H); 13 C NMR (CDCl 3) d 163.0, 159.8, 152.5, 146.6, 136.4, 136. 1, 130.0, 129.9, 123.7, 119.7, 115.2, 114.9, 111.6, 96.2, 74.5, 60.8, 60.7, 55.8, 53.7, 42.8, 32.8, 28.7. Example 91 Scheme I, step c: a- (2,3-Dimethoxyphenyl) -1-f2- (4-fluorophenyl) et.N-4-piperidinemethanol (5) A suitable reactor is charged with 4- [1- hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (20) (63.6 kg, 164 mol, approximately 18% by weight in toluene) and the The concentration was adjusted to approximately 12% by weight by the addition of toluene. To this solution is added methyl borane sulfide complex, 96.1% (27.2 kg, 344 mol) while maintaining the temperature at about 25 ° C. The solution is heated to about 50 ° C for at least 3 hours. The methanol (41.3 kg) is added to the solution while maintaining the temperature at about 50 ° C. The solution is then heated to about 65 ° C. Diethylenetriamine (44.5 kg) is added and the transfer line is leveled with approximately 9 kg of methanol the solution is then maintained at about 65 ° C for at least 3 hours. Water (approximately 1 90 kg) is added while maintaining a temperature above about 55 ° C and the phases are separated. The organic phase is rinsed with approximately 190 kg of water and the phases are separated at about 60 ° C. The concentration d. a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol (5) in the organic phase is adjusted to approximately 14 to 30% by weight by atmospheric distillation.2 The mixture was cooled to approximately -15 ° C and a- (2,3-dimethoxyf in yl) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidine meta nol (5) was collected by filtration. The wet cake is rinsed with approximately 32 kg of toluene to provide approximately 49 kg of a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) (80% strength). product) .3,4 1 A portion of the toluene used in the concentration adjustment may be reserved for leveling the transfer line of methyl borane sulfide solution. 2 The concentration of α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is eliminated by mass balance. Additional toluene may be added as necessary to adjust the concentration. 3 The product is determined using the loss in drying and HPLC analysis. 4 a- (2, 3-Dimethoxyf in yl) -1 - [2- (4-f luorofenyl) ethyl] -4-piperidinemethanol (5) can be recovered from the filtrates by concentrating in vacuo to about 1 1% by weight (determined by HPLC analysis) and then acidified at approximately 25 ° C with 1 N HCl. The organic phase is discarded and the aqueous phase is neutralized with a sodium hydroxide solution. a- (2,3-Dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is extracted into toluene and the aqueous phase is discarded. The toluene solution is concentrated by atmospheric distillation to approximately 25-30% by weight (see comment 2). The solution is cooled to about -10 ° C and a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5) is collected by filtration. The wet cake is rinsed with cold isopropanol to provide additional a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (5).

Example 92 Scheme J, step a: 4-f 1 -oxo-1 - (2,3-dimethoxyphenyl) methyl-1-N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) In a three-necked flask 1 L necks equipped with a mechanical stirrer, a nitrogen bubbler and a 125 mL addition funnel were placed 4- (2,3-dimethoxybenzoyl) piperidine (16) (1 06.1 g of 1 9.24% by weight of the toluene, 20.4 g 0.08 mol) and diisopropylethylamine (16.8 g, 0.13 mol). The solution was cooled to -12 ° C and the addition funnel was charged with 4-fluorophenylacetyl chloride (71.5 g of a 25.5% by weight solution in toluene, 1 9.0 g, 0.1 1 mol). The acid chloride / toluene solution was added over a period of 17 minutes to keep the internal reaction temperature below 5 ° C. The reaction mixture was allowed to warm to 25 ° C and stir for 1 hour. Concentrated hydrochloric acid (4.7 g) and water (100 g) were added to the reaction mixture. The mixture was stirred for 5 minutes, separated by phase, and the organic phase was concentrated by rotary evaporation (29 Hg, bath at 60 ° C) to give an orange-brown solution (128.4 kg). This solution of 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) can be used in Example 85, Scheme I , stage a without further purification. Example 93 Scheme J, step a: 4-f 1 -oxo-1 - (2,3-dimethoxyphenyl) meth nn-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) In a three-necked flask necks of 500 mL equipped with a mechanical stirrer, a 125 mL addition funnel and a nitrogen bubbler were placed 4- (2,3-dimethoxybenzoyl) piperidine (16) (85.9 g of 1 7.34% by weight of solution in toluene , 14.83 g 0.059 mol), water (15 g), and 50% by weight of aqueous sodium hydroxide solution (7.2 g, 0.09 mol). The solution was cooled to 10 ° C and the addition funnel was charged with 4-fluorophenylacetyl chloride (64.2 g of a 19.1% by weight solution in toluene, 12.25 g, 0.071 mol). The acid chloride / toluene solution was added over a period of 5 minutes, resulting in an exotherm of 12 ° C. The two-phase reaction mixture was allowed to warm to 25 ° C and stir for 1 hour. 20% by weight of aqueous sodium chloride solution (15 g) was added to the reaction mixture. The phases are separated and the organic phase is concentrated by rotary evaporation (28 Hg, 60 ° C) to give a brown solution (154 g). This solution of the main compound (4) can be used in Scheme E, step a without further purification. Purification by flash chromatography on silica gel (1: 1 heptane / ethyl acetate) gave the main compound as a thick clear oil. 1 H NMR (CDCl 3) d 7.24-6.93 (m, 7H, aromatic), 4.42 (br-singlet, 1 H); 3.87 (s, 3H, -OCH3), 3.83 (s, 3H, -OCH3), 3.67 (s, 2H, Ph-CH2-CO-), 3.25 (m, 1 H), 3.08 (t, 1 H, J = 5.8 Hz), 3.81 (t, 1 H, J = 5.7 Hz), 1.84-1.76 (m, 2H), 1.47 (br-singlet, 2H); 13C NMR (CDCI3) d 205.3, 169.2, 163.4, 160.2, 152.8, 147.1, 133.8, 130.7, 130.2, 1 30.1, 124.2, 120.4, 1 1 5.7, 1 1 5.4, 1 1 5.3, 96.1, 61.7, 56.0 , 47.7, 45.6, 41.5, 40.1. Example 94 Scheme J, step a: 4-H -oxo-1 - (2,3-dimethoxyphenyl) methyH-N-2- (4-f luorofenyl-1-oxo-ethyl) piperidine (4) In a stirred reactor 4-fluorophenylacetic acid (79.4 kg, 515 mol), N, N-dimethylformamide (0.5 kg, 6.8 mol) and toluene (318 kg) are charged. Oxalyl chloride (68.3 kg, 538 mol) is added at a rate to keep the temperature below 35 ° C. The solution is stirred for at least 7 hours at about 25 ° C, typically providing a 22.1% by weight solution of 4-fluorophenylacetyl chloride. 1 A suitable reactor is charged with 4- (2,3-dimethoxybenzoyl) piperidine (16) (20.4 kg, 86.3 mol, -20% by weight in toluene). 50% by weight of sodium hydroxide solution (1 1 .6 kg, 145 mol) and approximately 29 kg of water. The mixture is cooled to approximately 10 ° C. The solution of 4-fluorophenylacetyl-toluene chloride (17.0 kg, 90.2 mol) is added at a rate to maintain the temperature below 25 ° C. The addition line is leveled with approximately 10 kg of toluene and the mixture is maintained for the next 30 minutes at approximately 25 ° C2. The phases are separated and the organic phase is rinsed with 20% by weight of sodium chloride solution (29 kg). The organic solution is concentrated by vacuum distillation to about 1/3 of its original volume 3 and used as a toluene solution in Example 87, Scheme I, step a. 1 The solution is sampled and analyzed by HPLC analysis to determine the weight% of 4-fluorophenylacetyl chloride and product. 2 The mixture is sampled and analyzed by HPLC analysis to confirm the formation of 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine. (4). 3 The concentrate is shown and weighed to determine the amount of 4- [1 -oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) by HPLC analysis. The water content is determined by Karl Fischer analysis if the water content is greater than 300 ppm can add additional toluene and the distillation is continued.

Example 95a Scheme J, step b: N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) p-Fluoroacetic acid (31.4 g, 0.203 mol) is treated with SOCI2 (45 mL, 0.62 mol) and the The resulting solution was heated to reflux for 4 hours. The reaction mixture is diluted with toluene and concentrated by distillation to remove remaining SOCI2. When the temperature of the distillate reaches 14 ° C, the distillation is discontinued and the reaction mixture is cooled to room temperature. A solution of 4-piperidinecarboxylic acid (13) (31.5 g, 0.24 mol) in 100 mL of aqueous caustic (10 g, 0.25 mol NaOH), which has a pH meter, is cooled to 0 ° C and treated per serving drop with the acid chloride solution; 10% by weight of NaOH (aqueous) is added periodically during the addition of acid chloride to maintain the pH of the reaction mixture between 9 and 9.5.

After the addition is complete, the mixture is stirred at room temperature for 90 minutes to complete the reaction. The mixture is acidified to pH 2.0 with 6 N HCl to precipitate the product. The product is separated by filtration, rinsed with H2O and the filter cake is mixed in ether at reflux for 3 hours. The mixture is filtered, the product is dried 60 ° C overnight to provide the main compound (21) (42.81 g, 79% product). Example 95b Scheme J, step b: N- (4-fluorophenylacetyl) - 4-carboxylpiperidine (21) In a 100 mL three-necked flask equipped with a magnetic stir bar, a 60 mL addition funnel, a stopper and a nitrogen bubbler were placed 5.0 g (0.039 mol). ) of isonipecotic acid (1 3), 20 g of acetone, 20 g of water and 2.7 gd (0.02 mol) of potassium carbonate. The mixture was heated to about 32 ° C and evolution of gas was observed. The addition funnel was charged with 7.3 g (0.039 mol) of 4-fluorophenylacetyl chloride. The 4-fluorophenylacetyl chloride was added to the reaction mixture over a period of 10 minutes. The reaction mixture was allowed to cool to 25 ° C and stir for 1.5 hours. The reaction mixture was transferred to a single neck flask and concentrated by rotary evaporation to provide a white slurry. The sludge was treated with 39 mL (0.039 mol) of a 1 N aqueous hydrogen chloride solution and 50 g of toluene. After stirring for 30 minutes the phases were separated and the organic layer was concentrated. The resulting residue was treated with 50 g of ethyl acetate and 30 g of water. The phases are separated and the volume of the organic phases is reduced by approximately 50% by rotary evaporation. The solution was allowed to stand at 25 ° C for 72 hours and crystallize. The mixture was cooled to 0 ° C and the product was collected by suction filtration and dried under vacuum (30 in Hg) at 50 ° C for 8 h to provide 7.3 g (67% product) of N- (4- fluorophenylacetyl) -4-carboxylpiperidine (21). 1 H NMR (CDCl 3) d 11.0 (br, 1 H, -CO 2 H), 7.22-7.17 (m, 2 H), 7.00 (t, 2 H, J = 8.6 Hz), 4.39 (d, 1 H, J = 13.5 Hz), 3.80 (d, 1H, J = 13.2 Hz), 3.72 (s, 2H), 3.11 (t, 1H, J = 11.0 Hz), 2.90 (t, 1H, J = 10.8 Hz), 2.85-2.49 (m, 1H) , 1.95 (dd, 1H, 1J = 9.0, 2J = 3.2 Hz), 1.82 (dd, 1H, 1J = 9.1 Hz, J = 2.8 Hz), 1.51 (qt-d, 1H, 1J = 10.9 Hz, 2J = 3.8 Hz), 1.43 (qt-d, 1H, 1J = 11.0, 2J = 3.8 Hz); 13C NMR (CDCl3) d 178.6, 169.6, 163.4, 160.1, 130.6, 130.2, 115.7, 115.4, 45.3, 41.2, 40.4, 40.0, 28.0, 27.5 Example 96 Scheme 1, step c N- (4-Fluorophenylacetyl) -4- (NON-dimethylhydroxyaminocarboxypiperidine (22) N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) (10.0 g, 37.7 mmol) is mixed in methylene chloride (100 mL) and treated with solid carbonyldiimidazole (7.33 g, 45 mmol) After stirring for 2 hours, the solution is treated with N, O-dimethylhydroxylamine hydrochloride (5.25 g, 54 mmol) and the reaction is allowed to proceed overnight.The reaction is cooled with 1 N HCl (150 mL) and The phases are separated The organic phase is rinsed with H 2 O (150 mL), extracted with saturated 1/2-NaHCO 3, dried, filtered and concentrated under reduced pressure.The resulting oil can be distilled through Kugeirohr at 205 ° C to 0.05 ° C. Hg mm; however, this sample was chromatographed instantaneously (4 cm x 16 cm column of SiO2, EtOAc) to give the main compound (22) as a colorless oil (1.7 g, 98%). Example 97 Scheme J, step d: 4-f 1 -oxo-1 - (2,3-dimethoxyphenyl) meth nn-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) A verratrola solution ( 3.80 g, 27.5 mmol) in tetrahydrofuran (30 mL) is cooled to -70 ° C and treated with a solution of BuLi hexane (2.5 M, 11 mL, 27.5 mmol). The reaction mixture was allowed to warm to room temperature, after stirring for 3 hours. The mixture is cooled to -70 ° C and treated, drop by drop, with a solution of N- (4-fluorophenylacetyl) -4- (N, O-dimethylhydroxyaminocarboxy) piperidine (22) (4.04 g, 1 3.1 mmol) in tetrahydrofuran (30 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with NH 4 Cl (saturated, 40 mL), diluted with toluene (60 mL) and the phases separated. The organic phase is rinsed with H2O, dried, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography (SiO 2, column 4 cm x 1 5 cm, 30% EtOAc / toluene, column loaded material as a toluene solution), gives the main compound (4) (1.86 g, 4.8 mmol).

Example 98a Scheme J. stage e: 4-f 1 -oxo-1 - (2,3-dimethoxyphenyl) methyl-1-N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) A solution of veratrola ( 5.4 g, 39 mmol) in tetrahydrofuran (1000 mL) is cooled to -70 ° C and treated with a solution of BuLi hexane (2.5 M, 16 mL, 40 mmol). The reaction mixture was allowed to warm to room temperature. After 3 hours, the mixture is cooled to -70 ° C and treated with a mixture of N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21) (3.0 g, 11 mmol) in tetrahydrofuran (50 mL). The reaction mixture is allowed to warm to room temperature and is stirred overnight. The dark solution is cooled with NH CI, diluted with toluene, and the organic phase is separated. The organic phase is extracted with H2O, dried, filtered and concentrated under reduced pressure. The resulting oil is flash chromatographed (SiO2, 30% EtOAc / toluene), to provide the main compound (4) as an oil (1.0 g, 23% product). Example 98b Scheme J, step f: N- (4-Fluorophenylacetyl) -4-carboxylpiperidine, lithium salt (21 a) In a 1 L flask equipped with a magnetic stirring bar and nitrogen bubbler was placed 5.0 g ( 0.053 mol) of N- (4-fluorophenylacetyl) -4-carboxylpiperidine (21), 2.24 g (0.053 mol) of lithium hydroxide monohydrate, 1 75 g of tetrahydrofuran, and 75 g of water. The mixture was stirred at 25 ° C for 30 min and the solvent was removed by rotary evaporation. To the resulting residue was added 500 g of toluene and the mixture was azeotropically dried by rotary evaporation. To the resulting white solid was added 200 g of toluene and the product was collected by suction filtration. The wet cake was rinsed with toluene and dried under vacuum (29 in Hg) at 65 ° C for 18 h to provide 15.2 g (99% product) of N- (4-fluorophenylacetyl) -4-carboxylpiperidine, lithium salt ( 21 a) as a white powder. 1 H NMR (D 2 O) d 7.28-7.23 (m, 2H), 7.1 3 (t, 1 H, J = 8.9 Hz), 4. 35 (d, 1 H, J = 1 3.5 Hz), 4.01 (d, 1 H, J = 14.3 Hz), 3.82 (s, 2H), 3.17 (dt, 1 H, 1 J = 12.9, 2J = 2.6 Hz ), 2.81 (dt, 1 H, 1 J = 12.5, 2J = 2.3 Hz, 2.46- 2.36 (m, 1 H), 1.86 (t, 2H, J = 13.4 Hz), 1.44 (qt-d) , 2H, 1 J = 13.3, 2J = 3.8 Hz), 13C NMR (D2O) d 186.5, 1 74.9, 166.1, 162.9, 1 33.8, 1 33.3, 1 18.4, 1 18.1, 49.1, 46.8, 45.2, 41 .7 , 31 .9, 31 .4 Example 98c Scheme J, step q: 4-ri -oxo-1 - (2,3-dimethoxyphenyl) metiN-N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine ( 4) In a 1 00 mL three-necked flask equipped with a magnetic stir bar, a septum, a 40 mL addition funnel and a thermometer were placed 4.3 g (0.031 mol) of verrale and 35 g of tetrahydrofuran. cooled to -25 ° C and the addition funnel was charged with 12.8 mL (0.032 mol) of a 2.5 N solution of n-butyllithium in hexanes.The n-butyllithium solution was added at such a rate to maintain the temperature of internal reaction below 0 ° C. The solution was maintained at 0 ° C for 1 h before and heat at 25 ° C for 1 hour. The resulting mixture was then cooled to -25 ° C. In a 250 mL four-necked flask equipped with a magnetic stir bar, a thermocouple with a thermocouple, a septum, and a nitrogen bubbler were placed 7.0 g (0.025 mol) of N- (4-fluorophenylacetyl) -4-carboxylpiperidine. , lithium salt (21 a) and 35 g of tetrahydrofuran. The mixture was cooled to -20 ° C and the litiated veratrola mixture was added through a cannula for a period of 1 5 min. The reaction mixture was allowed to warm to 0 ° C for 1 h before heating to 25 ° C. After stirring at 25 ° C for 6 hours, the reaction mixture was quenched with 20.0 g of a saturated aqueous ammonium chloride solution. Toluene (20 g) was added and the phases separated. The organic phase was dried over MgSO and concentrated to provide a thick oil. Purification by flash chromatography on silica gel EM (230-400 mesh) using heptane and ethyl acetate (1: 1) afforded 3.0 g (31% product) of 4- [1 -oxo-1 - (2,3 -methoxyphenyl) methyl] -N-2- (4-fluorophenyl-1-oxo-ethyl) piperidine (4) as a thick transparent oil. 1 H NMR (CDCl 3) d 7.24-6.93 (m, 7H, aromatic), 4.42 (br-singlet, 1 H); 3.87 (s, 3H, -OCH3), 3.83 (s, 3H, -OCH3), 3.67 (s, 2H, Ph-CH2-CO-), 3.25 (m, 1 H), 3.08 (t, 1 H, J = 5.8 Hz), 3.81 (t, 1 H, J = 5.7 Hz), 1.84-1.76 (m, 2H), 1.47 (br-singlet, 2H); 13C NMR (CDCI3) d 205.3, 169.2, 163.4, 160.2, 1 52.8, 147.1, 1 33.8, 1 30.7, 1 30.2, 130.1, 124.2, 120.4, 1 1 5.7, 1 1 5.4, 1 1 5.3, 96.1, 61. 7, 56.0, 47.7, 45.6, 41.5, 40.1. Example 99 Scheme K, step a: 4-f 1 -Oxo-1 - (2,3-dimethoxyphenyl) metill-N-2- (4-fluorophenylethyl-piperidine (6) K2CO3 solid (1 84 g, 1.33 mole ) and Kl (5.5 g, 0.03 mol) were added to a solution of 4- (2,3-dimethoxybenzoyl) piperidine (16) (190 g, 0.67 mol) and 2- (4-fluorophenyl) ethyl bromide (135 g). 0.67 mol) in tetrahydrofuran (3 L) and water (720 mL) The resulting mixture was stirred under reflux for 18 hours The mixture was concentrated (40 ° C / 20 torr) to remove most of the tetrahydrofuran. it was extracted with methylene chloride (3 x 1.2 L) and the combined organic solutions were rinsed with brine (1.5 L) and dried (MgSO4) .The mixture was filtered through a pad of silica gel (SiO2). 60, 230-400 mesh, 10 cm x 16 cm id) and SiO2 was rinsed with EtOAc (5 L) .The combined filtrates were concentrated (35 ° C / 20 torr) to a residue which was dissolved in EtOAc (2 L). The solution was treated with HCl gas until the solution became acidic (moist pH paper) The mixture was filtered to provide the main compound (6) as a non-white solid after air drying (226 g, 84%); m.p. 232-234 ° C. IR (KBr) 3431, 2935, 2629, 2548, 1676, 1580, 1512, 1476, 1487, 1317, 1267, 1227, 1161, 1076, 1017, 1001, 954, 836, 764 cm'1; 1H NMR (DMSO-d6) d 11.0 (s, 1H, HCl), 7.0-7.4 (m, 7H, aryl), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 4H), 2.0 (m, 4H); 13C NMR (DMSO-de) d 203.6, 161 .1 (d, JF.C = 241 .0 Hz), 1 52.5, 146.6, 1 33.4, 133.3, 1 32.7, 130.6, 124.3, 1 1 9.8, 1 16.1, 1 1 5.4 (d, JF.C = 21.2 Hz), 61.3, 56.5, 56.0, 50.9, 44.9, 28.4, 25.0; 19 F NMR (DMSO-de) -1 16.0; MS (Cl, CH4) m / z (inverse intensity) 372 (MH +, 1 00%), 352 (36), 320 (10), 262 (88); Anal Cale for C 22 H 26 FNO 3 HCl (407.9): C, 64.78; H, 6.67; N, 3.43. Found: C, 64.54; H, 6.86; N, 3.30. Example 1 00 Scheme K, step a: 4-ri -Oxo-1 - (2,3-dimethoxy-phenyl) -methyl-N-2- (4-fluorophenylethyl-piperidine (6) To a solution of 2- (4-) alcohol fluorophenyl) ethyl (1 3.4 mL, 107 mmol) in dry toluene (150 mL) at 0 ° C was added phosphorous tribromide (21.1 mL, 224 mol) The resulting mixture was stirred at room temperature for 5 days and then it was cooled to 0 ° C and crushed ice was added (200 g) The aqueous layer was extracted with ether (2 x 120 mL) and the combined organic extracts were then rinsed with saturated aqueous sodium bicarbonate solution (2 x 30 mL). ), dried (MgSO4) and concentrated in vacuo.The distillation gave 2- (4-fluorophenyl) ethyl bromide as a colorless oil (14.08 g, 31%), bp 103 ° C @ 1 2 mm Hg. - (2,3-dimethoxybenzoyl) piperidine (16) (18.5 g, 64.7 mmol), 2- (4-fluorophenyl) ethyl bromide (13.2 g, 65.0 mmol), potassium carbonate (1 7.92 g, 129.7 mmol) and potassium iodide (0.54 g, 3.25 mmol) in tetrahydrofuran (300 mL) and water (70 mL) was heated to reflux overnight. The resulting mixture was allowed to cool and then concentrated in vacuo to remove the tetrahydrofuran. The residual material was extracted with methylene chloride (3 x 120 mL) and the combined organic extracts were rinsed with brine (1 50 mL), dried (MgSO 4), filtered through a silica gel plug with ethyl acetate ( 500 mL) and concentrated in vacuo to give the main compound (6) as a yellow oil (22.69 g, 94%). Example 1 01 Scheme K, step b: Ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (241 A 250 mL flask, equipped with a magnetic stir bar, Dean-Stark network, reflux condenser and drying tube was CaCl2 , charged with 4-piperidinecarboxylic acid, ethyl ester (23) (79.82 g, 0.507 mol), p-fluoroacetophenone (46.75 g, 0.338 mol), sulfide (13 g, 0.406 mol), p-toluenesulfonic acid (1. 0 g), and toluene (60 mL) The reaction mixture was heated to reflux with azeotropic removal of H 2 O for 2.25 hours, then refluxed for an additional 75 hours, then cooled, diluted with toluene (300 mL ) and extracted with HCl (2 N, 250 mL) The organic phase is rinsed with H 2 O (100 mL) and the aqueous rinse is combined with the acid phase and extracted again with toluene (1 00 mL). Toluene is combined with the original organic phase, rinsed with H2O (150 mL), extracted with NaHCO3 (250 mL, saturated), dried, filtered and concentrated under reduced pressure. duo was diluted with 20% aqueous EtOH (500 mL) and treated with filter aid. The filter aid is rinsed with 20% aqueous EtOH (100 mL), the combined filtrate and the rinse are decanted away from a dark, thick oil. The clear, yellow, aqueous EtOH solution is concentrated under reduced pressure and the residual oil is redissolved in toluene (500 mL) then re-concentrated to remove the remaining water. The oil is passed through an intake of SiO2 (14 cm high x 9 cm diameter), eluting with toluene (2 L), then 20% EtOAc in toluene (2 L) to provide the main compound (24) (57.94 g of 88% pure material, 49% of product). A small amount of this material was purified by Kugeirohr distillation; b.p. 180-195 ° C / 0.8 mm Hg. Example 102 Scheme K, step c: 1 - (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (251 Ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine (24) pure (20.61 g of 88% purity, 66 mmol) is treated with a solution of BH3XSMe2 (40 mL of 2 M in tetrahydrofuran) at room temperature. The degassing begins after 30 seconds and the reaction mixture is heated. After stirring for 30 minutes at room temperature, the reaction is quenched with MeOH (200 mL) and concentrated by atmospheric distillation to remove B (OMe) 3. The residue was treated with an additional 200 mL of MeOH and the distillation was continued. The concentrate is diluted with toluene and concentrated under reduced pressure. This concentration, diluted with toluene, is repeated to ensure total removal of B (OMe) 3.

Kugeirohr distillation (b.p. 148-160 ° C / 0.8 mm Hg) provides the main compound (25) (1 3.1 g, 73% product). Example 103 Scheme K, step d: 1- (4-carboxypiperidin) -2- (4-fluorophenyl) ethane (261 1 - (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) ( 13.6 g, 48.7 mmol), AcOH (50 mL) and HCl (50 mL of 6M) are refluxed for 3 hours, the mixture is concentrated to half the volume by atmospheric distillation, then the remaining solvent is removed under reduced pressure. The residue is recrystallized from isopropanol (100 mL) to give the main compound (26) (9.82 g, 70% product), mp 21 5-221 ° C. Example 104 Scheme K_, step e 1 - (4'- (N, O-dimethylhydroxylaminocarboxyperidine) -2- (4'-f luorofeniPethane (27) A mixture of 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane (26) (4.36 g, 15.2 mmol) in chloroform (30 mL) is treated with 1.1-carbonyldiimidazole (2.75 g, 17 mmol) Within 30 seconds of the addition, the evolution of CO2 begins and the solution becomes clear. 45 minutes at room temperature, the solution is treated with N, O-dimethylhydroxylamine hydrochloride (2.1 g, 21 mmol) and stirred overnight. The mixture is concentrated under reduced pressure, then re-mixed in toluene and re-concentrated to ensure complete removal of CHCl3. The residue is stirred in 50% toluene / ether (100 mL) and extracted with NaOH (2.5 M, 60 mL). The organic phase is separated, extracted twice with H2O (60 mL each), dried, filtered and concentrated. The solid residue is purified by Kugeirohr distillation (b.p. 1 55-175 ° C / 1 mm Hg) to give the main compound (27) as a white solid (3.80 g, 85% product). Example 105a Scheme K, step f: 4-p -Oxo-1 - (2,3-dimethoxy-phenyl) methyl-N-2- (4-fluorophenylethyl-piperidine (6) Veratrola (2.0 g, 14.5 mmol) in tetrahydrofuran (12 mL) is treated with BuLi (6 mL of 2.5 M hexane solution) at -60 ° C. The reaction mixture is allowed to warm to 20 ° C for 45 minutes, then the yellow mixture is cooled to - 20 ° C and treated with a solution of 1 - (4 '- (N, O, methylhydroxy, the same, rboxppiperid and no) -2- (4'-fluorophenyl) ethane (27) (3.8 g, 12.9 mmol) in tetrahydrofuran (20 mL) After the addition is complete, the reaction mixture is allowed to warm to room temperature and react for 45 minutes, then cooled with H2O and diluted with toluene.The organic phase is separated, rinsed with H2O, dried filter and concentrate to provide the main compound (6) as an oil Example 1 05b Scheme K, step q: 1 - (4-carboethoxypiperidine) -2- (4-fluorophenitethane (251 In a three-necked flask) 500 mL equipped with an agitator In a panic, a reflux condenser covered with a nitrogen sparger and a stopper were placed 13.0 g (0.083 mol) of 4-piperidinecarboxylic acid, ethyl ester (23), 19.9 g (0.091 mol) or 4-fluorophenylethyl mesylate (2 ), 12.6 g (0.091 mol) of potassium carbonate, 1.37 g (0.0091 mol) of sodium iodide and 208 g of acetonitrile. The reaction mixture was heated to 75 ° C and stirred under a nitrogen atmosphere overnight. The contents of the reaction after cooling to 25 ° C were transferred to a 1 L single neck neck containing 56 g of water. The mixture was concentrated by rotary evaporation to provide a yellowish aqueous solution. The aqueous solution was extracted with methylene chloride (2 x 75 g) and the combined extracts were dried over MgSO 4. Filtration and concentration by rotary evaporation gave 23 g (99% of product) of 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25) as a pale yellow liquid (purity: 97% area, GC analysis). 1 H NMR (CDCl 3) d 7.1 3 (t, 2 H, J = 7.3 Hz), 6.97-6.91 (m, 2H), 4.15-4.08 (m, 2H), 2.90 (t, 2H, J = 1 1 .0 Hz), 2.75 (t, 2H, J = 7.3 Hz), 2.54 (t, 2H, J = 9.1 Hz) , 2.31 -2.24 (m, 1 H), 2.06 (t, 1 H, J = 1 1 .2 Hz), 1.91 (d, 2H, J = 1 1.5 Hz), 1.83-1. 70 (m, 2H), 1.24 (t, 3H, J = 7.0Hz); 13C NMR (CDCI3) d 175.0, 163.0, 159.8, 136.1, 1 30. 1, 1 30.0, 1 15.2, 1 14.9, 60.6, 60.2, 53.0, 41.2, 32.9, 28.4, 14.2 Example 1 05c Scheme K, step h: 1 - (4- carboethoxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) In a 1 00 mL two-necked flask equipped with a magnetic stir bar, a reflux condenser covered with a nitrogen sparger, and a thermocouple with a thermocouple was placed 5.0 g (0.01 8 mol) of 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane (25), 0.75 g (0.018 mol) of lithium hydroxide monohydrate, 40 g of tetrahydrofuran and 20 g of water. The mixture was heated to 63 ° C and kept there under a nitrogen atmosphere overnight (1 8 hours). The reaction mixture was then cooled to 25 ° C and concentrated by rotary evaporation to provide a slurry. Toluene (150 g) was added and removed by rotary evaporation to azeotropically dry the product. The resulting solid was dried under vacuum (27 in Hg) at 70 ° C for 6 h to provide 4.6 g (>99% product) of 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) as a white powder. 1 H NMR (D 2 O) d 7.02 (t, 2 H, J = 6.3 Hz), 6.44 (t, 2 H, J = 8.4 Hz), 3.00-2.95 (m, 2 H), 2.82-2.75 (m, 2 H), 2.58 -2.48 (m, 2H), 2.30-2.20 (m, 1 H), 1.97-1.72 (m, 4H), 1.54-1.42 (m, 2H); 13C NMR (D2O) d 1 87.6, 165.8, 162.6, 139.1, 133.2, 1 33.1, 1 18.3, 1 1 8.0, 62.9, 55.6, 47.7, 47.2, 34.3, 31.8, 31.5. Example 105d Scheme K, step i: 4-H -Oxo-1 - (2,3-dimethoxyphenyl) metip-N-2- (4-fluorophenylethyl-piperidine (6) In a 1 00 mL three-necked flask equipped with a magnetic stirring bar, a septum, a thermocouple with a thermocouple, and a nitrogen bubbler were placed 1.8 g (0.01 3 mole) of verratrola and 30 g of tetrahydrofuran.The solution was cooled to -20 ° C before 5.1 mL (0.013 mol) of a 23.3% by weight solution of n-butyllithium in hexanes are added via syringe The n-butyllithium / hexane solution was added at such a rate to maintain the internal reaction temperature below -10 ° C during the addition The mixture was then heated to 25 ° C and stirred for 2 h before cooling to -20 ° C. In a suitable 1 00 mL coated lower drain pan with a four union head equipped with a mechanical stirrer, a thermocouple with a thermocouple, a reflux condenser covered with a nitrogen bubbler, and a septum is placed Rum 3.0 g (0.012 mol) of 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane, lithium salt (25a) and 30 g of tetrahydrofuran. the mixture was cooled to -1 5 ° C and the veratrole / lithiated tetrahydrofuran mixture was added through a cannula while maintaining the internal reaction temperature below -5 ° C. The reaction mixture was then kept at 5 ° C for 1 h, before being heated to 6 ° C. The reaction mixture was allowed to stir overnight at 6 ° C during a nitrogen atmosphere (1 5 h). The reaction was determined to be complete by GC analysis. To the reaction mixture was added 50 g of water (at 6 ° C) and the solution was heated to 25 ° C. The phases are separated and the organic phase is dried over MgSO. Filtration and concentration by rotary evaporation afforded 3.1 g (70% product) of 4- [1 -Oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylethyl) -piperidine (6) , 98% pure by GC analysis. 1 H NMR (CDCl 3) d 7.24-7.1 9 (m, 2H), 7.1 5-7.08 (m, 3H), 7.00 (t, 2H, J = 8.5 Hz), 3.90 (s, 3H), 3.85 (s, 3H), 3.70-3.60 (m, 2H), 3.48-3.39 (m, 2H), 3.27-3.10 (m, 2H), 3.01-2.60 (m, 3H), 2.45-2.31 (m, 2H), 2.16 ( d, 2H, J = 14.1 Hz); 13C NMR (CDCI3) d 203.7, 152.5, 146.6, 133.4, 133.35, 132.7, 130.6, 124.3, 119.8, 115.5, 115.2, 61.3, 56.5, 56.0, 50.1, 48.7, 44.9, 39.5, 28.4, 25.0. Example 106 Scheme L, step a: 4- (2,3-dimethoxybenzoiPpiperidine (16) 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-1-dimethyl ethyl ester (7) (-0.1128 mol) is cooled to 0 ° C, treated with fluoroacetic acid (85 mL) and stirred at room temperature for 1 hour, followed by concentration in vacuo, the material was dissolved in water (300 mL), rinsed with hexane (2 x 110 mL) and then treated with sodium hydroxide (18 g) The resulting solution was then extracted with methylene chloride (3 x 170 mL) The combined organic extracts were rinsed with brine (220 mL), dried (MgSO 4) and concentrated in vacuo. The resulting residue was dissolved in ethanol (110 mL), cooled to 0 ° C, treated with anhydrous hydrogen chloride gas to acid, diluted with ether (110 mL) and stirred for 1 hour.The resulting solid was collected by filtration , then rinsed with a mixture of ethanol and ether (1: 1, 110 mL) to provide hydrochloride salt of 4- (2,3- dimethoxybenzoyl) piperidine (16) as a white solid (19.18 g, 53%). Example 107 Scheme L, step a: 4- (2,3-dimethoxybenzoyl) piperidine (16) In a 25 mL three-necked flask equipped with a thermocouple with a thermocouple, a reflux condenser, a stopper and a magnetic stir bar acid 4- (2, 3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1-dimethylethyl ester (7) (1.1 g, 3.0 mmol) and 9.7 g of tetrahydrofuran. After 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) was dissolved, 6.3 g of 3N aqueous hydrochloric acid were added in one portion. The reaction was stirred at 18 hours at room temperature and then heated at 60 ° C for 4 hours to give 4- (2,3-d-methoxy benzoyl) piperidine hydrochloride. Into a 250 mL flask containing a stir bar was placed 4- (2,3-dimethoxybenzoyl) piperidine hydrochloride (1.2 g, 0.046 mol), 66 g of 2-butanol and 6.6 g of water. The mixture was heated to reflux before it was allowed to cool slowly to room temperature. The crystalline mixture was cooled to 0 ° C before the product was collected by vacuum filtration. The wet cake was rinsed with 10 g of 2-butanol (0 ° C) and dried under vacuum (25 in Hg) at 90 ° C for 72 hours. Drying afforded 4- (2,3-dimethoxybenzoyl) piperidine hydrochloride (1.0 g, 76%); m.p. 198-200 ° C. 1 H NMR (D 2 O) d 7.32-7.24 (m, 2H, aromatic), 7.14 (s, 2H, J = 7.4 Hz, aromatic), 4.89 (s, 1 H, -NH), 3.94 (s, 3H, - OCH3), 3.85 (s, 3H, -OCH3), 3.62-3.51 (m, 3H), 3.19 (d, 2H, J = 12.5, 2.6 Hz), 2.18 (d, 2H, J = 12.1 Hz), 1. 95-1.80 (m, 2H); 13 C NMR (D 2 O) d 21 0.4, 1 55.6, 149.6, 1 35.2, 128.3, 1 20.1, 65.1, 59.3, 47.6, 46.3, 27.4; IR (KBr) 3433, 2935, 2711, 1670, 1577, 1473, 1420, 1314, 1256, 1,003, 992, 750 cm '1. In a 250 mL single neck flask equipped with a stir bar and condenser reflux were placed 5.0 g (0.017 mol) of 4- (2,3-dimethoxybenzoyl) piperidine hydrochloride (16) (5.0 g, 0.01 7 mol), 2.0 g of a 50% by weight aqueous sodium hydroxide solution and 70 g of water. The solution was stirred at 25 ° C for 1 hour before 75 g of toluene was added. After stirring for 30 minutes the phases are separated and the organic phase is dried over 5 g of magnesium sulfate. 10 Filtration and concentration by rotary evaporation (29 in Hg), bath temperature at 60 ° C) resulted in a pale yellow liquid. The liquid was also concentrated under vacuum (0.05 mm Hg) at 25 ° C for 20 hours to provide 4- (2,3-dimethoxybenzoipiperidine (16) as a thick yellow, pale oil (3.97 g, 94%). 1 H NMR (D 2 O) d 7.12-6.96 (m, 3H, aromatic), 3.89 (s, 3 H, -OCH 3), 3.87 (s, 3 H, -OCH 3), 3.27-3.1 0 (m, 3 H), 2.71 - 2.64 (m, 3H); 13C NMR (D2O) d 206.2, 152.6, 146.9, 1 34.1, 124.1, 120.2, 20 1 14.8, 61.6, 55.8, 48.3, 45.8, 28.8. Example 1 08 Scheme L, step a: 4- (2,3-dimethoxybenzoiPpiperidine (16) To the reaction solution of 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1- 1 -dimethylethyl ester (7) Example 76, Scheme G, step c; Approximately 1 88 kg was added -É-icHb-B-H-iiri water and 37% hydrochloric acid (39 kg, 395 mol). The solution was heated to about 60 ° C for approximately 18 hours1.

The mixture was cooled to approximately 25 ° C and approximately 47 kg of toluene are added. The phases are separated and the organic phase is discarded. About 78 kg of water, 50% by weight of sodium hydroxide solution (31 kg, 391 mol), and about 99 kg of toluene are added to the aqueous phase. The phases are separated and the aqueous phase is discarded. The organic phase is concentrated by vacuum distillation. The concentration of 4- (2,3-dimethoxybenzoiPPiperidine (16) in solution varies from 17 to 53% by weight1, providing 14.6 to 17.9 kg of 4- (2,3-dimethoxybenzoyl) piperidine (16) (65-76% of product) 1 The solution is sampled and analyzed by HPLC analysis to confirm complete deprotection to provide 4- (2,3-dimethoxybenzoipiperidine (16).) The reaction is complete if less than 5% of 4- (2, 3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1 -1-dimethylethyl ester (7).

Example 109 Scheme L, step a: 4- (2,3-dimethoxybenzoyl) piperidine (16) Trifluoroacetic acid (1.1 kg, 745 mL) was added to the residue obtained from Scheme G, step c, Example 70 and the mixture was mixed. stirred at room temperature for 1 hour. The resulting solution was concentrated (35 ° C / 20 torr) and the residue was dissolved in water (2.5 L). The aqueous solution was rinsed with hexane (2 x 1 L) and treated with 50% NaOH (300 g). The resulting solution was extracted with methylene chloride (3 x 1.5 L). The combined organic solutions were rinsed with brine (2 L) and dried (MgSO). The mixture was filtered and the filtrate was concentrated (30 ° C / 20 torr). The residue was dissolved in anhydrous EtOH (1 L) and treated with hydrogen chloride (gas) with stirring until the solution became acidic (wet pH paper). Ethyl ether (1 L) was added to the mixture which was stirred for 1 hour. The solid was collected by filtration and rinsed with 1: 1 EtOH: Et 2 O (1 L) to give the main product (16) (212 g, 74%) after air drying; m. p. 198-200 ° C. IR 3433, 2934, 271 1, 2509, 1670, 1578, 1472, 1420, 1 314, 1266, 1224, 1002, 992, 750 cm'1; 1 H NMR (CDCl 3) d 9.6 (br, s, 1 H), 9.4 (br, s, 1 H), 7.0 (m, 3H, aryl), 3.89 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.4 (m, 3H), 3.1 (m, 2H), 2.2 (m, 2H), 2.1 (m, 2H); 13 C NMR (CDCl 3) d 203.4, 1 52.6, 147.0, 132.6, 124.6, 120.5, 1 15.6, 61.7, 55.9, 44.5, 42.8, 24.8; MS (El) m / z (Reí. Intensity) 249 (MH +, 38%), 21 8 (21), 193 (100), 165 (49), 122 (1 5); 82 (17), 77 (1 9), 56 (60); Anal Cale for C 14 H 19 NO 3 HCl (285.7): C, 58.84; H, 7.05; N, 4.90. Found: C, 58.56; H, 7.14; N, 5.01. Example 1 Scheme L, step a: 4- (2,3-d-methoxybenzoyl) piperidine (16) To the reaction mixture of Scheme G, step c, Example 71 at 10 ° C were added 1 87.5 g of water and 62.5 g of 37% aqueous hydrochloric acid. The reaction mixture was then heated to 60 ° C and stirred for 12 hours (evolution of mild gas was observed). The reaction mixture was cooled to 40 ° C and 75 g of toluene were added. The phases are separated and the organic phase is discarded. The aqueous phase was cooled to 0 ° C and 50 g of a 50% by weight aqueous solution of sodium hydroxide was added while maintaining the internal reaction temperature below 25 ° C. The resulting pale green solution 5 (pH 12.7) turned purple-brown and finally orange in the addition of 200 g of toluene. The mixture was stirred for 30 minutes before being allowed to stand and separated by phase at 30 minutes. The phases are separated and the organic phase is azeotropically dried by vacuum distillation (29 in Hg), 60 ° C). The solution was concentrated to approximately 40% of its original volume to provide the main compound (16) as an orange-brown solution (17.35 g, 14.6% by weight of solution, 80% of product). Example 1 1 1 15 Scheme M, step a: 4- (2,3-dimethoxybenzoyl) pperidine (16) A 1 00 mL four-necked round bottom flask equipped with a reflux condenser, mechanical stirrer, addition funnel, The thermocouple, and nitrogen bubbler, was charged with 3.23 g (13.1 mmol) of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) and 50 mL of toluene. 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine did not completely dissolve in toluene. The reaction vessel was then charged with 4 mL of 5 N sodium hydroxide solution (20 mmol). The reaction mixture was cooled to 2 ° C with a cold bath. The addition funnel was charged with 2.71 g (1 5.7 mmol) of 4-25 fluorophenylacetyl chloride dissolved in 15 mL of toluene. The solution of < KI-H < < É-i > --ci-cM-t.

Acid chloride was added to the reaction vessel for 12 minutes. The temperature of the reaction mixture was added to the reaction vessel for 12 minutes. As acid chloride is added, 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine appears to dissolve. However, before it completely adds acid chloride, a gummy ball of solid formed in the reaction vessel. It takes approximately 15 minutes for the gummy solid to dissolve. The reaction mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was diluted with 25 mL of a 20% aqueous solution of sodium chloride and transferred to a separatory funnel. The organic phase was dried over anhydrous magnesium sulfate, filtered through a medium sintered glass funnel, and evaporated to dryness using a rotary evaporator and vacuum oven overnight at room temperature. The isolated product (20) was a pale yellow foam that weighed 5.34 g and was used in Scheme E, step c, without further purification. Example 1 12 Scheme M, step a: 4-f1-hydroxy-1 - (2,3-dimethoxy-phenyl-N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) In a suitable reactor, acid is charged 4-flurophenylacetyl (122.5 kg, 795 mol), N, N-dimethylformamide (0.37 kg, 5.1 mol) and toluene (490 kg) Oxalyl chloride (105.2 kg, 829 mol) is added at a rate to maintain the temperature at about 35 ° C. The solution is stirred for at least 7 hours at about 25 ° C., typically providing a solution of approximately 22.1% by weight of 4-fluorophenylacetyl chloride (99% product as determined by HPLC analysis). Suitable inert reactor is charged with 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11), (45.6 kg, 181 mol, approximately 6% by weight of solution in methanol) and the concentration of 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) was adjusted to approximately 20% by weight or more by atmospheric distillation.1 Toluene (approximately 550 kg) is added and the distillation is continued until the temperature reaches approximately 1 10 ° C. 2 Toluene is added although at reflux to adjust the mixture to approximately 9% by weight of solution of 4- [1-hydroxy-1 - (2, 3-dimethoxyphenyl) methyl] piperidine (11). The reaction mixture was cooled to about 30 ° C, causing the precipitation of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) 3 before they added 50% by weight of solution of sodium hydroxide (1 7.4 kg, 217 mol) and approximately 1 82 kg of water. The solution of 4-fluorophenylacetyl / toluene chloride (32.8 kg, 1 90 mol) is added at a rate to maintain the temperature at about 25 ° C. The addition line is rinsed with 10 kg of toluene4. The phases are separated and the organic phase is rinsed with approximately 1 80 kg of water. The organic phase is concentrated and dried by atmospheric distillation5. The concentration of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) is about 18% by weight as determined by HPLC analysis, provided approximately 67 kg of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) (95% of product) .6 The approximate weight% of 4- [1-hydroxy-1- (2, 3-dimethoxyphenyl) methyl] piperidine (11) is achieved by removing about two thirds of the initial solvent. Exact weight% can be obtained by HPLC analysis of the solution. The amount of toluene added again is determined by weighing the distillate and knowing the amount of toluene initially added. 3 4- [1-Hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) can be isolated at this stage if it is desired to increase its purity by cooling to about 20 ° C and removing it by filtration. 4 The mixture is sampled and analyzed by HPLC analysis to confirm the formation of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1 -oxo-ethyl) piperidine (20). The reaction is complete if less than 3% of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (1 1) is detected. 5 The solution is sampled and the water content is determined by Karl Fischer trituration. If the water content is above 500 ppm, the additional toluene can be added and the distillation continued. 6 The solution of 4- [1-hydroxy-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) / toluene is filtered through a cartridge filter and stored in cylinders to be used in Scheme L stage c. Example 1 1 3a Scheme M. stage a: 4-f 1 -hydroxy-1 - (2,3-dimethoxyphenyl) metill-N-2- (4-fluorophen-1-oxo-ethylpiperidine (20) In a three-necked flask 1 L necks equipped with a 2nd mechanical agitator, an additional funnel, and a nitrogen bubbler ventilated to a water cleaner were placed 60.0 g (0.389 mol) of 4-fluorophenylacetic acid, 0.18 g, 0.002 mol) of N, N-dimethylformamide and 250 g of toluene . The addition funnel was charged with 50.4 g (0.397 mol) of oxalyl chloride and added to the mixture reaction over a period of 10 minutes resulting in i ^ a ^ gas evolution (an exotherm of 4.7 ° C was observed). The reaction mixture was stirred at room temperature for 2.5 hours (evolution of complete gas) and the upper space of the reaction flask was flushed with nitrogen for 10 minutes before storing the material. HPLC analysis of the solution indicated that 9.1 9.1% by weight of the solution was 4-fluoroacetyl chloride, thus providing a 99% product. Purification of 4-fluorophenylacetyl chloride by vacuum distillation (57-58 ° C, 0.1 5 mm Hg) gives 4-fluorophenylacetyl chloride as a clear liquid in 90% product. 1 H NMR (CDCl 3) d 7.25-7.21 (m, 2 H, aromatic), 7.05 (t, 2 H, J = 8.6 Hz, aromatic), 4.1 1 (s, 2 H, -CH 2); 13 C NMR (CDCl 3) d 171.6, 1 64.2, 160.9, 1 31.2, 131.1, 127.1, 127.0, 1 16.4, 1 1 5.7, 52.1; In a 250 mL coated lower drainage vessel equipped with a thermocouple with thermocouple and a suitable four union head with mechanical stirrer, a distillation head with receiver, and two stoppers were placed 108.4 g (0.027 mol) of a 6.2 solution. Weight% of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) in methanol of Example 90, Scheme I, step c. The solution was heated and 81.6 g of methanol distillate were collected. 80.7 g of toluene were added to the mixture and the distillation was continued. Distillation was terminated when the temperatures of both the vessel and the distillation head were stabilized at 10 ° C (141 g of distillate was collected). To the mixture was added an additional 25.9 g of toluene, before heating to 11 ° C to completely dissolve all the 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) . The solution was allowed to cool and crystallize for a period of 30 minutes at 28 ° C. To the mixture was added 2.55 g (0.032 mol) of a 50 wt% solution of aqueous sodium hydroxide and 26.9 g of water. The flask was equipped with an additional funnel which was charged with 22.2 g (0.028 mol) of a 22.2% by weight solution of 4-fluorophenylacetyl chloride in toluene. After all three phases had been mixed for 15 minutes, the solution of 4-fluorophenylacetyl / toluene chloride was added dropwise over a period of 5 minutes. This resulted in the formation of a two-phase solution. The mixture was allowed to stir at room temperature under a nitrogen atmosphere for 2 hours before monitoring by HPLC. The reaction was determined to be complete by HPLC, stirring was stopped and the phases allowed to separate. The phases are separated and the organic phase is rinsed with 1.4 g of water. The toluene / 4-fluorophenylacetyl chloride solution was azeotropically dried and concentrated by distillation until the temperatures of both the vessel and the distillation head reached 1110 ° C. Distillation afforded 31.9 g of a pale yellow solution containing 30.6% by weight of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1-oxo) ethyl) piperidine (20) by HPLC analysis (95% product). Concentration and purification by flash chromatography on silica gel EM, 230-400 mesh (particle size 0.040-0.063 mm) using heptane and ethyl acetate (4: 1) gave 4- [1-hydroxy-1 - (2, 3-d imethoxy in il) methyl] -N-2- (4-f luorof en-1-oxo-ethyl) piperidine (20) as a thick transparent oil. 1 H NMR (CDCl 3) d 7.20-7.13 (m, 2H, aromatic), 7.05-6.93 (m, 3H, aromatic), 6.87-6.82 (m, 2H, aromatic), 4.61-4.54 (m, 2H, -CH2) , 3.91-3.65 (m 6H, -OCH3), 6.54 (d, 2H, J = 9.4 Hz), 3.02-2.71 (m, 1H), 2.63 (s, 1H), 2.60-2.35 (m, 1H), 2.02-1.80 (m, 2H), 1.32-1.09 (m, 4H); 13C NMR (CDCI3) d 169.0, 163.3, 160.0, 152.4, 146.4, 136.1, 135.9, 131.0, 130.2, 130.1, 123.9, 119.4, 119.3, 115.5, 115.2, 111.6, 111.5, 73.5, 73.2, 60.7, 60.3, 55.7, 46.2, 46.1, 43.0, 42.0, 41.9, 40.0, 28.9, 28.7, 28.3, 27.9; Example 113b Scheme M, step a: 4-ri-hydroxy-1- (2,3-dimethoxyphenyl) metiN-N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) In a flask four 500-mL necks equipped with a mechanical stirrer, a thermocouple with a thermocouple, a 125 mL addition funnel covered with a nitrogen bubbler, and a distillation head were placed with 70.5 g (0.031 mol) of 4- [1-hydroxy] -1- (2,3-dimethoxyphenyl) methyl] pipepdine (11) as a 11.1% by weight solution in methanol (containing 2.9% by weight of acetic acid). The solution was heated and approximately 2/3 of the methanol was removed by atmospheric distillation. To the concentrated solution was added 110 g of toluene and the distillation was continued until the temperature of the distillation head reached 98 ° C. At the end of the solvent exchange the proportion of toluene unit was adjusted to 1 0. This was carried out when determining the distillate weight and knowing the amount of toluene initially added. The solution of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine (11) / toluene / acetic acid was allowed to cool to 60 ° C. To the solution 47 g of water were added. The resulting mixture was allowed to stir for 15 min and the addition funnel was charged with 27.1 g (0.034 mol) of a 21.7% by weight solution of 4-fluorophenylacetyl chloride in toluene. The solution of 4-flurophenylacetyl / toluene chloride was added in one portion to the mixture at 40 ° C, resulting in an exotherm of 4 ° C. Within the minutes of addition, the three-phase system became a two-phase system. The reaction mixture was allowed to cool to room temperature and stir for 2 h. The phases are separated and the organic phase is rinsed with 5.7 g of 1 N hydrochloric acid solution and 15.7 g of water. The solution of 4- [1-hydroxy-1 - (2,3-di methoxyf in yl) methyl] -N-2- (4-f luorof en-1-oxo-ethyl) piperid i na (20) / toluene was concentrated and dried azeotropically by rotary evaporation to provide 95% product of 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophen-1 -oxo-ethyl) piperidine (20) as a 1 15.5% by weight solution in toluene. Example 1 14 Scheme M, stage b: 4-f1-hydroxy-1 - (2,3-dimethoxyphenyl) meth1l-N-2- (4-fluorophen-1-oxo-ethyl) piperidine (20) A solution of 4- [1 -oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenyl-1 -oxo-ethyl) piperidine (4) (1.0 g, 2.5 mmol), EtOH ( 10 mL) was treated with 1 drop of 5N NaOH and NaBH 4 (0.20 g, 5.2 mmol). The resulting solution was stirred at room temperature overnight, quenched with acetone (2 mL) and stirred for an additional 30 minutes. The solution is concentrated under reduced pressure, the residue was partitioned between EtOAc (30 mL) and 2 N NaOH (30 mL). The phases are separated and the organic phase is rinsed with water then brine (saturated) and dried. The mixture is filtered and the filtrate is concentrated under reduced pressure to provide an oil. Flash chromatography (SiO2, 3: 1 EtOAc / toluene) gives the main compound (20) as a semi-solid (0.69 g, 70% product). As stated previously, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is a 5HT2 receptor antagonist useful in the treatment of a number of disease states, including schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, peripheral or coronary vasospasm, fibromyalgia, cardiac arrhythmias, thrombotic affection and to control the extrapyramidal symptoms associated with neuroleptic therapy. The present invention provides methods for treating these diseases comprising administering an effective amount of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) which has a range of particle size from about 25 μm to about 250 μM, such treatment being in accordance with the techniques and procedures provided in US Patent No. 5,134,149 issued July 28, 1992; the Patent of E. U. No. ,700, 81 3 issued on December 23, 1 997; U.S. Patent No. 5,700, 812 issued December 23, 1997 and U.S. Patent No. 5,561, 144 issued October 1, 1996, the description of each of which is incorporated herein by reference. In effecting the treatment of a patient, effective amounts of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) can be administered orally in the form of solid single dose, including tablets, and the present invention provides pharmaceutical compositions containing effective amounts of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ( 3) in combination with one or more inert ingredients. These pharmaceutical compositions may contain (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) of an unspecified particle size or may contain (R ) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) having a particle size range of about 25 μm to about 250 μm. As used herein, the term "inert ingredient" refers to those therapeutically inert ingredients that are known in the art of pharmaceutical science that can be used alone or in various combinations, and include, for example, binders, diluents, lubricants , glidants, sweetening agents, antioxidants, solubilizing agents, coating agents and the like, as described in The United States Pharmacopoeia, XXII, 1990 (1989 The United States Pharmacoeia Convention, Inc.), pages 1857-1859, which is incorporated in the present for reference. For example, the following inert components can be used alone or in various combinations: binders such as gelatin, polyvinylpyrrolidone (PVP), pregelatinized starch, providone, cellulose derivatives, including methyl cellulose, carboxymethyl cellulose, methyl hydroxypropyl cellulose, cellulose carboxymethyl, methyl hydroxypropyl cellulose (HPMC), hydroxy cellulose (HPC), sucrose and the like; diluents such as calcium carbonate, lactose, starch, macrocrystalline cellulose, and the like; lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, hydrogenated vegetable oil and the like; glidants such as silicon dioxide, talc and the like, disintegrants such as alginic acid, methacrylic acid, DVB, degraded PVP, macrocrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and the similar. A preferred combination of inert ingredients comprises lactose monohydrate, macrocrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. A preferred pharmaceutical composition according to the present invention is as follows: A more preferred pharmaceutical composition according to the present invention is as follows: An even more preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: Another most preferred pharmaceutical composition according to the present invention is as follows: As stated previously, in all of the above compositions, (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) in the composition may have a unspecified particle size or may have a particle size range of about 25 μM to about 250 μM. When the pharmaceutical compositions of the present invention is in the solid single dose form, such as tablets, the uniformity of content of the composition is desirable. Since the uniformity of content of the improved single dose form results when the particle size distribution of the drug substance approximates the particle size distribution of the excipients used, the most preferred particle size distribution of ( R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) for the formulation in solid single dose composition, such as tablets, is one in which The particle size distribution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) approximates the particle size distribution of the excipients used in formulating the tablet. For example, as shown above, the preferred pharmaceutical compositions of the present invention comprise lactose monohydrate as a major component. In any given amount of lactose monohydrate, not less than about 50% by weight of the lactose monohydrate typically occurs as particles that are between about 75 μm and about 25 μm in size. Therefore, since the improved tablet content uniformity results when the particle size distribution of the drug substance approximates the particle size distribution of the excipients used, it is preferred that, in compositions of the present invention comprising lactose monohydrate as a main component, not less than about 50% by weight of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ( 3) have a particle size between about 75 μm and about 250 μm. Therefore, the present invention also provides an optional crystallization technique by which (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorofenyl) ethyl] -4- can be prepared piperidinemethanol (3) with a particle size range of from about 25 μm to about 250 μm, including (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-f luorof in yl) ethyl ] -4-piperid ina meta nol (3) with not less than about 50% by weight of its particles within the size range of between about 75 μm and about 250 μm in size. This crystallization technique typically provides (R) -a- (2, 3-d imethoxy in il) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3) having a particle size range of from about 25 μm to about 250 μm, more typically having a particle size of from about 30 μm to about 240 μm, and more typically and more preferred, having a range of particle size from about 38 μm to about 224 μm. (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) thus crystallized also demonstrates a particle size distribution wherein typically, about 3% by weight to about 60% by weight of the material has a particle size of less than about 45 μm, about 0.5% by weight to about 60% by weight of the material has a particle size of more than about 90 μm, and about 25% by weight. Weight% to about 85% by weight of the material has a particle size range of from about 45 μm to about 90 μm. More typically, the distribution is about 5% by weight to about 55% by weight of the material having a particle size of less than about 40 μm, about 1% by weight to about 55% by weight of the material having a size of particle of more than 95 μm, and about 30% by weight to about 80% by weight of the material having a particle size range of from about 40 μm to about 95 μM. More typically and more preferred, the distribution is about 8% by weight to about 53% by weight of the material having a particle size range of less than about 38 μm; from about 33% by weight to about 78% by weight of the material having a particle size range of between about 38 μm to about 101 μm, and about 2% by weight to about 50% by weight of the material having a range of particle size from about 101 μm to about 224 μm. This crystallization process is carried out in two stages. First, about 4% to about 20% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is used to produce seed crystals a through crystallization at high supersaturation and the solvent composition is adjusted (without dissolving the seed crystals) in such a way that (R) -a- (2,3-dlmethoxyphenyl) -1 - [2- (4-f luorofenil) remaining ethyl] -4-piperidinemethanol (3) is added, crystallized in the existing seed crystals. Second, a concentrated solution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is added to the seed crystals in such a way that the The composition of the solvent and the temperature change generate a supersaturation that is released by crystallization in the existing seeds. For example, first in a vessel, using from about 4% to about 20% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3 ) to be crystallized, a saturated solution of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidynamethanol (3) is formed (Solution 1). Then, the residue (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) is thermally dissolved in a solvent wherein (R) -a - (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) our a high degree of solubility at moderate temperature (ie, temperature from about 35 ° C to about 75 ° C), in such a way that the chosen solvent will produce a supersaturated solution when combined with the seed crystals present in Solution 1 and that is otherwise suitable for the recrystallization of (R) -a- (2,3-dimethoxypheniP -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3), such as aqueous isopropanol, thus forming Solution 2. Then, Solution 2 is added to Solution 1, adjusting the solvent composition as necessary by the addition of a suitable antisolvent, such as water, to maintain an acceptable product by minimizing the solubility at the isolation temperature. The dissolved (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) was then allowed to grow in the existing seed crystals. As used herein, the term "antisolvent" refers to a solvent deficient for the substance in question which, when added to a solution of the substance, causes the substance to precipitate or otherwise become less soluble . Solution 1 can be prepared by first dissolving about 1% to about 6% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) for crystallizing from a suitable solvent wherein (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-p -peridinemethanol (3) shows a relatively high level of solubility, such as methanol (Solution 3). Solution 3 and a suitable antisolvent, such as water, are then immersed, preferably by continuously feeding both Solution 3 and the antisolvent in a separate vessel, preferably at a constant rate and constant rate, thus forming Solution 4. Second, in a separate vessel, about 3% to about 12% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to be crystallized is dissolved in a solvent wherein (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) shows a lower degree of solubility than the solvent used in the Solution 2, such as isopropanol, thus forming Solution 5. Third, Solution 5 is added to Solution 4, forming the saturated solution containing seed crystals (Solution 1). Alternatively, Solution 1 can be prepared by dissolving about 1% to about 6% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to be crystallized from a suitable solvent wherein (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) shows a relatively high level of solubility, such as methanol (Solution 3). Solution 3 and a suitable antisolvent, such as water, are then immersed, preferably by continuously feeding both Solution 3 and the antisolvent in a separate vessel, preferably at a constant rate and constant rate, thereby forming Solution 4. The precipitate of Small crystals that form in Solution 4 are isolated by I filtration. Second, in a separate vessel, about 3% to about 12% of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) to be crystallized is dissolved in a solvent wherein (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) shows a lower degree of solubility than the solvent used in Solution 2, such as isopropanol, thus forming Solution 5. Third, the seed crystals are isolated from Solution 4 and added to Solution 5, forming the saturated solution containing seed crystals (Solution 1). In a typical manufacturing process, tablets containing (R) -a- (2, 3-dimethoxy-enyl) -1- [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol (3) can be prepared by the following procedure; all the components selected before manufacturing: 1) a premix comprised of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and a portion of the total lactose is prepared by the addition of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) and the lactose to a suitable mixer and mix; 2) add approximately one half of the remaining lactose to another suitable mixer and add croscarmellose sodium, cellulose (preferably macrocrystalline cellulose), and mix premix to the mixer, followed by the remaining lactose; 3) mix the excipients and premix; 4) add magnesium stearate and colloidal silicon dioxide to the mixer; 5) Mix the ingredients; and 6) compress the final mixture into tablets. A film coating can then be applied to the tablets. The portion of the total lactose used in step 1) is typically from about 15% w / w to about 40% w / w and is more typically from about 20% w / w to about 30% w / w of the total lactose used in the composition. For example, approximately 28% weight / weight of the final alactose is added in step 1) and the remaining 51% weight / weight of the total approximate weight / weight 79% is added in step 2) in the next composition: In another example, approximately 23% weight / weight of the final lactose is added in step 1) and the remaining 51% weight / weight of the total approximate weight / weight of 74% is added in step 2) in the following composition: In another typical manufacturing process, the tablets containing (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (3) can be prepared by the following procedure; all the components selected before manufacturing: 1) a premix comprised of (R) -a- (2,3-dimethoxyphenyl) -1-

Claims

CLAIMS 1. A compound of the formula (1) which is (R) -a- (2,3-dimethoxyphenyl) -4-piperidinemethanol: m.
2. A compound of the formula (4) which is 4- [oxo-1 (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylyl-1-oxoethyl) piperidine: (4).
3. A compound of the formula (3a) which is (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, acid salt (2S, 3S) ) - (+) - di- (p-anisoyl) tartaric: (3a) 4. A compound according to claim 3 characterized by a melting point range of about ^ ^ -? r 110 ° C to about 115 ° C. 5. A compound according to claim 3, characterized by a melting point range from about 170 ° C to about 172 ° C. 6. A compound of the formula (10) which is 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine: (10) 7. A compound of the formula (12) which is 4- (2,3-dimethoxybenzoyl) pyridine: (12) 8. A compound of the formula (20) which is 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] -N-2- (4-fluorophenylyl-1-oxo-ethyl) piperidine: (2 .. '»..i 9. A compound of the formula (3) having a particle size range of from about 25 μm to about 250 μm. 1 0. A compound according to claim 9, characterized in that the range of particle size is from about 30 μm to about 240 μm. eleven . A compound according to claim 10, characterized in that the range of particle size is from about 38 μm to about 22 μm. A compound according to claim 9, characterized in that about 3% by weight to about 60% by weight of the compound has a particle size of less than about 45 μm, about 0.5% by weight to about 60% by weight of the compound has a particle size greater than about 90 μm, and about 25% by weight to about 85% by weight of the compound has a particle size range of from about 45 μm to about 90 μm. A compound according to claim 1 characterized in that about 5% by weight to about 55% by weight of the compound has a particle size of less than about 40 μm, about 1% by weight to about 55% by weight of the compound has a particle size greater than 95 μm, and about 30% by weight to about 80% by weight of the compound has a particle size range of about 40 μm to about 95 μm. A compound according to claim 1 characterized in that about 8% by weight to about 53% by weight of the compound has a particle size range of less than about 38 μm, from about 33% by weight to about 78% by weight of the The composite has a particle size range from about 38 μm to about 101 μm, and about 2% by weight to about 50% by weight of the compound has a particle size range of from about 101 μm to about 224 μm. 1 5. A process for preparing the compound of the formula (3) which is (R) -a- (2,3-dimethoxy-phenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol: (3) which comprises reacting the compound (1) with a suitable 4-flurophenylethyl alkylating agent of the structure (2): wherein X is methanesulfonate. 16. A process for preparing the compound (3) comprising reacting the compound (4) with a suitable chiral reducing agent. 17. A process according to claim 16, characterized in that the chiral reducing agent is (+) - β-chlorodiisopinocanphenylborane. 18. A process for preparing the compound (3) which comprises reacting a compound of the formula (6) which is 4- [1-oxo-1 - (2,3-dimethoxyphenyl) methyl] -N-2- (4- fluorophenylethyl) piperidine: (6) with a suitable chiral reducing agent. 19. A process according to claim 18, characterized in that the chiral reducing agent is (+) - β-chlorodiisopinocanphenylborane. 20. A process for preparing the compound (3) containing the steps of: a) reacting the compound of the formula (5) which is a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol; (5) b) with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid to give a racemic mixture of the compound (3a) and a compound of the formula (3b) which is (S) - a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, (2S.3S) - (+) - di- (p-anisole) tartaric acid salt; c) separating compound (3a) from compound (3b) by selective crystallization; d) reacting the compound (3a) with a suitable base to give the compound (3). twenty-one . A process for preparing the compound (3a) by reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoiptartaric acid in a suitable solvent 22. A process for preparing the compound (3a) which comprises separating the compound (3a) from the compound (3b) by a selective crystallization; 23. A process for preparing the compound (3) comprising separating the compound (3a) with a suitable base 24. A process according to claim 21 , characterized in that the suitable solvent is 2-butanone 25. A process according to claim 21, characterized in that the suitable solvent is methanol 26. A process according to claim 21, characterized in that the suitable solvent is aqueous acetic acid. A process for preparing the compound (3a) containing the steps of: a) subjecting a compound of the formula (5a) which is a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidinemethanol, butyrate ester; (0 b) for a selective enzymatic hydrolysis provide a mixture of the compound (3) and a compound (5b) which is (S) a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4 piperidinemethanol, butyrate ester; 5 _ii_ - «^ • * • - c) separating the compound (3) from the compound (5b). 28. A process according to claim 27, characterized in that the selective enzymatic hydrolysis is conducted using Candida cylindracea lipase. 29. A process for preparing the compound (3) containing the steps of: a) reducing a compound of the formula (24) which is ethyl N- (4-fluorophenylthioacetyl) -4-carboxylpiperidine with a suitable reducing agent to produce a compound of the formula (25) which is 1- (4-carboethoxypiperidine) -2- (4-fluorophenyl) ethane; (25) b) hydrolyzing the compound of the formula (25) with a suitable hydrolyzing agent to produce a compound of the formula (26) which is 1- (4-carboxypiperidine) -2- (4-fluorophenyl) ethane; -. l. j. ^ », ... (26) c) react the compound (26) with N, O-dimethylhydroxylamine to produce a compound of the formula (27) which is 1- (4 '- (N, O-dimethylhydroxylaminocarboxy) piperidino) - (4'-fluorophenyl) ethane; (27) d) reacting the compound (27) with litiated veratrola to produce a compound of the formula (6) which is 4- [1-oxo-1- (2,3-dimethoxyphenyl) methyl] -N-2- ( 4-fluorophenylethyl) -piperidine; (6) e) reducing the compound (6) with a suitable reducing agent to produce a compound (5); f) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid to give a racemic mixture of the compound (3a) and the compound (3b); g) separating compound (3a) from compound (3b) by selective crystallization; h) reacting the compound (3a) with a suitable base to produce the compound (3). 30. A process for preparing the compound (3) containing the steps of: a) hydrolyzing the compound (25) which is with a suitable hydrolyzing agent to produce the compound of the formula (26); b) reacting the compound (26) with N, O-dimethylhydroxylamine to produce a compound (27); c) reacting the compound (27) with litiated veratrola to produce the compound (6); d) reducing the compound (6) with a suitable reducing agent to produce the compound (5); e) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoiptartaric acid to give a racemic mixture of the compound (3a) and the compound (3b): f) the compound is separated ( 3a) of the compound (3b) by selective crystallization; g) reacting the compound (3a) with a suitable base to give the compound (3). 31 A process for preparing the compound (3) comprising the steps of: a) reacting the compound of the formula (21) which is (N-4-fluorophenylacetyl) -4-carboxylpiperidine with N, O-dimethylhydroxylamino to produce the compound of the formula (22) which is (N-4-fluororhexyl) -4- (N, O-dimethylhydroxyaminocarboxypiperidine; b) reacting compound (22) with litiated veratrola to produce compound (4); c) reducing the compound (4) with a suitable chiral reducing agent to produce the compound (3); 32. A process for preparing the compound (3) having a particle size range of from about 25 μm to about 250 μm comprising the steps of: a) in a container, using from about 4% to about 20% of the compound (3) to be crystallized, producing a saturated solution of compound (3) containing seed crystals of compound (3); b) in another container, producing a solution of the remaining compound (3) by dissolving the compound (3) in a solvent wherein the compound (3) shows a high degree of solubility at a moderate temperature such that the solvent will produce a solution supersaturated when combined with the seed crystals present in the solution formed in step a; c) adding the solution formed in step b) to the solution formed in step a) while adjusting the solvent composition by the sum of a suitable anti-solvent to maintain an acceptable product by minimizing the solubility at the isolation temperature; d) allowing the compound (3) in solution to crystallize on the seed crystals. 33. A process according to claim 32, characterized in that the saturated solution containing the seed crystals of step a) is formed by the steps of: 1) in a vessel, dissolving about 1% to about 6% of the compound (3) in solvent where the compound (3) shows a degree - "" - »« - ~ relatively high solubility; 2) immerse the solution of step 1) and a suitable anti-solvent in a separate container; 3) in a separate vessel, dissolving about 3% to about 12% of the compound (3) in a solvent wherein the compound (3) shows a lower degree of solubility than that used in step D; 4) add the solution from step 3) to the solution from step 2). 34. A process according to claim 33, characterized in that the solution of step 1) and the appropriate antisolvent are immersed in step 2) by continuously feeding both into a suitable container. 35. A process according to claim 34, characterized in that the solution of step 1) and the suitable antisolvent are continuously fed to a suitable vessel at a constant rate and constant rate. 36. A process according to claim 33, characterized in that the solvent used in step 1) is methanol. 37. A process according to claim 33, characterized in that the antisolvent used in step 2) is water. 38. A process according to claim 33, characterized in that the solvent used in step 3) is isopropanol. 39. A process according to claim 32, characterized in that the solvent used in step b) is aqueous isopropanol. 40. A process according to claim 32, characterized in that the antisolvent used in step c) is water. 41 A process for preparing the compound of the formula (11) which is 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine; (11) which comprises subjecting a compound of the formula (10) which is 4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] pyridine; (10) to catalytic hydrogenation using a suitable catalyst. 42. A process according to claim 41, characterized in that the catalyst is a rhodium in carbon catalyst. 43. A process for preparing a compound of the formula (8) which is (R) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) -1-piperidinecarboxylic acid, 1,1-dimethylethyl ester; (8) which comprises reacting a compound of the formula (7) which is 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid, 1,1-dimethyl ethyl ester; (7) with a suitable chiral reducing agent. 44. A process according to claim 43, characterized in that the chiral reducing agent is (+) - β-chlorodiisopinocanphenylborane. 45. A process according to claim 43, characterized in that the chiral reducing agent is potassium 9-O- (1, 2-isopropylidine-5-deoxy-aD-xylofuranosyl-9-borabicyclo [3.3.1] nonane. process for preparing the compound (1) comprising the steps of: a) reacting the compound (11) with a suitable chiral acid to give a racemic mixture of (R) -4- [1-hydroxy-1 - (2, 3- dimethoxyphenyl) methyl] piperidine, chiral acid salt and (S) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, chiral acid salt; b) separating (R) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, chiral acid salt of (S) -4- [1-hydroxy-1 - (2,3- dimethoxyphenyl) methyl] piperidine, chiral acid salt; c) reacting (R) -4- [1-hydroxy-1- (2,3-dimethoxyphenyl) methyl] piperidine, a salt of chiral acid with a suitable base to give the compound (1). 47. A process according to claim 46, characterized in that the chiral acid is (2R, 3R) - (-) - di- (p-toluoyl) tartaric acid. 48. A process according to claim 46, characterized in that the chiral acid is (2R, 3R) - (-) - di- (p-anisoiptartaric acid) 49. A process for preparing the compound (1 1) comprising reacting the compound (12) with a suitable reducing agent 50. A process according to claim 49, characterized in that the reducing agent is rhodium / alumina, 51. A process according to claim 49, characterized in that the reducing agent is rhodium / carbon. A process for preparing a compound (20) comprising reacting the compound (4) with a suitable reducing agent 53. A process for preparing a compound (1 1) comprising reacting lithiated veratrola with a compound of the formula (9) which is a 4-pyridinecarboxaldehyde in the presence of a suitable aprotic solvent 54. A process according to claim 53, characterized in that the aprotic solvent is toluene 55. A process according to claim 53, characterized in that the aprotic solvent is a mixture of toluene and tetrahydrofuran. 56. A process according to claim 53, characterized in that the aprotic solvent is a mixture of toluene and hexane. 57. A process for preparing the compound (20) comprising reacting the compound (11) with a suitable 4-fluorophenylacetylation reagent, in the presence of a suitable base and a suitable solvent. 58. A process for preparing the compound (5) comprising reacting the compound (20) with a suitable reducing agent in the presence of a suitable solvent. 59. A process for preparing the compound (3) comprising the steps of: a) reacting the compound (20) with a suitable reducing agent in the presence of a suitable solvent to provide the compound (5); b) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoithartaric acid to give a racemic mixture of the compound (3a) and the compound (3b); c) separating compound (3a) from compound (3b) by selective crystallization; d) reacting the compound (3a) with a suitable base to give the compound (3); 60. A process for preparing the compound (3) comprising the steps of: a) reacting the compound (11) with a suitable reagent of 4-fluorophenylacetylation, in the presence of a suitable base and a suitable solvent to provide the compound (twenty); b) reacting the compound (20) with a suitable reducing agent in the presence of a suitable solvent to provide the compound (5); c) reacting compound (5) with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid to give a racemic mixture of compound (3a) and compound (3b); d) separating the compound (3a) from the compound (3b) by selective crystallization; e) reacting the compound (3a) with a suitable base to give the compound (3). 61 A process for preparing the compound (3) comprising the steps of: a) subjecting the compound (10) to catalytic hydrogenation to provide the compound (11); b) reacting the compound (11) with a suitable reagent of 4-fluorophenylacetylation, in the presence of a suitable base and a suitable solvent to provide the compound (20); c) reacting the compound (20) with a suitable reducing agent in the presence of a suitable solvent to provide the compound (5); d) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoithartaric acid to give a racemic mixture of the compound (3a) and the compound (3b): e) separating the compound (3a) ) of the compound (3b) by selective crystallization; f) reacting the compound (3a) with a suitable base to give the compound (3). 62. A process for preparing the compound (3) comprising the steps of: a) reacting lithiated veratrola with the compound (9) in the presence of a suitable aprotic solvent to provide the compound (10); b) subjecting the compound (10) to catalytic hydrogenation to provide the compound (1 1); c) reacting the compound (11) with a suitable reagent of 4-fluorophenylacetylation, in the presence of a suitable base and a suitable solvent to provide the compound (20); d) reacting the compound (20) with a suitable reducing agent in the presence of a suitable solvent to provide the compound (5); e) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoiptartaric acid to give a racemic mixture of the compound (3a) and the compound (3b); f) separating the compound (3a) ) of the compound (3b) by selective crystallization; d) reacting the compound (3a) with a suitable base to give the compound (3). 63. A process for preparing the compound (20): a) reacting lithiated veratrola with the compound (9) in the presence of a suitable aprotic solvent to provide the compound (10); b) subjecting the compound (10) to catalytic hydrogenation to provide the compound (11); c) reacting the compound (11) with a suitable reagent of 4-fluorophenylacetylation, in the presence of a suitable base and a suitable solvent to provide the compound (20); 64. A process for preparing the compound (20) comprising the steps of: a) subjecting the compound (10) to catalytic hydrogenation to provide the compound (11); b) reacting the compound (11) with a suitable reagent of 4-fluorophenylacetylation, in the presence of a suitable base and a suitable solvent to provide the compound (20); 65. A pharmaceutical composition comprising (R) -α- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenophenyl) -4-piperidinemethanol; lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; of colloidal silicon; and magnesium stearate: 66. A pharmaceutical composition according to claim 65, comprising from about 3% w / w to about 15% w / w of (R) -a- (2,3-dimethoxyphenyl). ) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidynametanol, from about 50% w / w to about 90% w / w of lactose monohydrate; from about 3% w / w to about 15% w / w of microcrystalline cellulose; from about 2% w / w to about 10% w / w of croscarmellose sodium; from about 0.1% w / w to about 1% w / w of colloidal silicon dioxide; and from about 0.1% weight / weight to about 2% weight / weight of magnesium stearate. 67. A pharmaceutical composition according to claim 66, comprising from about 4% w / w to about 11% w / w of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- ( 4-fluorophenyl) ethyl] -4-piperidinemethanol; from about 70% w / w to about 85% w / w of lactose monohydrate; from about 5% w / w to about 11% w / w of microcrystalline cellulose; from about 3% w / w to about 6% w / w of croscarmellose sodium; from about 0.2% weight / weight to about 0.5% weight / weight of colloidal silicon dioxide; and from about 0.4% weight / weight to about 0.8% weight / weight of magnesium stearate. 68. A pharmaceutical composition according to claim 67, comprising about 5% w / w of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol; about 79% w / w of lactose monohydrate; about 10% w / w of microcrystalline cellulose; about 5% w / w sodium of croscarmellose; about 0.4% weight / weight of colloidal silicon dioxide; and about 0.5% w / w of magnesium stearate. 69. A pharmaceutical composition according to claim 67, comprising about 10% w / w of (R) -a- (2,3-dimethoxyf in yl) -1 - [2- (4-f luorof in yl) ethyl ] -4-piperidinemethanol; about 74% w / w of lactose monohydrate; about 10% w / w of microcrystalline cellulose; about 5% w / w sodium of croscarmellose; about 0.4% weight / weight of colloidal silicon dioxide; and about 0.5% w / w of magnesium stearate. 70. A pharmaceutical composition according to claim 67, comprising about 6% w / w of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol; about 83% w / w of lactose monohydrate; about 6% w / w of microcrystalline cellulose; about 3% w / w sodium of croscarmellose; about 0.2% weight / weight of colloidal silicon dioxide; and about 0.75% w / w of magnesium stearate. 71 A pharmaceutical composition according to claim 67, comprising about 7% w / w of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol; about 80% w / w of lactose monohydrate; about 7% w / w of microcrystalline cellulose; about 4% w / w of croscarmellose sodium; about 0.3% w / w of colloidal silicon dioxide; and about 0.75% w / w of magnesium stearate. 72. A pharmaceutical composition according to claim 65, characterized in that the (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol has a particle size of between approximately 25μm. and approximately 250 μm. 73. A pharmaceutical composition according to claim 72, characterized in that not less than about 50% by weight of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- Piperidinemethanol has a particle size range of between approximately 75μm. and about 250 μm and, characterized in that not less than 50% by weight of the lactose monohydrate has a particle size range of between about 75 μm and about 250 μm. 74. A pharmaceutical composition according to claim 73, characterized in that the solid single dose form is a tablet. 75. A process for the manufacture of a tablet comprising (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol; lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; colloidal silicon dioxide; and magnesium stearate, the process comprises the steps of: 1) preparing a premix comprised of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol and a portion of the total lactose by adding (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol and lactose in a suitable mixer and mixing; 2) add approximately one half of the remaining lactose to another suitable mixer and add croscarmellose sodium, microcrystalline cellulose, and the premix mixture to the mixer, followed by the remaining lactose, and mix; 3) add magnesium stearate and colloidal silicon dioxide to the mixer, and mix to form a final mixture; 4) Compress the final mixture in tablets. 76. A process according to claim 75, characterized in that the portion of the total lactose used in step 1) is from about 15% w / w to about 40% w / w of the total lactose used in the composition. 77. A process according to claim 76, characterized in that the portion of the total lactose used in step 1) is from about 20% w / w to about 30% w / w of the total lactose used in the composition. 78. A process for the manufacture of a tablet comprising (R) -a- (2,3-d-methoxy in i) -1 - [2- (4-f luorof in yl) ethyl] -4-piperidinemethanol; lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; colloidal silicon dioxide; and magnesium stearate, the process comprises the steps of: 1) preparing a premix comprised of (R) -a- (2,3-di methoxyf eni I) - 1 - [2- (4-f luorof en il) ethyl ] -4- piperidinemethanol, lactose, microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide when adding (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidine methanol, lactose, microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide to a suitable mixer and mix; 2) select the premix through a screen in another mixer and mix; 1) select the magnesium stearate containing the selected premix and mix; 4) Compress the final mixture in tablets. 79. A method of treating schizophrenia, anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, peripheral or coronary vasospasms, fibromyalgia, cardiac arrhythmias, which comprises administering a therapeutically effective amount of (R) -a- (2 , 3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol having a particle size range of between about 75 μm and about 250 μm to a patient in need thereof. 80. A method of controlling extrapyramidal symptoms associated with neuroleptic therapy comprising administering a therapeutically effective amount of (R) -a- (2,3-dimethoxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4- piperidine methanol having a particle size range of between about 75 μm and about 250 μm to a patient in need thereof. 81 A process for preparing the compound (3) comprising the steps of: a) hydrolyzing the compound (25) to produce the compound (26); b) reacting the compound (26) with lithium hydroxide to produce the compound (25a) which is 1- (4-carboxypiperidine) -2- (4-fluoropiperidine) -2- (4-fluorophenyl) ethane, lithium salt; d) reacting the compound (25a) with litiated veratrola to produce the compound (6); e) reducing the compound (6) with a suitable reducing agent to produce a compound (5); f) reacting the compound (5) with (2S, 3S) - (+) - di- (p-anisoyl) tartaric acid to give a racemic mixture of the compound (3a) and the compound (3b) g) separating the compound ( 3a) of the compound (3b) by selective crystallization; h) reacting the compound (3a) with a suitable base to give the compound (3). 82. A process for preparing a compound (3) comprising the steps of: a) the reaction compound (21) is reacted with lithium hydroxide to produce a compound (21 a), which is N- (4-fluorophenylacetyl) ) -4-carboxylpiperidine, lithium salt; (21a) b) reacting the compound (21 a) with litiated veratrola to produce a compound (4); c) reducing the compound (4) with a suitable chiral reducing agent to produce a compound (3);