CH638495A5 - Derivatives of perhydroazaheterocycles - Google Patents

Abstract

The novel derivatives of perhydroazaheterocycles of the formula <IMAGE> in which X denotes the oxo radical or hydrogen and the radical OR1, in which R1 represents hydrogen or an optionally substituted aliphatic, an optionally substituted araliphatic or an optionally substituted aromatic hydrocarbon or an acyl radical, R2 denotes hydrogen or an optionally substituted aliphatic hydrocarbon radical, Y represents oxygen or sulphur, n1 and n2 in each case represent the values 1 to 3, where n1 + n2 is at most four, and Ar represents an optionally substituted aromatic hydrocarbon radical, and their acid addition salts inhibit, in particular, noradrenalin and serotonin uptake and can be used as antidepressants. They are prepared by processes known per se.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 acceptable acid addition salts according to claim 1. 



   13.  Compounds of formula I according to claim 1, in which X is hydrogen and ORI, wherein Rl has the meaning given in claim 1, and R2, Ar, Y, nl, n2 and nl and n have the meaning given in claim 1, and their Acid addition salts. 



   14.  Compounds of formula I according to claim 1, in which X represents the oxo radical and R2, Ar, Y, ni, n2 and ni and n2 have the meaning given in claim 1, and their acid addition salts. 



   15.  Pharmaceutical composition, characterized by a content of a compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier. 



   16.  Pharmaceutical composition according to claim 15, characterized in that it contains a compound according to one of claims 2 to 5, 13 and 14 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier. 



   17th  Pharmaceutical composition according to claim 15, characterized in that it contains a compound according to one of claims 6 to 12 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier. 



   The present invention relates to new derivatives of perhydro-aza-heterocycles and their acid addition salts and pharmaceutical preparations which contain the new compounds. 



   The compounds according to the invention correspond to the formula
EMI2. 1
 where X represents the oxo radical or hydrogen and the radical ORI, where R represents hydrogen or an optionally substituted aliphatic, an optionally substituted araliphatic or an optionally substituted aromatic hydrocarbon radical or an acyl radical, R2 represents hydrogen or an optionally substituted aliphatic hydrocarbon radical, Y represents oxygen or sulfur, ni and n each represent the values 1 to 3, where nl + n2 is at most four, and Ar represents an optionally substituted aromatic hydrocarbon radical. 



   Aliphatic hydrocarbon radicals R1 and R2 are primarily lower alkyl, but can also be lower alkenyl or lower alkynyl. 



   Araliphatic hydrocarbon radicals are in particular phenyl-lower alkyl, also phenyl-lower alkenyl or phenyl-lower alkynyl. 



   Aromatic hydrocarbon radicals are in particular phenyl, and also naphthyl, such as 1- or 2-naphthyl, hydrogenated
Naphthyl such as 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetra hydro-2-naphthyl, anthryl such as 1-2- or 9-anthryl, 9,10 dihydro-9, 1 0-ethanone anthracenyl such as 9.1 0-dihydro-9, 10-ethanone anthracene-l-yl or 9.1 0-dihydro-9, 1 0-ethenoane thracenyl such as 9.1 0-dihydro-9, 1 0-ethenoanthracene 1 -yl, -2-yl or -9-yl. 

  Substituents in the phenyl part of phenyl-lower alkyl, phenyl-lower alkenyl and phenyl-lower alkynyl, or in an aromatic ring of naphthyl of the type specified or in one or two aromatic rings of anthryl, 9,10-dihydro-9,10-ethanoanthracenyl or 9,10 dihydro-9, 1 0-äthenoanthracenyl each of the above type are such. B.  optionally, such as halogen, substituted lower alkyl, such as lower alkyl or trifluoromethyl, optionally etherified or esterified hydroxy, such as
Hydroxy, lower alkoxy, methylenedioxy or halogen, and / or optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. B.  Lower alkoxycarbonyl, amidated carboxy, e.g. B.  optionally N-substituted carbamoyl, such as carbamoyl, N-lower alkyl carbamoyl or N, N-di-lower alkyl carbamoyl, further z. B. 

  Nitro or cyan, where the radicals indicated are each 1-, 2- or 3-fold and can be either identical or different from one another and substituted radicals can have one or more substituents in any of the positions suitable for substitution. 



   Substituents of lower alkyl, and lower alkenyl or lower alkynyl are, for. B.  optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy, phenyloxy and / or halogen, or optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. B. 



  Lower alkoxycarbonyl, amidated carboxy, e.g. B.  Carbamoyl, N-lower alkyl carbamoyl or N, N-di lower alkyl carbamoyl, or cyan. 



   In connection with the present invention, radicals and compounds denoted by preferably contain up to 7, in particular up to 4, acyl radicals up to 5 carbon atoms. 



   The general terms used in connection with the present invention have e.g. B.  the following meanings:
Lower alkyl can be unbranched or, especially at the a-carbon atom, branched and is z. B.  Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl, tert.  Butyl. 



   Lower alkenyl contains one or more double bonds and is e.g. B.  Allyl, 1- or 2-methylallyl or 3,3-dimethylallyl, while lower alkynyl z. B.  Propargyl means. 



   Phenyl lower alkyl is e.g. B.  Benzyl, 1- or 2-phenylethyl, while phenyl-lower alkenyl z. B.  Cinnamyl, and phenyl-lower alkynyl e.g. B.  3-Phenylpropargyl, wherein the radical R z. B.  can also be styryl or phenylethynyl. 



   Lower alkoxy is e.g. B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy or tert. -Butyloxy, also n-pentyloxy or neopentyloxy. 



   Halogen is especially chlorine or bromine, but can also be fluorine and iodine. 



   Lower alkoxycarbonyl is e.g. B.  Methoxycarbonyl or ethoxycarbonyl, while N-lower alkyl and N, N-di-lower alkyl-carbamoyl, e.g. B.  Is N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-Nmethyl-carbamoyl or N, N-diethylcarbamoyl. 



   Lower alkoxy-lower alkyl is e.g. B.  Methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, I-methoxy-2-propyl, l-ethoxy-2-propyl or l-ethoxy-2-butyl, where lower alkoxy is preferably from the linking carbon atom of the lower alkyl part by at least 2, usually 2- 3 carbon atoms is separated.   



   Phenyloxy lower alkyl is e.g. B.  Phenyloxymethyl or esp



  special 2-phenyloxyethyl, with phenyl in such residues z. B.  how an aromatic radical in an araliphatic group R1 can be substituted. 



   Halogen lower alkyl is e.g. B.  Fluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl or 2-bromoethyl. 



   Carboxy lower alkyl is e.g. B.  Carboxymethyl, 2-carboxy ethyl or l-carboxy-2-propyl, while Niederalkoxycarbonylniederalkyl z. B.  Methoxycarbonylmethyl, 2-methoxycarbonylethyl, I-methoxycarbonyl-2-propyl, I-ethoxycarbonyl-2-butyl, 1-ethoxycarbonyl-3-butyl, 2-ethoxycarbonyl ethyl or 1-ethoxycarbonyl-2-propyl. 



   Optionally N-substituted carbamoyl-lower alkyl is e.g. B.  Carbamoylmethyl, carbamoylethyl, l-carbamoyl-2propyl, N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-N-methylcarbamoylmethyl, 2-N-ethylcarbamoyl-ethyl, 2-N-methylamamoyl 2-propyl or IN, N-dimethylcarbamoyl-2-propyl.    



   Cyan lower alkyl means e.g. B.  Cyanomethyl, 1- or 2-cyanoethyl, 3-cyanopropyl and 1-cyano-2-propyl. 



   Acyl radicals Rl correspond to the formula -C (= O) -R, in which R denotes an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical, such as optionally substituted lower alkyl, furthermore lower alkenyl or lower alkynyl, optionally substituted mono- or polycyclic cycloalkyl, optionally substituted phenyl or phenyl-lower alkyl, and phenyl-lower alkenyl or phenyl-lower alkynyl. 



  Substituents of lower alkyl and lower alkenyl or lower alkynyl are e.g. B.  optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and / or halogen, such as cycloalkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkenyl and phenyl-lower alkynyl optionally, for. B.  by halogen, substituted lower alkyl, such as lower alkyl or trifluoromethyl, optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy or halogen, and / or functionally modified carboxy, such as esterified carboxy, such as. B.  Lower alkoxycarbonyl, amidated carboxy, e.g. B.  Carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, or cyan, wherein substituted radicals can have one or more substituents in any of the positions suitable for substitution. 



   Monocyclic cycloalkyl is e.g. B.  Cyclopropyl, cyclopentyl or cyclohexyl, while polycyclic cycloalkyl z. B.    Bicyclo [2,2,1] heptyl (norbornyl), bicyclo [2,2,2] octyl or adamantyl such as l-adamantyl. 



   Salts of compounds of formula I are acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts with suitable inorganic acids, e.g. B.  Hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, e.g. B.  Formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, acetic acid, 4-hydroxybenzoic acid, sulfonic acid, emulsonic acid, sulfonic acid, emulsonic acid, sulfonic acid, emulsonic acid, emulsonic acid, sulfonic acid, emulsonic acid, sulfonic acid, sulfonic acid, emulsonic acid, sulfonic acid, emulsonic acid, Chlorobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid. 

  As a result of the close relationships between the new compounds in free form and in the form of their salts, the corresponding salts or  understand free connections. 



   The compounds of the present invention can be in the form of mixtures of isomers, e.g. B.  of mixtures of compounds of the cis and trans configuration, or of uniform isomers, e.g. B.  the cis or trans configuration, furthermore in the form of racemates or optical antipodes. 



   The new compounds of general formula I have valuable pharmacological properties; in particular, they have antidepressant effects, which can be demonstrated on the basis of corresponding pharmacological tests.  So these substances cause an inhibition of noradrenaline uptake such. B.  by inhibiting the emptying of norepinephrine in the rat brain caused by 3-hydroxy-4-methyl-a-methyl-phen ethylamine [A.  Carlsson, H.  Corrodi, K.  Fuxe and T.  Hoekfelt: Europ.  J.  Pharmacol.  5, 367 (1969) 1 after oral administration of 100 mg / kg.  They also potentiate serotoninergic effects, which can be demonstrated by potentiating the head tremor induced by 5-hydroxytryptophan on the mouse after intraperitoneal administration of 3 to 100 mg / kg. 

  In particular, these substances have an inhibition of serotonin uptake, as can be seen by inhibiting the emptying of serotonin caused by 2-hydroxy-4-methyl-a-ethyl-phenethylamine [A.  Carlsson et al. : Europ.  J.  Pharmacol.  5, 357 (1969)] in the rat brain after oral administration of doses of 3 to 10 mg / kg. 



   These pharmacological properties characterize the new compounds and their pharmaceutically acceptable acid addition salts as antidepressants, which can be used in the form of pharmaceutical preparations for the treatment of various types of depression. 



   The invention relates in particular to compounds of the formula I in which X is the oxo radical or hydrogen and the radical ORI, in which R1 is hydrogen, lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-lower alkylcarbamoyl-lower alkyl, N, N-di-lower-alkyl-carbamoyl-lower alkyl or cyan-lower alkyl, and also phenyl or phenyl-lower alkyl or phenyloxy-lower alkyl which is optionally branched on the a-carbon atom, phenyl in each case optionally being substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N-di-lower alkylcarbamoyl or cyano and in which R can also be acyl where acyl represents the group -C (= O) -R, where R is lower alkyl,

   Lower alkoxy-lower alkyl or halogen-lower alkyl, furthermore phenyl or phenyl-lower alkyl, where phenyl can in each case be substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, R2 is hydrogen, lower alkyl or propargyl, Y has the above meaning and Ar is phenyl, naphthyl, tetrahydronaphthyl or anthryl Is in which each phenyl or an aromatic ring of naphthyl or anthryl may optionally be substituted by lower alkyl, hydroxy, lower alkoxy, halogen, trifluoromethyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, nitro or cyano, where these substituents are each 1, 2 or 3 times present and can either be identical or different from one another, and m, n2 and nl + n2 have the above meaning, and their acid addition salts,

   especially pharmaceutically acceptable acid addition salts. 



   The invention relates in particular to compounds of the formula I in which X is the oxo radical or hydrogen and the radical ORI, in which R1 is hydrogen or lower alkyl having up to 4 carbon atoms, and optionally N-lower alkyl- or N, N-di-lower-alkyl-substituted carbamoyl-lower alkyl , e.g. B.  Carbamoylmethyl, I-carbamoyl-2-propyl, 1-N-methylcarbamoyl-2-propyl or 1 -N, N-dimethylcarbamoyl-2-propyl, or cyano-lower alkyl, e.g. B. 

  Cyanomethyl or l-cyan-2-propyl, furthermore preferably branched phenyl-lower alkyl in the lower alkyl part, e.g. B.    l-methyl-2-phenyl-ethyl or 1-methyl-3-phenyl-propyl, carbamoylphenyl-lower alkyl or carbamoylphenyloxy-lower alkyl, e.g. B.  2- (2-or 4-carbamoylphenyl) ethyl or 2- (2- or 4-carbamoylphenyloxy) ethyl, or acyl, where acyl represents the group -C (= O) -R, where R is lower alkyl, e.g. . B. 

  Methyl or ethyl, lower alkoxy-lower alkyl or halogen-lower alkyl, each with up to 4 C atoms in the lower alkyl parts, is also phenyl or phenyl-lower alkyl, where phenyl can be substituted by lower alkyl or lower alkoxy, each with up to 4 C atoms in the lower alkyl part, halogen and / or trifluoromethyl , R2 is hydrogen or lower alkyl having up to 4 carbon atoms or propargyl, and in which Y has the above meaning and Ar is phenyl, naphthyl or tetrahydronaphthyl, phenyl, naphthyl or the aromatic ring of tetrahydronaphthyl optionally by lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl , N-lower alkyl carbamoyl or N, N-di-lower alkyl carbamoyl is substituted, with lower alkyl each having up to 4 carbon atoms, or being substituted by halogen, trifluoromethyl, carbamoyl, nitro or cyano,

   where these substituents are each 1- or 2-fold and can either be the same or different, and nl, n2 and nl + n2 have the above meaning, and their acid addition salts, in particular pharmaceutically acceptable acid addition salts.  The invention relates above all to compounds of the formula I in which X denotes the oxo radical or hydrogen and the radical ORx, in which R1 is hydrogen, lower alkyl, e.g. B. 



  Methyl, cyano-lower alkyl, e.g. B.  Cyanomethyl, or carbamoyl-lower alkyl, each with up to 4 carbon atoms in the lower alkyl part, e.g. B.  Carbamoylmethyl, further phenyl, which is optionally substituted in the manner indicated below for Ar, or acyl, wherein acyl stands for the group -C (= O) -R, where R is lower alkyl with up to 4 C atoms, e.g. B. 



  Methyl or ethyl, R2 means hydrogen or lower alkyl having up to 4 carbon atoms, e.g. B.  Methyl, ethyl or isopropyl, furthermore propargyl, and Ar means phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, which may be by lower alkyl, lower alkoxy, each having up to 4 carbon atoms, halogen, trifluoromethyl, carbamoyl, nitro or cyan are substituted at most twice, the substituents mentioned being aromatically bonded and in each case once or in the case of lower alkyl, lower alkoxy and halogen also twice and may be identical or different from one another, Y, nl, n2 and nl + n2 are as defined above, but preferably Y. Oxygen and nl + n2 together mean 3, and their acid addition salts, in particular pharmaceutically acceptable acid addition salts. 



   The invention relates primarily to compounds of the formula I in which X is the oxo radical or hydrogen and the radical ORI, in which R1 is hydrogen or lower alkyl, in particular methyl, R2 is hydrogen or lower alkyl, in particular methyl or propargyl, and Ar phenyl, naphthyl or 5,6,7,8-tetrahydro-naphthyl, where phenyl can preferably be substituted at most twice by lower alkyl, in particular methyl, lower alkoxy, in particular methoxy, or halogen, in particular chlorine, fluorine or bromine at most twice, or by trifluoromethyl, where the substituents mentioned can be identical or different from one another, and Y, nl, n and nl + n2 have the meaning given above,

   However, preferably oxygen, nl and n together means 3, and nl especially 1 and n2 2, and their acid addition salts, in particular pharmaceutically acceptable acid addition salts. 



   The invention relates in particular to the compounds of the formula I mentioned below: trans-3-hydroxy-4- (1-naphthyloxy) pyrrolidine, trans-3-hydroxy-4- (3,4-dimethylphenoxy) pyrwlidine, trans-3-hydroxy-4-phenylthio-pyrrolidine, trans-3-hydroxy-4- (1-naphthyloxy) piperidine, trans-3-hydroxy-4- (1-naphthyloxy) - 1-methyl-piperidine, trans- 3-hydroxy-4-phenylthio-piperidine, trans-3-hydroxy-4-phenylthio-1-methylpiperidine, trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine, trans-3- Hydroxy-4- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine, trans-4-hydroxy-3- (3, 4-dimethyl-phenoxy) -piperidine, trans-4-hydroxy-3 - (3rd , 4-dimethyl-phenoxy) -1-methyl-piperidine, trans-3-hydroxy-4- (m-chlorophenoxy) -piperidine, trans-3-methoxy-4- (3, 4-dimethyl-phenoxy) -piperidine,

   trans-3-methoxy-4- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine, trans-3-acetyloxy-4- (3,4-dimethyl-phenoxy) -piperidine, trans-3-acetyloxy- 4- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine, trans-3-hydroxy-4- (3, 4-dimethyl-phenoxy) -piperidine, trans-3-hydroxy-4- (2,3 -dimethyl-phenoxy) -piperidine, trans-3-hydroxy-4- (2,3-dimethyl-phenoxy) - 1 -methyl-piperidine, trans-3-methoxy-4- (2,3-dimethyl-phenoxy) - piperidine, trans-3-methoxy-4- (2,3-dimethyl-phenoxy) -1-methyl-piperidine, trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) - piperidine, trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) - I-methyl-piperidine, trans-3-hydroxy-4- (p-fluorophenoxy) piperidine,

   trans-3-hydroxy-4- (p-fluorophenoxy) -1-methyl-piperidine, trans-3-hydroxy-4- (2-bromo-4-methoxy-phenoxy) piperidine, trans-3-hydroxy- 4- (2-bromo-4-methoxy-phenoxy) -1-methylpiperidine, trans-3-hydroxy-4- (p-trifluoromethyl-phenoxy) -piperidine, trans-3-hydroxy-4- (p-trifluoromethyl-phenoxy ) - 1-methylpiperidine, trans-4-hydroxy-5- (3, 4-dimethyl-phenoxy) -hexahydro-1 hazepine, trans-4-hydroxy-S- (3,4-dimethyl-phenoxy) -hexahydro-1 methyl H-azepine, trans-4-hydroxy-5- (p-trifluoromethylphenoxy) hexahydro-I-1H-azepine, trans-4-hydroxy-5- (p-trifluoromethylphenoxy) hexahydro-1-methyl 1 H-azepine, cis-3-hydroxy-4- (3, 4-dimethylphenoxy) piperidine,

   cis-3-hydroxy-4- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine, cis-3-methoxy-4- (3, 4-dimethyl-phenoxy) -piperidine, cis-3-methoxy- 4- (3,4-dimethyl-phenoxy) -1-methyl-1-pipidine, cis-3-hydroxy-4- (2,3-dimethyl-phenoxy) -piperidine, cis-3-hydroxy-4- (2,3-dimethyl-phenoxy) -1-methyl-pipidine, cis-3-methoxy-4- (2,3-dimethyl-phenoxy) -piperidine, cis-3-methoxy-4- (2,3 -dimethyl-phenoxy) -1-methyl-piperidine,

   cis-3-Hydroxy-4- (m-chlorophenoxy) piperidine, cis3-Hydroxy4- (m-chloro-phenoxy) -l-methyl-piperidine, cis-3-Hydroxy-4- (l -naphthyloxy) -piperidine, cis-3-hydroxy-4- (1-naphthyloxy) - 1 -methyl-piperidine, cis-3-hydroxy-4- (5,6,7,8-tetrahydro-1 -naphthyloxy) -piperidine, cis -3-hydroxy-4- (5,6,7,8-tetrahydro-l-naphthyloxy) 1-methyl-piperidine, cis-3-hydroxy-4- (p-fluorophenoxy) piperidine, cis-3- Hydroxy-4- (p-fluorophenoxy) -1-methyl-piperidine, 4- (3,4-dimethyl-phenoxy) -3-piperidone, 4- (2,3-dimethyl-phenoxy) -3-piperidone, 4- (m-chlorophenoxy) -3-piperidone, 4- (1-naphthyloxy) -3-piperidone, 4- (5,6,7,8-tetrahydro-1-naphthyloxy) -3-piperidone,

   4- (p-fluoro-phenoxy) -3-piperidone, 3- (3,4-dimethyl-phenoxy) -4-piperidone, and their acid addition salts, especially pharmaceutically acceptable acid addition salts. 



   The new compounds of formula I can be prepared in a manner known per se. 



   So you get this z. B. by using a compound of formula
EMI5. 1
 wherein Xl and X2 together represent epoxy and X3 are hydrogen, or Xl is free or reactive esterified hydroxy, X2 is the group -ORx or reactive esterified hydroxy and X3 is hydrogen or X2 and X3 are together the oxo radical and R2 is always as defined under formula I. , with a compound of the formula Ar-YH (III) in which Ar and Y have the above meaning, or a salt thereof.  Salts of the starting material of formula III are primarily metal, especially alkali metal, e.g. B. 



  Sodium or potassium salts. 



   A reactive esterified hydroxy group Xl and optionally Xi is a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, bromic or hydroiodic acid, or sulfuric acid, or a strong organic sulfonic acid, e.g. B.  Methanesulfonic acid, 4-methylbenzenesulfonic acid or 4-bromobenzenesulfonic acid, esterified hydroxy group, and primarily represents halogen, e.g. B.  Chlorine, bromine or iodine, or aliphatic or aromatic substituted sulfonyloxy, e.g. B.  Methylsulfonyloxy or 4-methylphenylsulfonyloxy. 



   The reaction using starting materials in which Xl and optionally Xi are reactive esterified hydroxy or X and Xi together are epoxy is carried out in a manner known per se, advantageously in the presence of a basic agent, such as an inorganic base, for. B.  an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic base such as an alkali metal lower alkanolate, and / or an excess of the basic reactant, usually in the presence of a solvent or solvent mixture and, if necessary, with cooling or heating, e.g. B. 

   in a temperature range from about -20 "to about + 150, preferably from room temperature to about 100, in an open or closed vessel and / or in an inert gas atmosphere, e.g. B.  in a nitrogen atmosphere. 



   Suitable inert solvents are, for example, hydrocarbons such as benzene, ethereal liquids such as tetrahydrofuran, dioxane or di-lower alkyl ether of ethylene glycol or diethylene glycol, e.g. B.  Diethylene glycol dimethyl ether, furthermore lower alkanones, such as acetone or methyl ethyl ketone, furthermore carboxamides such as N, N-dimethylformamide, furthermore carboxylic acid nitriles such as acetonitrile, furthermore phosphoric acid amides such as hexamethylphosphoric acid triamide, furthermore tetramethylurea, sulfolane or lower alkanols such as methanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol or ethanol, ethanol, like ethanol sec or tert. -Butanol, or mixtures of such solvents.  If a compound of formula III is not used as a salt, a suitable condensing agent, such as inorganic or organic bases or mixtures thereof, is used in the reaction. 

  Inorganic bases are e.g. B.  the carbonates, hydroxides or oxides of alkali or alkaline earth and earth metals, e.g. B.  Lithium, sodium, potassium or calcium carbonate, lithium, sodium or potassium hydroxide or magnesium or calcium oxide, also amines, preferably tertiary amines such as tri-lower alkylamines, e.g. B.  Triethylamine, ethyldiisopropylamine or tris- (2-hydroxy-1-propyl) amine, I-lower alkylpiperidines, e.g. B.    I-ethyl piperidine, also alkali metal alkanolates such as alkali metal alkanolates, e.g. B.  Sodium methylate or ethylate or tert. -butanolate, potassium methylate or ethylate or potassium tert. -butanolate. 



   If a compound of the formula II in which Xl is free hydroxy, X2 is the group ORI and X3 is hydrogen and R2, nl, ni and nl + ni have the meaning given under the formulas, but R2 is preferably different from hydrogen, with a compound of the formula III, such as phenol, p-cresol, m-cresol, 3,4-dimethylphenol, p-methoxyphenol, p-chlorophenol, m-chlorophenol, p-fluorophenol, p-nitrophenol, or 2-naphthol, are used as a condensing agent triphenylphosphine in the presence of an azodicarboxylic acid ester, such as an azodicarboxylic acid lower alkyl ester, e.g. B.  

  Azodicarboxylic acid diethyl ester.  The reaction is carried out in a solvent, for example a lower alkanol, such as ethanol, under anhydrous conditions and expediently under a protective gas, for example nitrogen, the reaction temperature being kept in a range from -20 "to +50. 



   The starting materials required for this process variant can be prepared in a manner known per se, those of the formula II z. B.  by treating a compound of the formula
EMI5. 2nd
 wherein X8 is an optionally substituted aliphatic hydrocarbon residue or by reaction with an acyl halide, e.g. B.  Chloroformic acid 2,2,2-trichloroethyl or benzyl ester, obtained cleavable group means, with an oxidizing agent, such as a peroxide, e.g. B.  Hydrogen peroxide.  It is convenient to work in a solvent such. B.  in such an inert character, e.g. B.  a halogenated hydrocarbon such as methylene chloride.  Advantageously, one works in the presence of a further agent promoting oxidation, e.g. B. 



  a suitable acid anhydride, such as trifluoroacetic anhydride, and in a temperature range from about -10 "to +50.     This gives an epoxide corresponding to formula II, in which Xl and X2 together mean epoxy, which, if desired, by reaction with an acid corresponding to the meaning of Xl, such as hydrogen chloride, or a sulfonic acid, such as p-toluenesulfonic acid, or a carboxylic acid, such as an alkane carboxylic acid , for example acetic acid, or an aryl carboxylic acid, such as benzoic acid, optionally in a solvent, for example dioxane, is converted into a compound of the formula II, in which X1 on the one hand is an acid radical of the type mentioned and X2 is hydroxy,

   or on the other hand Xl is hydroxy and X2 is -ORI, where Rl is acyl. 



   If an N-acyl derivative of a compound of the formula II is obtained in accordance with the meaning of X8, this is by deacylation, for example by solvolysis, for. B.  by hydrolysis using acidic or alkaline compounds, converted into a compound of the formula II in which R2 is hydrogen.  The starting materials of the formula II can preferably be formed in a trans configuration. 



   Starting materials of formula II, wherein Xl and X2 are hydroxy, can be used in a conventional manner, e.g. B.  by oxidation of a compound of formula IIa using a permanganate, e.g. B.  Potassium permanganate in buffered aqueous solution in a suitable temperature range, e.g. B.  at low temperatures, for example at -40, and subsequent elimination of the radical X4, for example by means of hydrolysis in an acidic medium.  The starting materials can preferably be obtained in the cis configuration.  If the oxidation is carried out in a known manner with a peroxide in an acidic solution, for example in the presence of a carboxylic acid, for example formic acid, the carboxylic acid advantageously being used as the peracid, for. B. 

  Per-formic acid can be used, a starting material of the formula II, in which Xi and X2 are hydroxyl, can preferably be obtained in the trans configuration. 



   Starting materials of formula II, wherein Xi is reactive esterified hydroxy and X2 is the group -ORI, where Rl is acyl, are obtained in a conventional manner, for. B. 



  by reacting a compound of formula II with a carboxylic acid, such as a lower alkane carboxylic acid such as acetic acid, propionic acid, n-butyric acid, chloroacetic acid, dichloroacetic acid, or an aryl carboxylic acid, such as benzoic acid, or a reactive derivative thereof in the presence or absence of a solvent, for example a hydrocarbon such as benzene. 



   Other starting materials of the formula II, in which Rl denotes an optionally substituted aliphatic or araliphatic hydrocarbon radical, can be prepared in a conventional manner, e.g. B.  by reacting a compound of the formula II in which X2 corresponds to the meaning of O-Me and Me is the remainder of a metal, for example an alkali metal such as sodium or potassium, or an ammonium radical, in a solvent such as ethanol, n-butanol, benzene or Toluene, with a reactive esterified hydroxy compound derived from an optionally substituted aliphatic or araliphatic hydrocarbon. 



   Other starting materials of the formula II, in which Rl is an optionally substituted aromatic hydrocarbon radical, can be obtained by reacting a compound of the formula II in which Xi is hydroxy with a corresponding aromatic hydroxy compound, for example phenol, a substituted phenol or 2-naphthol, in the presence of triphenylphosphine and diethyl azodicarboxylate in an anhydrous solvent, such as ethanol, at temperatures from -20 to +50 under a nitrogen atmosphere. 



   Of the starting materials of the formula II, in which X1 is reactive esterified hydroxy and Xi and X3 together represent the oxo radical, individual representatives, such as l-methyl-3-bromo-4-piperidone [Chemical Abstracts 58, 12544c], the third -Brom-4-piperidone and l-ethyl-3-bromo-4-piperidone [both Chemical Abstracts 72, 100685g] are known, and the isomeric compounds l-methyl-, 1-ethyl- and l-propyl-4-bromo -3-piperidone can according to DT-OS 2205 065 by bromination of the corresponding, known l-alkyl-3-piperidones [Helv.     Chem.  Acta 37, (1954)] in glacial acetic acid. 

  Analogously, further representatives of both types of compounds and ring homologues can be obtained. 



   Other starting materials of the formula II, in which X2 is hydroxy and X3 is hydrogen and Xi has the above meaning, and which are present in cis or trans form can, for. B.  by means of stereospecific reduction of the compounds of the formula II mentioned below, in which X2 and X3 together represent the oxo radical and Xl, R2, ni, ni and nl + ni have the above meaning. 



   So z. B.  possible by reducing such an oxo compound using Raney nickel in aqueous alkalis, e.g. B.  In sodium hydroxide solution for several hours to obtain a reduction product of the formula II in which the proportion of the cis isomer is increased or even predominant, while the reduction is carried out using an amalgam, for example an alkali metal amalgam, such as 4% sodium amalgam, for example in aqueous solution, e.g. . B.  for several hours with ice cooling and stirring with subsequent addition of an inorganic base, such as sodium bicarbonate, and further stirring for several hours, provides a reduction product of the formula II in which the proportion of the trans isomer is increased or even predominates. 



   The use of organometallic hydrides of transition metals, such as that of tin, e.g. B.  Diphenyltin hydride, in a water-moist ether-like solvent, such as diethyl ether, opens up the possibility of a stereospecific reduction in the sense explained above. 



   The starting materials of the formula II described above, in which X2 denotes the group -ORI, can also be in the cis or trans configuration, for the preparation of which starting materials of the formula II, in which X2 is hydroxy, and which in the cis or trans Configuration. 

 

   In addition, starting materials of the formula II in which Rl is acyl and which are in the cis or trans configuration can be obtained by those esterification methods in which an inversion of the configuration also occurs. 



   So you can z. B.  a compound of formula II, wherein X2 is hydroxy and which is in the trans configuration, with a carboxylic acid of the formula R-COOH, e.g. B.  a lower alkane carboxylic acid, such as formic acid or acetic acid, or an aryl carboxylic acid, such as benzoic acid, in the presence of triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to give a compound of the formula II in the cis configuration. 



   The new compounds of the formula I can also be obtained by b) in a compound of the formula IV,
EMI7. 1
 in which Ar, Y, ni, ni and nl + ni have the above meaning, and in which X4 denotes an optionally ketalized oxo radical, or hydrogen and the group OX5, in which Xs has the meaning of Rl or another group which can be replaced by hydrogen, and X6 has the meaning given for Ri or a group which can be replaced by hydrogen, with the proviso that at least one of the radicals X5 and X6 is a group which can be replaced by hydrogen or the oxo radical X4 is in ketalized form, or in a salt of a compound of the formula IV , the or 



  the radicals not corresponding to the definition of formula I and, if appropriate, also an acyl radical Rl are removed or 



  optionally rearranged an acyl residue on the N atom to the O atom. 



   Salts of starting materials of the formula IV are primarily acid addition salts, in particular corresponding salts with inorganic acids, for. B.  Mineral acids, as well as with organic acids. 



   Cleavable radicals Xs and X6 are in particular acyl groups corresponding to the formula -C (= O) -R, especially lower alkanoyl, e.g. B.  Formyl, acetyl, propionyl or pivaloyl, as well as benzoyl or primarily acyl radicals of semi-derivatives, in particular semi-esters of carbonic acid, such as, if appropriate, for. B.  by etherified or esterified hydroxy, such as aryloxy, e.g. B.  optionally substituted phenyloxy, halogen, e.g. B.  Chlorine, bromine or iodine, or arylcarbonyl, e.g. B. 



  optionally substituted benzoyl, substituted lower alkoxycarbonyl, which is preferably branched in the a-position and / or substituted in the a- or ss-position, such as lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or ethoxycarbonyl, especially tert. -Lower alkoxycarbonyl, such as tert.  Butyloxycarbonyl or tert. -Pentyloxycarbonyl, a-aryloxy lower alkoxycarbonyl, e.g. B.  Bis (4-methoxyphenyloxy) methoxycarbonyl, or 2-halogeno lower alkoxycarbonyl, e.g. B. 



  2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl or the easily convertible into this 2-bromoethoxycarbonyl, or a-arylcarbonyl-lower alkoxycarbonyl, e.g. B.  Phenacyloxycarbonyl, or 4-bromophenacyloxycarbonyl, or optionally, e.g. B.  phenyl- or biphenylyl-lower alkoxyxcarbonyl substituted by lower alkyl, optionally etherified or esterified hydroxy, such as hydroxy or lower alkoxy, and / or nitro, where the aromatic radicals are preferably in the a-position and one or more optionally substituted phenyl radicals may be present, such as optionally by lower alkyl, e.g. B.  tert. -Butyl, hydroxy, lower alkoxy, e.g. B.  Methoxy, and / or nitro substituted benzyloxycarbonyl, e.g. B. 

  Benzyloxycarbonyl, 4-hydroxy-3, 5-di-tert. -butylbenzyloxycarbonyl, 4-methoxy-benzyloxy-carbonyl or 4-nitrobenzyloxycarbonyl, optionally, e.g. B.  substituted by lower alkoxy, diphenylmethoxycarbonyl, e.g. B.  Diphenylmethoxycarbonyl or 4,4 '- dimethoxy-diphenylmethoxycarbonyl, or optionally substituted biphenylylmethoxycarbonyl, e.g. B.  2- (4-biphenylyl) -2-propyloxycarbonyl.  The cyano group can also be regarded as a cleavable acyl radical Xs and especially X6.  Other cleavable residues X5 and especially X6 are acyl residues of organic sulfonic acids, primarily lower alkyl sulfonyl, e.g. B.  Methylsulfonyl, or arylsulfonyl, e.g. B.  Phenylsulfonyl or p-tolylsulfonyl. 



   Also suitable as hydrogen-replaceable radicals X5 and X6 are especially a-aryl-lower alkyl radicals, in which aryl primarily optionally, for. B.  by lower alkyl, such as tert.  Butyl, optionally etherified or esterified hydroxy, such as lower alkoxy, e.g. B.  Methoxy, or halogen, e.g. B.  Chlorine or bromine, and / or nitro-substituted phenyl, it being possible for one or more aryl radicals to be present, such as optionally substituted benzyl, and also trityl. 



   Further cleavable radicals Xs and X6 are also easily cleavable organic stannyl groups which carry substituted, in particular aliphatic hydrocarbon radicals as substituents.  Such silyl or stannyl are u. a.  Tri-lower alkylsilyl, e.g. B.  Trimethylsilyl or tert.  Butyl-dimethylsilyl, lower alkoxy-lower alkyl-halosilyl, e.g. B.  Chloro-methoxy-methyl-silyl, or tri-lower alkylstannyl, e.g. B.  Tri-n-butyl stannyl. 



   Ketalized oxo radicals X4 are preferably oxo radicals ketalized with methanol, ethanol or ethylene glycol. 



   Depending on their type, the groups Xs and X6 which can be replaced by hydrogen can be split off in various ways, preferably solvolytically or reductively, in particular hydrogenolytically.  Acyl residues, furthermore the trityl group, as well as the organic silyl or stannyl residues can generally be removed by means of solvolysis, primarily by means of hydrolysis, furthermore by means of alcoholysis or acidolysis. 



   The organic silyl and stannyl can be z. B. 



  by treating with water or an alcohol such as one
Lower alkanol, without the addition of a hydrolysis catalyst, such as an acid or a base. 



   The acyl residues of carbonic acid derivatives, u. a.  also the
Cyano group, as well as organic carboxylic acids, also the trityl group, can be hydrolysed, usually in the presence of a hydrolysis catalyst, such as a mineral acid, for. B.  Split off hydrochloric acid, hydrobromic acid or sulfuric acid and replace with hydrogen. 

  Suitable substituted benzyloxycarbonyl groups, such as 4-hydroxy-3, 5-bis-tert. -butyl-benzyloxycarbonyl, z. B.  also by treatment with an optionally water-free, weak base, such as an alkali metal salt of an organic carboxylic acid, e.g. B.  the sodium or potassium salt of 2-ethyl-pentanecarboxylic acid, with an alkali metal salt of a thiophenol, e.g. B.  the sodium salt of thio phenol, or with a suitable amine, e.g. B.    Ethylamine or cyclohexylamine, and appropriately substituted Niederal kanoyl, e.g. B.  Trifluoroacetyl, split off by hydrolysis under weakly basic conditions.  An alkali metal salt of one
Thiophenols is also suitable for cleaving an a-aryl carbonyl-lower alkoxycarbonyl group, e.g. B.  Phenacyloxycar bonyl. 

 

   Certain acyl residues X5 and X6 of semi-derivatives, especially half-esters, of carbonic acid can also be used
Acidolysis, e.g. B.  split off by treatment with a strong organic carboxylic acid such as formic acid or trifluoroacetic acid, optionally in the presence of a suitable nucleophilic compound such as anisole.  These are especially tert. -Lower alkoxycarbonyl, e.g. B.  tert. -Butyloxycar bonyl, and optionally substituted diphenylmethoxy carbonyl or biphenylylmethoxy-carbonyl, e.g. B.  Diphenyl methoxycarbonyl or 2- (4-biphenylyl) -2-propyloxycarbonyl. 



   By means of chemical reduction, i.e. H.  by treatment with a suitable metal or a suitable metal compound, cleavable radicals Xs and X6 are primarily 2-halo gene lower alkoxycarbonyl or a-arylcarbonyl-lower alkoxycarbonyl, e.g. B. 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, or phenacyloxycarbonyl.  Suitable reducing agents are primarily zinc and zinc alloys, such as zinc copper, preferably in the presence of a suitable acid, e.g. B.  optionally diluted with water acetic acid, and chromium (II) salts, e.g. B.  Chromium (II) acetate or Chromium (II) chloride.  Further residues that can be split off by chemical reduction are the acyl residues of organic sulfonic acids, e.g. B.  Lower alkylsulfonyl, such as methylsulfonyl, or arylsulfonyl, such as phenylsulfonyl or p-tolylsulfonyl. 

  Corresponding starting materials of the formula II in which X4 is not a free oxo radical are preferably used, and the cleavage is carried out in a conventional manner, for. B.  using sodium in a lower alkanol, especially butanol, or preferably using a complex hydride, e.g. B.  by means of sodium bis (2-methoxyethoxy) aluminum hydride in benzene. 



   Hydrogenolytic, i.e. H.  when treated with hydrogen in the presence of a catalyst, z. B.  a-phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, and primarily a-aryl-lower alkyl, such as benzyl.  Nickel catalysts and primarily noble metal catalysts, such as platinum or palladium catalysts, are used as catalysts, the reaction optionally being carried out under elevated pressure.  Under mild conditions, this process variant can also be used for starting materials of the formula IV with a free Oxorest X4. 



   An acyl radical X6 located on the N atom, which corresponds to the definition for Rl and should be present in the end product as Rl, can, as already mentioned, be rearranged to the O atom, if desired. H.  when the acyl radical on the N atom not corresponding to formula I is removed, acylate the hydroxyl group with the same radical at the same time.  This reaction, known as N, O-acyl migration, is carried out in a manner known per se, e.g. B.  by the action of acidic reagents such as an anhydrous inorganic acid or a derivative thereof, e.g. B.  Hydrogen chloride or thionyl chloride, in an anhydrous medium, e.g. B.  in anhydrous dioxane or when using hydrogen chloride also in an anhydrous lower alkanol, e.g. B.  Methanol. 



   The release of the oxo group X from a ketalized oxo group X4 can also be carried out in a conventional manner, e.g. B.  by acidic hydrolysis, e.g. B.  by means of dilute hydrochloric acid, or by solvolysis, e.g. B.  Cooking in acetone in the presence of a small amount of benzenesulfonic acid or p-toluenesulfonic acid. 



   The above reactions are carried out in a manner known per se, usually in the presence of a solvent or solvent mixture, suitable reactants also being able to function as such at the same time and, if necessary, with cooling or heating, e.g. B.  in a temperature range from about 200 to about + 1500, in an open or closed vessel and / or in the atmosphere of an inert gas, e.g. B.  Nitrogen. 



   In the event that Xs is an acyl radical corresponding to the meaning of R1, which is to be retained in the desired compound of the formula I, the process conditions for removing a radical which corresponds to the meaning of X6 are selected such that the acyl group Ri is not attacked . 



   The starting materials of the general formula IV can in turn be prepared by various processes known per se.  For example, they can be obtained analogously to process a) above, by replacing the starting material of the formula II with one of the formula
EMI8. 1
 used, wherein nl, ni and nl + ni those under formula 1, Xl those under formula II, X6 those under formula IV and X2a and X33 those under formula II for Xi and  X3 have the meaning given or together can also mean a ketalized oxo radical. 



   Furthermore, starting materials of the general formula IV in which X4 is an oxo radical can also be prepared by oxidation of corresponding compounds in which X4 is hydrogen and the hydroxyl group.  The oxidation can be carried out, for example, using the Pfitzner and Moffat method, cf.  J.  Amer.  Chem.  Soc.  85, 3027 (1963) and us 87, 5661-70 and 5670-78, especially 5675 (1965), using dimethyl sulfoxide and dicyclohexylcarbodiimide, e.g. B.  in the presence of pyridine and trifluoroacetic acid, further using the method of Albright and Goldman, J.  Amer.  Chem.    Soc.  89, 2416 (1967) using dimethyl sulfoxide and acetic anhydride, according to the method of Corey and Kim, J.  Amer. 

  Chem.    Soc.  94,7586 (1972) using N-chlorosuccinimide and dimethyl sulfoxide, or by the Oppenauer method by reaction with aluminum tri-tert. -butoxide in the presence of an excess on a ketone, such as acetone or cyclohexanone. 



   Conversely, starting materials of the general formula IV in which X4 is hydrogen and the hydroxyl group can also be prepared by reducing corresponding compounds in which X4 is the oxo radical.  As a reduction process come the usual, e.g. B.  those mentioned in connection with the production of corresponding starting materials of the formula II.  Of particular interest is the preparation of starting materials of the formula IV with the cis configuration of the hydroxyl group located in X4 and the radical Ar-Y by stereoselective reduction of oxo compounds falling under the formula IV, which, for example, previously occur by oxidation of corresponding trans-hydroxy compounds the above methods were obtained. 



   The reduction can e.g. B.  with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum, palladium black or copper chromite, using a suitable solvent, such as a lower alkanol, such as. B.  Ethanol or isopropanol used, and hydrogenated at normal, but especially under increased hydrogen pressure.  As a reducing agent can also be a metal alkanolate, such as a Erdmetallalkanolat, such as, for example, using the Meerwein-Ponndorf-Verley method. B.  Aluminum isopropylate, in the presence of the corresponding alcohol, are used, which is also used as a solvent.  Also alkali metals, e.g. B.  Sodium metal in a lower alkanol, such as ethanol, or an amalgam, e.g. B.  Sodium amalgam, in water or aqueous lower alkanols are suitable as reducing agents. 

 

   The reduction can also be carried out using Raney nickel in aqueous or aqueous alkaline solution.  Such process conditions make it possible to carry out a stereospecific reduction by increasing or even outweighing the proportion of one or the other isomer in the final reduction product obtained, which is a mixture of the cis and trans isomers.   



   So it is z. B.  possible by reducing a compound of formula IV using Raney nickel in aqueous alkalis, e.g. B.  In. Sodium hydroxide solution, preferably for several hours, to obtain a reduction end product in which the proportion of the cis isomer is increased or even predominates, during the reduction by means of an amalgam, for example an alkali metal amalgam, such as 4% sodium amalgam, for example in aqueous solution. e.g. B.  over several hours with ice cooling and stirring with subsequent addition of an inorganic base, such as sodium bicarbonate and further stirring for several hours, provides a reduction end product in which the proportion of the trans isomer is increased or even predominates. 



   The use of organometallic hybrids of transition metals, such as that of tin, e.g. B.  Diphenyltin hydride, in a water-moist ether-like solvent, such as diethyl ether, opens up the possibility of a stereospecific reduction in the sense explained above. 



   But above all, are suitable as reducing agent complexes hydrides, for. B.  Alkali metal borohydrides such as sodium borohydride, hydrogen bromide compounds such as diborane, or alkali metal aluminum hydrides such as lithium aluminum hydride, and in particular alkali metal tri-lower alkyl borohydrides and related boron compounds such as potassium tris (sec. butyl) borohydride or    Lithium tris (triamylsilyl) borohydride, which is ether-like in an inert solvent, such as dioxane, diethyl ether or, in particular, tetrahydrofuran, or, if sodium borohydride is used, also in an anhydrous alkanol or its mixture with tetrahydrofuran, or in aqueous-lower alkanol solution can be used. 

  While already with the reduction with potassium borohydride the ratio of the resulting cis compound to the trans compound is approx.  2 to I, the reduction with potassium tris (sec-butyl) borohydride (K-selectride) in tetrahydrofuran is carried out in a temperature range from -78 to approx.    +40 practically only get the corresponding cis compound. 



   Further starting materials of the formula IV can be obtained by using an N-acylpyrroline [see reports of the German chem.  Society 22.2512 (1889); Chem.  Pharm. 



  Bull , (12), 2478 (1970)], or an N-acyl-tetrahydropyridine [J.  Pharm.  and Pharmacol.  14, (1962)] of the general formula X with an oxidizing agent, such as a peroxide compound, e.g. B.  oxidized with hydrogen peroxide in methylene chloride in the presence of trifluoroacetic anhydride to give the corresponding 3,4-epoxy compound and the latter is reacted with a compound of the formula III. 



   The compounds of formula 1 in which X is hydrogen and an ORI group, with the exception of the acyloxy groups and R2 is an optionally substituted primary aliphatic hydrocarbon radical, and Ar, Y, Rl, ni, ni and ni + n have the above meanings can also be obtained by c) in a compound of formula
EMI9. 1
 wherein Rf is hydrogen, lower alkoxy or an optionally substituted aliphatic hydrocarbon radical and Ri, Ar, Y, ni, ni and ni + ni have the meaning given under the formula I, the carbonyl group or 

  Alkoxycarbonyl group reduced. 



   Possible reducing agents are, for example, meal hydrides, such as diisobutyl aluminum hydride, or complex metal hydrides, such as lithium aluminum hydride, or hydrogen boron compounds, especially diborane.  Inert solvents, e.g. B.  ether-like character such as diethyl ether, di-n-butyl ether, tetrahydrofuran or dioxane are used, working in a temperature range from 200 to + 100, in an open or, if necessary, closed vessel and under a protective gas such as nitrogen.  In the reduction, an acyl group Rt which may be present is replaced by hydrogen. 



   Starting materials of the formula V can be obtained analogously to the methods given for the starting materials of the formula IV and are partly identical to these.  For example, a compound of formula Va
EMI9. 2nd
 with an oxidizing agent, such as a peroxide compound, e.g. B.  Oxidize with hydrogen peroxide, in methylene chloride in the presence of trifluoroacetic anhydride to the corresponding 3, SEpoxide compound and then react the latter analogously to process a) with a compound of the formula III. 



   Furthermore, starting materials of the formula V can also be prepared from end products of the formula I in which R 2 is hydrogen by means of customary acylation methods, it being possible to ensure that an optionally present hydroxyl group ORI can be obtained either by choosing the acylating agent, its amount and the reaction conditions is not acylated, or accept its acylation and then remove the O-acyl group by mild hydrolysis or, as already mentioned, split off in the course of the reduction. 

  The lower alkyl esters, such as the methyl esters and ethyl esters of the carboxylic acids corresponding to the radicals R 1, are particularly suitable for selective N-acylation, but other carboxylic acid derivatives customary as acylating agents, such as anhydrides, halides and mixed anhydrides, e.g. B.  with carbonic acid mono lower alkyl esters. 

 

   Furthermore, starting materials of the formula V can be obtained by isomerizing compounds of the formula I in which R 1 is acyl and R 2 is hydrogen.  This isomerization known as O, N-acyl migration is carried out in a manner known per se, for example.  by the action of alkaline reagents, such as an alkali hydroxide, alkali carbonate or alkali bicarbonate, such as sodium hydroxide, potassium carbonate or sodium bicarbonate, or an amine, such as ammonia or benzylamine, in a lower alkanol, such as methanol, or in water, with a temperature range of about + 100 to + 1000, advantageously with stirring, works.  This isomerization can also be carried out in an anhydrous solvent, such as benzene or toluene, at an elevated temperature.   



   Compounds of the formula I according to the invention can be converted into other compounds of the formula I in a manner known per se. 



   Thus, the new compounds of the formula I in which X is hydrogen and a hydroxy group ORI which is etherified by definition and / or R is different from hydrogen, while Ar, Y, ni, ni and ni + ni have the meaning given under formula I, obtained by converting the hydroxy group into the ether group corresponding to the definition of Rt and / or the hydrogen atom R2 by an optionally substituted aliphatic in a compound of the formula I in which the hydroxyl group and / or R is hydrogen as ORl Hydrocarbon residue replaced. 

  Z. B.  To introduce such a radical, a pure compound of the formula I in which R is hydrogen is reacted with a compound of the formula R2d-X, (VI) in which R2d is an optionally substituted aliphatic hydrocarbon radical and X7 is reactive esterified hydroxy.  As reactive esterified hydroxy groups X7 come e.g. B.  the groups mentioned above for XI into consideration. 



   The reaction can be carried out in the presence or absence of an inert organic solvent. 



  Suitable inert solvents are, for example, hydrocarbons, such as benzene, ether-like liquids, such as tetrahydrofuran, or di-lower alkyl ethers of ethylene glycol or diethylene glycol, e.g. B.  Diethylene glycol dimethyl ether, further lower alkanones such as acetone or methyl ethyl ketone, further carboxylic acid amides such as N, N-dimethylformamide, further carbonic acid nitriles such as acetonitrile, further phosphoric acid amides such as hexamethylphosphoric acid triamide, further tetramethyl urea, sulfolane or lower alkanols such as methanol or ethanol such as methanol or ethanol.  Basic condensing agents, such as inorganic or organic bases or mixtures thereof, are used in the reaction.  Inorganic bases are e.g. B.  the carbo nate hydroxides or oxides of alkali or alkaline earth metal as well as earth metals, e.g. B. 

  Calcium carbonate, sodium hydroxide or magnesium or calcium oxide, also amines, preferably tertiary amines such as tri-lower alkylamines z. B.  Triethylamine, ethyldiisopropylamine or tris (2-hydroxy-1-propyl) amine, 1-lower alkylpiperidines e.g. B.    1-ethylpiperidine, also alkali metal amides such as lithium amide, sodium or potassium amide, metal alkanolates such as alkali metal alkanolates, e.g. B.  Sodium methylate or ethylate or tert. -butanolate, potassium methylate or ethylate or potassium tert. -butanolate, also metal hydrides, such as alkali, alkaline earth or earth metal hydrides, e.g. B.  Sodium hydride, potassium hydride, lithium hydride, calcium hydride or aluminum hydride, furthermore organometallic compounds such as alkyl or aryllithium compounds, e.g. B.  Methyl, butyl or phenyllithium. 

  If an organometallic compound of the type mentioned is used, the corresponding N-metal compound can be formed in situ, one of the hydrocarbons mentioned advantageously being used as the inert solvent.  These reactions are carried out in a temperature range of e.g. B.    -20 "to + 180, optionally under a protective gas such as nitrogen.  As compounds of the formula VI, dialkyl sulfate, e.g. B. 

  Dimethyl sulfate or diethyl sulfate can be used, z. B.  in solutions of aqueous alkalis in a temperature range of approx.  + 10 to + 100 works; optionally the reaction is carried out in non-aqueous media, e.g. B.  in a lower alkanon or an ether of the type specified, it may be advantageous to use a condensing agent of the type specified, e.g. B.  use an alkali carbonate such as potassium carbonate or an organometallic compound such as methyl lithium; this is preferably carried out in a temperature range of approx.    + 10 - + 90.    



   Instead of a compound of the formula VI, an oxo compound of the formula R4-C (= O) -R5 (VIa) can also be used to replace a hydrogen atom R2 with an aliphatic hydrocarbon radical, where R4-C (=) - R5 is the divalent radical corresponding to the monovalent radical R2d Rest means to be used under reducing conditions. 



   As a reducing agent z. B.  Formic acid, or hydrogen in the presence of a hydrogenation catalyst such. B.  Raney nickel, platinum oxide or palladium-on-carbon, also a complex metal hydride, such as. B.  Lithium aluminum hydride, dihydro- [bis- (2-methoxy-ethoxy] sodium aluminate or tri-tert. -butyloxyaluminium hydride or sodium borohydride.  This reductive alkylation is carried out in a suitable solvent, such as a lower alkanol, e.g. B. 



  Methanol or ethanol, or an ether such as tetrahydrofuran or diethyl ether.  If formic acid is used as a reducing agent, it can also serve as a solvent.  These reactions are preferably carried out in a temperature range from + 10 to + 100. 



   To convert the hydroxygurppe ORl into an ether group corresponding to the definition of Rt in the formula I, a compound of the formula I in which Rt is hydrogen and R2 is an optionally substituted aliphatic hydrocarbon radical is used with a compound of the formula R6-Xl (VII), wherein R6 represents an optionally substituted aliphatic, araliphatic or aromatic hydrocarbon radical and Xl has the above meaning, um. 

  The reaction with compounds of formula VII, wherein Xl reactive esterified hydroxy and R6 is not an aromatic hydrocarbon radical, is advantageously carried out in a solvent, e.g. B.  of the type specified above, with the exception of water, in the presence of a basic condensing agent.  As such z. B.  one of the above; but is preferred a metal alkanolate, for. B.  of the specified type, especially sodium methylate or ethylate, or potassium methylate or ethylate and especially sodium tert. -butanolate and potassium tert. butanolate, also a metal hydride, especially lithium hydride, or a metal-organic compound, especially methyl lithium or phenyllithium. 

  It may be advantageous here to convert the hydroxyl group ORI first in situ into the corresponding metal compound and then to react it with the compound of the formula VII, working in an open or closed vessel and, if appropriate, under a protective gas, for example nitrogen. 



   If a compound of the formula VII in which Xl is hydroxy is used to etherify the hydroxyl group OR1, the process is carried out in a solvent, for example a halogenated hydrocarbon, such as methylene chloride, or in an ether, for example diethyl ether, in the presence of an anhydrous, strongly acid-reacting substance such as hydrogen chloride, boron fluoride or its adducts with ether, or strong anhydrous acids, e.g. B.  anhydrous phosphoric acid or fluoroboric acid, or a Lewis acid, such as antimony pentafluoride or tin tetrachloride, preferably in a temperature range from -20 "to +50, in an open, but especially in a closed, vessel.  Mixtures of the acidic substances mentioned above, optionally with the addition of further acids, for. B.  conc.  

  Sulfuric acid and / or trifluoroacetic acid can be used. 



   If the reaction is carried out with a compound of the formula VII in which R6 is an optionally substituted aromatic hydrocarbon radical and Xl is hydroxy, such as phenol, p-cresol, m-cresol, p-methoxyphenol, p-chlorophenol, p-nitrophenol or 2 -Naphthol, so is used as a condensing agent triphenylphosphine in the presence of an azodicarboxylic acid ester, such as a lower azodicarboxylic acid alkyl ester, for. B.  Azodicarboxylic acid di ethyl ester.  The reaction is carried out in a solvent, for example a lower alkanol, such as ethanol, under anhydrous conditions and expediently under a protective gas, for example nitrogen, the reaction temperature being kept in a range from -20 "to +50. 



   As compounds of the general formula VII, in which R6 is an optionally aromatic hydrocarbon radical and X is a reactive esterified hydroxyl group, in particular halogen, only those are suitable which contain at least one aromatically bound, activating substituent, such as. B.    1-chloro-2-nitrobenzene, 1-chloro-4-nitrobenzene, 1-chloro-2,4-dinitrobenzene or especially 1-chloro-3-fluorobenzene.     These can e.g. B.  with alkali metal compounds, e.g. B. 

  Sodium or lithium compounds, of compounds of general formula I, in which ORI is a hydroxy group, in an inert organic solvent, e.g. B.  the above, especially in N, N-dimethylformamide at room temperature or moderately elevated temperatures, e.g. B.  at approx  50 "-70" can be implemented. 



   The reactions described above, involving the cyclic NH group and / or the hydroxyl group ORI, can also be carried out simultaneously, provided that the same radicals are introduced in both groups. 



   The new compounds of the formula I, in which X is hydrogen and an acyloxy group ORI as defined, and R is an optionally substituted aliphatic carbon hydrogen radical, and Ar, Y, nt, nt and m + ni have the meaning given under formula I can also be used obtained by, according to e), a compound of the formula I in which the hydroxyl group is present as ORt and an optionally substituted aliphatic hydrocarbon radical is present as Ri and Ar, Y, nt, ni and nl + ni are those under
Have the meaning given for formula I, with a carboxylic acid of the formula R-CO-OH (VIII, where R is an optionally substituted aliphatic,

   means cycloaliphatic, aromatic or araliphatic hydrocarbon radical, or reacted with a reactive derivative thereof. 



   The reaction with a free acid of formula VIII can e.g. B.  by heating the reaction components with removal of water formed, such as azeotroping
Water-solvent mixtures.  Suitable solvents are e.g. B.  Butanol, benzene or xylene, where appropriate in the presence of further, preferably esterifying, acidic substances, for. B.  conc. 



  Sulfuric acid, thionyl chloride, benzenesulfonic acid, p-toluenesulfonic acid, chlorosulfonic acid, phosphoric acid or perchloric acid works. 



   Furthermore, acylation with a carboxylic acid can
Formula VIII in the presence of a condensing agent such as a carbodiimide, e.g. B.  N, N'-dicyclohexyl-carbodiimide, or a suitable carbonyl compound, such as carbonyldii midazole, take place, such reactions being carried out in an inert, anhydrous reaction medium. 



   However, a compound of the formula I defined above is preferably reacted with a reactive derivative of an acid of the formula VIII.  Such is in particular an anhydride, for example a mixed or internal anhydride of such an acid, furthermore a reactive ester, and also an organic silyl or stannyl ester, or a reactive amide of such an acid. 



   A mixed anhydride is e.g. B.  an anhydride mixed with a derivative e.g. B.  an ester containing halogen, e.g. B.  the chloroformic acid, such as a lower alkyl chloroformate, e.g. B.  -isobutyl ester, further with a hydrohalic acid, e.g. B.  Hydrochloric or hydrobromic acid, further formed with hydrochloric acid; Anhydrides with the latter are the corresponding acid halides, e.g. B.  chlorides or bromides, or  Acid azides.  Internal anhydrides are e.g. B.  the ketenes corresponding to the acid of the formula VIII or the suitable hydroxycarboxylic acids corresponding lactones. 



   Reactive esters of carboxylic acids of formula VIII are e.g. B.  Esters with lower alkanols which contain an electron-withdrawing group, such as a cyano group, in the a-position, e.g. B.  with cyanomethanol, with optionally, e.g. B. 



  by nitro or halogen, such as chlorine, substituted phenols or phenyl-lower alkanols, such as benzyl alcohols, e.g. B.    Phenol, 4-nitrophenol, 2,3,4,5,6-pentachlorophenol or 4-nitrobenzyl alcohol, or with suitable N-hydroxycarboxamides or imides, e.g. B.  N-hydroxy succinimide or N-hydroxyphthalimide.  Suitable silyl and stannyl esters are primarily tri-aliphatic substituted silyl or stannyl esters, such as tri-lower alkyl silyl or stannyl esters, e.g. B.  Trimethylsilyl or tri-n-butyl stannyl ester. 



   Reactive amides of acids of formula VIII are e.g. B.  the corresponding N-acyl compounds of aza-heterocyclic compounds, such as l-acyl-imidazolides or in the 1- and / or 5-position, if appropriate, for. B.  substituted by lower alkyl, 3-acyl hydantoins, e.g. B.  3-acyl-l, 5,5-trimethyl-hydantoin, and the corresponding N, N-di-acylamides of carboxylic acids, in particular of lower alkane carboxylic acids, for. B.  Formic acid or acetic acid. 



   The above-mentioned reactive derivatives of a carboxylic acid of the formula VIII can be used as such or under the conditions of the reaction, for. B.  from the free carboxylic acid or another derivative thereof in the presence of a suitable, the formation of the reactive derivative, e.g. B. 



  an anhydride, or a reactive ester or amide-inducing reagent. 



   The reaction of compounds of formula I by definition with carboxylic acids of formula VIII or derivatives thereof is carried out in a manner known per se, usually in the presence of a solvent, a suitable esterifying agent being able to serve as such at the same time and, if necessary, in the presence of e.g. B.  of acid-binding agents and / or catalysts, with cooling or heating, e.g. B.  in a temperature range from about -20 "to about 1500 in a closed vessel and / or in an inert gas, e.g. B.  Nitrogen atmosphere. 

 

   The reaction with symmetrical and mixed anhydrides, such as acid halides, can be carried out in the presence of agents which influence the acylation, z. B.  acid-binding agents, such as inorganic and organic bases, furthermore mixtures thereof, or acidic
Medium (e.g. B.  when using acid halides, e.g. B. 



   -chlorides), such as organic acids, which also act as
Solvents can be used.  Inorganic
Bases are e.g. B.  the carbonates, hydroxides or oxides of
Alkali or alkaline earth, as well as earth metals, e.g. B.  Calcium carbonate, sodium hydroxide or magnesium metal, further
Amines, preferably tertiary amines, such as tri-lower alkyl amines, e.g. B.  Triethylamine, ethyl-diisopropylamine, or tris (2-hydroxy-1-propyl) -amine, 1-lower alkyl-piperidine, e.g. B.    



  I-ethyl piperidine, or bases of the pyridine type, e.g. B.  Pyridine or picoline, or 4-dimethylamino-quinoline, and mixtures thereof.  Suitable organic acids are e.g. B. 



  strong organic carboxylic acids, such as strong, optionally substituted carboxylic acids, e.g. B.  Trifluoroacetic acid. 



   To increase the reaction rate and / or lower reaction temperatures, it may be advantageous to add further, preferably catalytically active and primarily acidic substances, such as inorganic acids or derivatives thereof, e.g. B.  Hydrogen chloride, sulfuric acid, phosphoric acid, thionyl chloride, perchloric acid, phosphorus oxychloride or phosphorus pentachloride, furthermore strong organic sulfonic and carboxylic acids, e.g. B. 



  Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-chlorosulfonic acid or 3-nitrobenzenesulfonic acid or trifluoroacetic acid, and also the acids of formula VIII corresponding to the anhydrides, furthermore Lewis acids, e.g. B. 



  Add antimony pentafluoride and boron trifluoride or its adducts with ethers.  In addition, the addition of an acid of the formula VIII corresponding carboxylic acid salts, such as alkali, alkaline earth or earth metal salts, further of corresponding transition metal, z. B.  Zinc, tin, antimony or lead salts, as well as optionally N-substituted ammonium salts of acids of the formula VIII have a favorable effect on the acylation. 



   Ketenes as internal anhydrides can usually be used without additional reagents, also in the presence of an acidic condensing agent, and in the presence of a suitable solvent. 



   The acylation with the aid of reactive amides of acids of the formula VIII is conveniently carried out in the presence of a condensing agent, such as a basic agent, e.g. B.  an anhydrous alkali metal or alkaline earth metal carbonate, hydroxide or oxide, or especially an alkali metal, alkaline earth metal or earth metal amide or lower alkanolate, e.g. B.  Sodium or potassium amide, or lithium, sodium or aluminum methanolate, ethanolate or in particular tert. -butanolate. 



   Reactive esters as acylating agents can in the presence of basic reagents, for. B.  the above, as well as acidic condensing agents.  The latter are u. a.  organic sulfonic acids, e.g. B. 



  p-toluenesulfonic acid, also mineral acids, e.g. B.  Phosphoric acid or an acid derived therefrom and obtainable by partial hydrolysis of phosphorus oxychloride with water. 



   Acyl compounds of the formula I in which Rt is acyl and which are in the cis or trans configuration can also be obtained by means of esterification methods which are associated with an inversion of the configuration.  So you can z. B.  from a compound of the formula I of the trans configuration by definition by esterification with a lower alkanoic acid, such as formic acid, acetic acid, propionic acid, or an arylcarboxylic acid, such as benzoic acid, in the presence of triphenylphosphine and an azodicarboxylic acid ester, such as diethyl azodicarboxylic acid, in an inert solvent, for example tetrahydrofuran receive an acyl compound of formula I of the cis configuration. 

  This is carried out in a temperature range from -20 "to +60, preferably from - 10 to +30, optionally under a protective gas, such as nitrogen. 



   The corresponding compounds of the formula I can be prepared by reacting a corresponding compound of the formula II, which may also be in the cis or trans configuration, with a compound of the formula III, as described above. 



   The new compounds of the formula I in which X is the oxo radical and R 2, Ar, Y, nt, n 2 and m + nid have the meaning given under the formula I, but Ru is preferably different from hydrogen, can also be prepared by a corresponding compound of the formula I in which X is hydrogen and the hydroxyl group and R2, Ar, Y, nl, n2 and nt + ni have the meaning given under the formula I, but R2 is preferably different from hydrogen, is oxidized.  The oxidation can be carried out, for example, by the methods mentioned for the preparation of starting materials of the formula IV, in particular by the Oppenauer method. 



   Conversely, the new compounds of the formula I in which X is hydrogen and the hydroxyl group is ORt and R 1, Ar, Y, nl, n 2 and m + nt have the meaning given under the formula I can also be prepared by g ) a corresponding compound of the formula I, in which X denotes the oxo radical, is reduced.  The methods mentioned for the preparation of corresponding starting materials of the formula IV can also be used for the reduction. 

  As with the starting materials of the formula IV, the two end products of the formula I also offer the oxidation and subsequent stereospecific reduction, e.g. B.  According to the methods given above, the reaction sequence gives the possibility of converting trans-hydroxy compounds of the formula I into cis-hydroxy compounds of the formula I in good yield. 



   In addition, substituents present in the compounds of the formula I obtained can be converted into other substituents according to the definition. 



   So you can z. B.  in compounds obtained unsaturated substituents such as lower alkenyl, e.g. B.  by treating with catalytically activated hydrogen. 



   A free carboxyl group can be used in the usual way, e.g. B. 



  by treatment with an alcohol in the presence of an acid or with a diazo compound, or  by reacting with ammonia, or with a primary or secondary amine, if necessary, in the presence of a water-binding agent such as dicyclohexylcarbodiimide, or by converting the carboxyl group into a halocarbonyl, e.g. B.  Chlorocarbonyl group, and treatment with an alcohol or a corresponding metal, e.g. B.  Alkali metal compound, or  by reacting with ammonia or with a primary or secondary amine, esterifying or 



  amidate. 



   In compounds with an esterified carboxyl group, this can be carried out in a conventional manner, e.g. B.  by hydrolysis, preferably in the presence of a suitable base or acid, e.g. B. 



  a strong mineral acid, in the free carboxyl group or z. B.  be converted into the corresponding carbamoyl group by ammonolysis or aminolysis. 



   Compounds with a carbamoyl group can in the usual manner, for. B.  by the action of dehydrating agents, such as phosphorus pentoxide or phosphorus oxychloride, preferably at higher temperatures to give the corresponding cyano compounds. 

 

   Compounds with a cyano group can be used in a conventional manner, e.g. B.  in the presence of a concentrated aqueous mineral acid, to the corresponding carbamoyl or directly to the carboxyl compounds, or z. B.  by addition of alcohols in the presence of an anhydrous acid, such as hydrogen chloride, and subsequent hydrolysis of the resulting imido ester to give the corresponding compounds having an esterified carboxyl group. 



   As with the production process, care must also be taken when carrying out the additional steps that undesired side reactions which could result in the conversion of existing groups, in particular the cleavage of an acyl group Rt, are avoided. 



   The reactions described above can optionally be carried out simultaneously or in succession, and in any order.  If necessary, they are carried out in the presence of diluents, condensing agents and / or catalytically active agents, at reduced or elevated temperature, in a closed vessel under pressure and / or in an inert gas atmosphere. 



   Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts which are also encompassed by the invention, the new compounds or salts thereof also being able to be present as hemi-, mono-, sesqui or polyhydrates thereof.  Acid addition salts of the new compounds can be prepared in a manner known per se, e.g. B.  by treatment with basic agents, such as alkali metal hydroxides, carbonates or bicarbonates or ion exchangers, into the free compounds and, in turn, if these contain acidic substituents, such as phenolic hydroxyl groups or carboxyl groups, with suitable strong basic substances into salts with bases.  On the other hand, obtained free bases with organic or inorganic acids, e.g. B.  form with the abovementioned acids, acid addition salts. 

  For the preparation of acid addition salts and salts with bases, in particular those acids and bases are used which are suitable for the formation of pharmaceutically acceptable salts. 



   These or other salts, especially acid addition salts of the new compounds, such as. B.  Picrates or perchlorates can also be used to purify the free bases obtained by converting the free bases into salts, separating and cleaning them, and releasing the bases from the salts. 



   Depending on the choice of starting materials and procedures, the new compounds can also be in the form of optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, as racemate mixtures. 



   Racemic mixtures obtained can, due to the physico-chemical differences of the diastereoisomers in a known manner, for. B.  by chromatography and / or fractional crystallization into which the two stereoisomeric (diastereomeric) racemates are separated. 



   Racemates obtained can be broken down into the antipodes by methods known per se, e.g. B.  by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, in particular acid, which forms salts with the racemic compound, and separation of the salt mixture obtained in this way, e.g. B. 



  due to different solubilities, into the diastereomeric salts, from which the free antipodes can be released by the action of suitable agents.  Particularly common, optically active acids are e.g. B.  the D and L forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.  The more effective of the two antipodes is advantageously isolated. 



   Depending on the process conditions and starting materials, the end products of the formula I are obtained as pure isomers or isomer mixtures.  Such can e.g. B.  Mixtures of compounds of the cis and trans configurations. 



   Mixtures of isomers of the above type are prepared in a conventional manner, e.g. B.  separated into the pure isomers by means of crystallization and / or chromatography methods, for example by means of a silica gel column using customary solvent mixtures as eluents.  Obtained cis isomers can be converted into trans isomers in a conventional manner, e.g. B.  by treating the solution of a cis isomer in, for example, acetic acid or methanol in the presence of catalytic amounts of heavy metal salts, for example mercury acetate, or by treating a solution of the cis isomers in a hydrocarbon, for example benzene with azo compounds, for example azodiisobutyronitrile and subsequent treatment with a solution of Iodine in a solvent e.g. B.  a hydrocarbon such as benzene or nitrobenzene. 

  Furthermore, the conversion can be effected by treating a solution of the cis compound in an acid, such as acetic acid, which contains small amounts of a strong acid, such as perchloric acid. 



   Obtained trans isomers can be converted into the cis isomers in a conventional manner, for example by irradiating a solution of the trans isomers in a hydrocarbon, such as benzene, which may contain an activator, for example diphenyl sulfide, by means of short-wave light, for example that of a high-pressure mercury lamp .  Furthermore, a compound of the formula I, in which R 1 has the above meaning, z. B.  Acyl means, by the action of a lower alkanol, such as ethanol, in the presence of an alkali salt, e.g. B.  Potassium acetate, or an alkaline earth metal salt, e.g. B.  Calcium carbonate, convert into the corresponding compound of the cis configuration. 



   Appropriately, for the implementation of the reactions, those starting materials are used which lead to the groups of end products which have been mentioned at the outset and in particular to the end products which have been specifically described or highlighted, for. B.  there may be starting materials in the cis or trans configuration. 



   The new connections can e.g. B.  find use in the form of pharmaceutical preparations which are suitable for enteral, e.g. B.  oral or rectal, or suitable for parenteral administration and contain a therapeutically effective amount of the active ingredient, optionally together with pharmaceutically acceptable excipients, where the excipients can be inorganic or organic, solid or liquid.  So you use tablets or gelatin capsules which contain the active ingredient, i.e. H.  a compound of formula I or a pharmaceutically acceptable salt thereof, together with diluents, e.g. B.  Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, e.g. B.  Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.  Tablets can also contain binders, e.g. B. 

  Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. B.  Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavors and sweeteners.  The new pharmacologically active compounds can also be used in the form of parenterally administrable preparations or infusion solutions.  Such solutions are preferably isotonic aqueous solutions or suspensions, these z. B.  in lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. B. 

 

  Mannitol, can be prepared before use. 



  The pharmaceutical preparations can be sterilized and / or auxiliary substances, e.g. B.  Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.  The present pharmaceutical preparations, which, if desired, may contain further pharmacologically active substances, are in a manner known per se, e.g. B.   



  produced by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



   The dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition.  The daily doses for oral administration are between approximately 0.5 mg / kg and approximately 50 mg / kg, for warm-blooded animals weighing approximately 70 kg, in particular between approximately 0.05 and approximately 3.0 g. 



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius. 



   example 1
4.5 g (0.015 mol) of 3-hydroxy-4-chloro-1 - (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine are dissolved in 45 ml of 90% acetic acid and, with cooling, in portions with an ice-water bath mixed with 4.5 g of zinc dust.  The mixture is stirred for one hour at room temperature, then filtered using a filter aid based on diatomaceous earth and the filtrate is evaporated to dryness in a high vacuum, the crude 3-hydroxy-4-chloro-pyrrolidine being obtained as a white residue. 



   The crude product obtained is taken up in 200 ml of acetonitrile and together with 2.85 g (0.03 mol) of phenol and 60 ml of 2-n.  Sodium hydroxide solution heated under reflux for 15 hours.  After cooling, the reaction mixture is reduced to approx.  half concentrated, then diluted with water and extracted 3 times with 100 ml of methylene chloride.  The organic phase is 3 times with l-n.  Sodium hydroxide solution and washed 3 times with aqueous sodium chloride solution, dried over sodium sulfate and evaporated in a water jet vacuum.  The oily residue is dissolved in a little chloroform and purified on a small silica gel column. 



  By eluting with a chloroform-methanol mixture (1: 1) trans-3-hydroxy-4-phenoxy-pyrrolidine is isolated, which with a solution of fumaric acid in methanol ether is a neutral fumarate of mp.  145-146 "results. 



   The 3-hydroxy-4-chloro I- (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine used as the starting material can be prepared as follows: a) 40.0 g (0.25 mol) of N-benzyl-3-pyrrolidine dissolved in 400 ml of benzene.  53.0 g (0.25 mol) of 2,2,2-trichloroethyl chloroformate are introduced into this solution at 0 and under a nitrogen atmosphere within 30 minutes.  The reaction mixture is stirred for a further 1 hour at 0, then twice at room temperature with 100 ml of a mixture of water and 2-n.  Hydrochloric acid (3: 1), then washed twice with water, dried over sodium sulfate and evaporated in a water jet vacuum. 

  The oily residue is distilled under high vacuum, the N- (ss, ss, ss-trichloro-ethoxycarbonyl) -3-pyrroline having a boiling point of 84-85 ° C./0.12 mm Hg being obtained after the removal of 24 g of benzyl chloride. 



   b) 12 ml of 90% hydrogen peroxide (0.48 mol) are dissolved in 40 ml of methylene chloride and 63.5 ml (0.45 mol) of trifluoroacetic anhydride are added at 0.  After stirring at 0 for 15 minutes, the solution becomes a suspension of 196 g of anhydrous disodium hydrogenphosphate in 800 ml of methylene chloride, which is kept at 0, in which 41.8 g (0.17 mol) of N- (ss, ss, ss-trichloroethoxycarbonyl) -3- pyrroline are dissolved, added dropwise.  The reaction mixture is then stirred at room temperature for 2 hours, then stirred into 900 ml of water and stirred for a further hour. 

  The organic phase is separated off and the aqueous phase is extracted 3 times with 200 ml of methylene chloride; the combined organic phases are washed successively with aqueous sodium chloride solution, aqueous iron (II) sulfate solution and then with water, dried over sodium sulfate and evaporated in a water jet vacuum, after which the 3,4-epoxy-l- (ss, ss, ss -trichloräthoxycarbonyl) -pyrrolidin as white crystals of mp.    52-55 receives. 



   c) 4.0 g of 3,4-epoxy-1 - (P, ss, ss-trichloroethoxycarbonyl) pyrrolidine are dissolved in 15 ml of dioxane and mixed with 50 ml of 6-n. 



  Hydrochloric acid treated.  The slightly exothermic reaction is kept at room temperature by means of a water bath, the reaction mixture is stirred for 15 hours, then diluted with water and extracted 3 times with 100 ml of methylene chloride.  The organic phase is with 01-n. 



  Sodium hydroxide solution, then washed with aqueous sodium chloride solution, dried over sodium sulfate, then evaporated to dryness in a water jet vacuum and then in a high vacuum, the 3-hydroxy-4-chloro-1 - (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine as pale yellow oil. 



   Example 2
2.6 g (0.01 mol) of the 3,4-epoxy-1 - (ss, ss, ss-trichloroethoxyearbonyl) pyrrolidine described in Example 1 together with 1.88 g (0.02 mol) of phenol and 10 ml ln.  Sodium hydroxide solution in 30 ml of acetonitrile heated under reflux for 5 hours.  After cooling, the reaction mixture is diluted with water, extracted 3 times with methylene chloride, the organic phase 2 times with 2-n. 



  Sodium hydroxide solution, then washed once with water, dried over sodium sulfate and evaporated in a water jet vacuum.  The oil obtained crystallizes from methylene chloride and hexane and provides the trans-3-hydroxy-4-phenoxy-1 - (ss, ss, ss- trichloroethoxycarbonyl) pyrrolidine of mp.    100-103.    



   1.77 g (0.005 mol) of the trans-3-hydroxy-4-phenoxy-1 - (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine obtained are dissolved in 20 ml of 90% acetic acid and at 0 in portions with 2 g Zinc dust added.  The reaction mixture is then stirred for one hour at room temperature, filtered through a layer of diatomaceous earth, the filtrate with conc.  Sodium hydroxide solution made alkaline and extracted 3 times with ether. 

  The organic phase is washed with water, dried over calcium chloride and evaporated in a water jet vacuum, giving trans-3-hydroxy-4-phenoxy-pyrrolidine as a crude base which crystallizes from methylene chloride-hexane, mp.  120-122 ".     The neutral fumarate of this compound is obtained from the mp by reaction with a solution of fumaric acid in methanol ether.  144-146 ".    



   Example 3
21.9 g (0.1 mol) of 3,4-epoxy-l-carbobenzyloxy-pyrrolidine [p.  Oida et al. , Chem.  Pharm.  Bull , 18 (12) 2478 (1970)] together with 18.8 g (0.2 mol) phenol and 100 ml 2-n.  Sodium hydroxide solution (0.2 mol) dissolved in 30 ml of acetonitrile.  The reaction mixture is heated under reflux for 5 hours, after cooling it is diluted with 600 ml of water and extracted with methylene chloride.  The organic phase is with 2-n.  Sodium hydroxide solution, then washed with water, dried over sodium sulfate and evaporated in a water jet vacuum, giving the trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine as a pale yellow oil. 

 

   28.2 g (0.09 mol) of trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine are dissolved in 280 ml of ethanol and in the presence of 3 g of a 5% palladium-on-carbon catalyst hydrogenated at normal pressure and room temperature. 



  When the uptake of hydrogen has ended, the catalyst is filtered off using diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  The residue is crystallized from methanol ether and provides the trans-3-hydroxy-4 phenoxypyrrolidine from the mp.    120-122 ".     By reacting the base with a solution of fumaric acid in methanol ether, the crystalline neutral fumarate of mp. 



     Obtained 145-146. 



   Example 4
Analogously to the procedure described in Example 3, from 3.4 g (0.023 mol) of 3,4-epoxy-l-carbo-benzyloxy-pyrrolidine and 6.25 g (0.046 mol)
4-hydroxy-benzamide after recrystallization from methylene chloride-methanol crystalline trans-3-hydroxy-4- (p-carbamoyl-phen oxy) -l-carbobenzyloxy-pyrrolidine of mp.  190-192 ".       After the hydrogenation carried out analogously to Example 3 of 0.07
After recrystallization from methylene chloride-methanol, the mol of this compound is the trans-3-hydroxy-4- (p-carbamoyl-phenoxy) pyrrolidine in the form of white crystals
M.p.    184 received.  The neutral one prepared from it
Fumarate crystallizes from methanol ether; M.p.    202-203.    



   Example 5
Analogously to the procedure described in Example 3, the trans-3-hydroxy-4- ((5.0 g (0.023 mol) of 3,4-epoxy-l-carbobenzyloxy-pyrrolidine and 5.7 g (0.046 mol) of hydroquinone monomethyl ether are obtained. p-methoxy-phe noxy) -1-carbobenzyloxy-pyrrolidine as a pale yellow oil.  After the hydrogenation of 0.021 mol of this compound, carried out analogously to Example 3, after recrystallization of the crude base from methanol ether, the trans-3-hydroxy-4 (p-methoxyphenoxy) pyrrolidine of mp.  126-128 "received.  The neutral fumarate crystallized from it looks from methanol ether; M.p.    168-169.    



   Example 6
Analogously to the procedure described in Example 3, 5.0 g (0.023 mol) of 3,4-epoxy-1-carbobenzyloxy-pyrrolidine and 6.6 g (0.046 mol) of l-naphthol are obtained after recrystallization from methylene chloride-hexane trans-3-hydroxy-4- (1-naphthyloxy) -1-carbobenzyloxy-pyrrolidine of mp.    122-124 ".     After the hydrogenation of 0.015 mol of this compound, carried out analogously to Example 3, after recrystallization of the crude base from methanol ether, the trans-3-hydroxy-4- (1-naphthyloxy) pyrolidine of mp.    Received 1l61l80.  The neutral fumarate prepared from it crystallizes from methanol ether; M.p. 



      120-122 ".    



   Example 7
Analogously to the procedure described in Example 3, 10-g (0.046 mol) of 3,4-epoxy-l-carbobenzyloxy-pyrrolidine and 9.8 g (0.092 mol) of o-cresol are used to obtain the trans-3-hydroxy-4- ( o-methyl-phenoxy) - 1-carbobenzyloxypyrrolidine, which after recrystallization from ether hexane as crystals of mp.    80-83 "is obtained.  After the hydrogenation of 0.036 mol of this compound, carried out analogously to Example 3, the trans-3-hydroxy-4- (o-methylphenoxy) pyrrolidine of mp is obtained after recrystallization of the crude base from ether.  100-103 '.     The neutral fumarate prepared from it crystallizes from methanol ether; M.p.  82-84 ".    



   Example 8
Analogously to the procedure described in Example 3, 15-g (0.068 mol) of 3,4-epoxy-1-carbobenzyloxy-pyrrolidine and 16.7 g of 3,4-dimethylphenol give trans-3-hydroxy-4- (3rd , 4-dimethyl-phenoxy) - 1-carbobenzyloxy-pyrrolidine as a pale yellow oil.  After the hydrogenation of 0.012 mol of this compound carried out analogously to example 3, crystalline trans-3-hydroxy-4- (3,4-dimethylphenoxy) pyrrolidine of mp is obtained after recrystallization from methanol ether.  97-99 ".     The neutral fumarate prepared therefrom crystallizes from methanol ether; M.p. 



      158-159 ".    



   Example 9
21.4 g (0.06 mol) of the trans-3 hydroxy-4- (3,4-dimethyl-phenoxy) -1-carbobenzyloxy-piperidine described in Example 19 are dissolved in 4.8 g (0.06 mol) of pyridine dissolved and added dropwise at room temperature with 18.4 g (0.18 mol) of acetic anhydride.  When the addition is complete, the mixture is stirred at room temperature for 20 hours and then poured onto 200 ml of ice water.  The precipitated white product is filtered off, washed with water, then with methanol and finally with ether and dried in a high vacuum at 40, after which the trans-3-acetoxy-4- (3,4 dimethyl-phenoxy) - 1-carbobenzyloxy-piperidine is obtained as white
Crystals from the smp.  109-112 ". 



   16.0 g (0.04 mol) of trans-3-acetoxy-4- (3,4-dimethyl-phen oxy) -l-carbobenzyloxy-piperidine are dissolved in 400 ml of methanol and in the presence of 1.5 g of a 5th % Palladium-on-carbon catalyst hydrogenated at normal pressure.  After the reaction has ended, the catalyst is filtered off by means of a layer of diatomaceous earth and the filtrate is evaporated in a water jet vacuum, after which the trans-3-acetoxy-4- (3,4-dimethyl-phenoxy) piperidine is obtained as a yellow oil. 



  By reacting the base with fumaric acid in ethanol ether, the crystalline acid fumarate of mp. 



      170-172 '.    



   Example 10
Analogously to the procedure described in Example 14, trans-3-hydroxy is obtained from 17.5 g (0.075 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 21.6 g (0.15 mol) of l-naphthol -4- (1-naphthyloxy) - 1-carbobenzyloxy-piperidine as a reddish oil.  The hydrogenation of 0.05 mol of this compound, carried out analogously to Example 14, gives the trans3-hydroxy-4- (l-naphthyloxy) piperidine as the crude base.  The acidic fumarate produced therefrom with fumaric acid crystallizes from methanol ether; M.p.    242-244 ".    



      Example 11
Analogously to the procedure described in Example 2, 10.8 g (0.04 mol) of the 3,4-epoxy-1- (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine and 8.8 described in Example 1b) are obtained g (0.08 mol) of thiophenol the trans-3 hydroxy-4-phenylthio-1 - (ss, ss, ss-trichloroethoxycarbonyl) pyrrolidine as a yellow oil.  After the treatment of 0.03 mol of this compound with zinc dust in glacial acetic acid, carried out analogously to Example 2, the trans-3-hydroxy-4-phenylthio-pyrrolidine is obtained after crystallization from methylene chloride ether.  By reacting the free base with a solution of fumaric acid in methanol ether, the crystalline line neutral fumarate is removed from the mp.    140-141 ". 

 

   Example 12
5.7 g (0.018 mol) of trans-3-hydroxy-4-chloro-1 - (ss, ss, ss-trichloro-ethoxycarbonyl) piperidine are dissolved in 60 ml of 90% acetic acid and cooled with an ice-water bath 4.7 g of zinc dust are added in portions and the reaction mixture is then stirred at room temperature for 3 hours, then filtered through a layer of diatomaceous earth and the filtrate is evaporated to dryness in a high vacuum, the crude trans-3-hydroxy-4-chloro-piperidine being white residue. 



   The crude product obtained is taken up in 300 ml of acetonitrile and together with 3.4 g (0.036 mol) of phenol and 100 ml of 2-n.  Sodium hydroxide solution heated under reflux for 15 hours.  The cooled reaction mixture is reduced to approx.    I / 3 of the original volume evaporated, then diluted with water and extracted 3 times with 20 ml of methylene chloride.  The organic phase is 3 times with l-n.  Sodium hydroxide solution and washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in a water jet vacuum.  The oily residue is dissolved in a little chloroform and applied to a small silica gel column. 

  By elution with a chloroform-methanol mixture (1: 1) after evaporation of the solvent, the trans-3-hydroxy-4-phenoxy-piperidine is isolated, which is a neutral fumarate of mp with fumaric acid.    180-183 ". 



   The trans-3-hydroxy-4 chloro-l- (ss, ss, ss-trichloroethoxycarbonyl) piperidine used as the starting material can be prepared as follows:
124.5 g (1.5 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 1200 ml of benzene.  124 g of sodium hydrogen carbonate are introduced into this solution, the mixture is then cooled to 0 ″ under a nitrogen atmosphere and within 31/2 hours at this temperature with a solution of 316 g (1.5 mol) of 2,2,2-trichloroethyl chloroformate in 250 ml of benzene are slowly added dropwise.  The resulting white suspension is then stirred for a further 15 hours at 0 "and then poured onto 2000 ml of ice water. 

  The benzene phase is separated off and the aqueous phase is shaken twice with 1000 ml of methylene chloride; the combined organic phases are with 1-n.  Hydrochloric acid, then washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a water jet vacuum, after which l- (ss, ss, ss-trichloroethoxycarbonyl) -1,2,5,6-tetrahydropyridine is obtained as a slightly reddish oil. 



   100 g (0.38 mol) of I - (ss, ss, ss-trichloroethoxycarbonyl) - 1,2,5,6-tetrahydropyridine are dissolved in 1200 ml of methylene chloride and added in portions with 157 g (0.77 mol) of 85% strength -Chlorperbenzoic acid added.  The slightly exothermic reaction is kept at room temperature with a water bath.  After the addition has ended (duration approx.  2 hours), the reaction mixture, in which a white suspension forms, is stirred for a further 15 hours at room temperature.  The precipitated m-chlorobenzoic acid is filtered off, the filtrate with saturated aqueous sodium carbonate solution, then with aqueous iron (II) sulfate solution, then with 0.1-n.     Sodium hydroxide solution and finally washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. 



  The remaining oil is dissolved in 100 ml of benzene and filtered through a layer of silica gel.  By eluting with a benzene / ethyl acetate mixture (1: 1) and evaporating the solvent, pure 3,4-epoxy-l- (ss, ss, ss-trichloroethoxycarbonyl) piperidine is obtained as a light orange colored oil. 



   5.0 g (0.018 mol) of 3,4-epoxy-1 - (ss, ss, ss-trichloroethoxycarbonyl) piperidine are dissolved in 50 ml of dioxane and mixed with 60 ml of 6-n.  Hydrochloric acid added.  The slightly exothermic reaction is kept at room temperature with a water bath and the reaction mixture is stirred for 15 hours, then diluted with water and extracted 3 times with 100 ml of methylene chloride.  The organic phase with 0.1 -n.  Sodium hydroxide solution, then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, then first evaporated to dryness in a water jet vacuum and then in a high vacuum, after which trans3-hydroxy-4-chloro-1 - (ss, ss, ss-trichloroethoxycarbonyl) -piperidine as a light yellow oil. 



   Example 13 40 g (0.146 mol) of the 3,4-epoxy-1 - (ss, ss, ss-trichloroethoxycarbonyl) piperidine obtained according to Example 12 are mixed together with 32 g (0.29 mol) of thiophenol and 146 ml (0.05 29 mol) 2-n.  Sodium hydroxide solution dissolved in 300 ml of acetonitrile.  The reaction mixture is heated under reflux for 4 hours, then cooled to room temperature and to approx.    1/3 of the original volume was concentrated.  The solution is then diluted with 900 ml of water and extracted 3 times with 1000 ml of methylene chloride; the combined organic phases are twice with 0.1 -n.  Sodium hydroxide solution, then washed with water, dried over sodium sulfate and evaporated in a water jet vacuum.  The remaining oil is dissolved in 50 ml of benzene and filtered through a layer of silica gel. 

  The trans-3-hydroxy-4-phenylthio-1 - (ss, ss, ss-trichloroethoxycarbonyl) piperidine is isolated as a light orange oil by elution with a benzene / ethyl acetate mixture (4: 1). 



   14.0 g (0.036 mol) of trans-3-hydroxy-4-phenylthio-I- (P, P, P-trichloroethoxycarbonyl) piperidine are dissolved in 140 ml of 90% acetic acid and added in portions with 9.5 g (0.05 14 mol) of zinc dust.  The reaction mixture is then stirred at room temperature for one hour and then filtered through a layer of diatomaceous earth.  The filtrate is evaporated in a high vacuum, the residue obtained is taken up in 500 ml of water, cooled to 0 "with an ice water bath and at this temperature with conc.  Sodium hydroxide solution is made strongly alkaline and the reaction mixture is extracted 3 times with 200 ml of methylene chloride. 

  The combined organic phases are washed once with water, dried over sodium sulfate and evaporated in a water jet vacuum, after which the trans-3-hydroxy-4phenylthipiperidine is obtained as a crystalline crude base which is recrystallized from methanol ether; M.p.    135-136 ".     The neutral fumarate made from the base with fumaric acid crystallizes from methanol ether; M.p.    171-173 ".    



   Example 14
8.2 g (0.025 mol) of trans-3-hydroxy-4-phenoxy-l-carbobenzyloxy-piperidine are dissolved in 140 ml of methanol and in the presence of 0.8 g of a 5% palladium-on-carbon catalyst Normal pressure and room temperature hydrogenated.  When the uptake of hydrogen has ended, the catalyst is filtered off using diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  The crude base crystallizes from methanol ether and provides the trans-3-hydroxy-4phenoxy-piperidine from the mp.    134-136 ".     The neutral fumarate prepared therefrom with fumaric acid crystallizes from methanol ether; M.p.  180-183 ".    



   The trans-3-hydroxy-4 phenoxy-1-carbobenzyloxypiperidine used as starting material can be prepared as follows: a) 83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene.  83 g of sodium hydrogen carbonate are introduced into this solution, the mixture is cooled to 0 ″ under a nitrogen atmosphere and 332 ml of a 50% strength solution of benzyl chloroformate in toluene (1 mol) are added dropwise at this temperature within one hour.  The reaction mixture is stirred for a further 21/2 hours at 0 "and then poured onto 1.5 liters of ice water.  The benzene phase is separated off, the aqueous phase is shaken out three times with 250 ml of methylene chloride; then the combined organic phases with l-n.  

  Hydrochloric acid, then washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a water jet vacuum.  The oily residue is distilled under high vacuum and provides the l-carbobenzyloxy-1,2,5,6-tetrahydropyridine with a boiling point of 102-113 "/ 0.01 mm Hg.   



      b) 108.5 g (0.5 mol I I-larbobenzyloxy-I, 2,5,6-tetrahydropyridine are dissolved in 1000 ml dichloroethane and in portions with 182 g (0.9 mol) 85% m-chlorine -perbenzoic acid added.  The slightly exothermic reaction is kept at room temperature with a water bath.  When the addition is complete, the reaction mixture, in which a white suspension forms, is stirred for a further 48 hours at room temperature, the precipitated m-chlorobenzoic acid is filtered off, the filtrate successively with saturated sodium carbonate solution, then with iron (II) sulfate solution, then with 0 , 1-n.    



  Sodium hydroxide solution and finally washed with water, the organic phase dried over sodium sulfate and evaporated in a water jet vacuum.  The 3, 4-epoxy-1-carbobenzyloxy-piperidine remaining as a yellowish oil is spectroscopic and thin-layer chromatographically uniform and can be used for further reactions without further purification.  When this compound is distilled under high vacuum at the boiling point 145-146 "/ 0.4 mm Hg, some decomposition occurs. 



   c) 23.3 g (0.1 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine together with 18.8 g (0.2 mol) of phenol and 100 ml of 2-n.  Sodium hydroxide solution (0.2 mol) dissolved in 400 ml of acetonitrile.  The reaction mixture is heated under reflux for 7 hours, then cooled to room temperature and to about approx.  1/3 of the volume concentrated.  The solution is then diluted with 500 ml of water, shaken 3 times with 100 ml of methylene chloride each time, the organic phase with 2-n.  Sodium hydroxide solution, then washed with water, dried over sodium sulfate and evaporated in a water jet vacuum.  The residue obtained is an oil which, in addition to the main product, trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-piperidine, approx.  Contains 5% of the isomer trans-3-phenoxy4-hydroxy-1-carbobenzyloxy-piperidine. 



   For identification, the two isomers can be separated from one another by column chromatography on silica gel using benzene-ethyl acetate as the eluent. 



   Example 15
Analogously to the procedure described in Example 14, 11.6 g (0.05 mol) of 3,4-epoxy-1-carbobenzyloxy-piperidine and 15.1 g (0.1 mol) of 3-methyl-4-hydroxybenzamide are obtained the crystalline trans-3-hydroxy-4- (2methyl-4-carbamoyl-phenoxy) -1-carbobenzyloxy-piperidine of mp.    175-177 ".     After hydrogenation of 0.018 mol of this product, carried out analogously to Example 14, the trans-3-hydroxy-4- (2-methyl-4-carbamoyl-phenoxy) -piperidine is obtained, which is recrystallized from methanol ether; M.p.    210-212 ".     An amorphous neutral fumarate can be obtained from the base with fumaric acid. 



   Example 16
Analogously to the procedure described in Example 14, trans-3-hydroxy is obtained from 23.3 g (0.1 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 24.8 g (0.2 mol) of hydroquinone monomethyl ether -4- (p-methoxy-phenoxy) - 1-car- bobenzyloxy-piperidine as a reddish oil.  The hydrogenation of 0.075 mol of this product, carried out analogously to Example 14, gives the trans-3-hydroxy-4- (p-methoxyphenoxy) piperidine of mp, after crystallization from methanol ether.  154-156 '.     The neutral fumarate prepared therefrom with fumaric acid crystallizes from methanol ether, mp.  171-173 '.    



   Example 17
Analogously to the procedure described in Example 14, trans-3-hydroxy-4 is obtained from 15.0 g (0.064 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 19.9 g (0.16 mol) of guaiacol - (o-methoxy-phenoxy) - 1-carbobenzyloxypiperidine as a yellowish oil.  The hydrogenation of 0.049 mol of this product carried out analogously to Example 14 yields the crystalline trans-3-hydroxy-4- (o-methoxy-phenoxy) piperidine.  By treatment with ethereal hydrogen chloride solution, the base is converted into the corresponding crystalline hydrochloride, which melts at 213-215 "after recrystallization from methanol ether. 



   Example 18
Analogously to the procedure described in Example 14, 9.3-g (0.04 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 12.3 g (0.08 mol) of 3,4-dimethoxy-phenol are obtained an oily crude product, which is dissolved in a little benzene, purified on a silica gel column and subsequent elution with a mixture of benzene and ethyl acetate (4: 1) and pure trans-3-hydroxy-4- (3,4-dimethoxy-phen oxy) -l-carbobenzyloxy-piperidine provides.  The hydrogenation carried out analogously to Example 14 with 0.014 mol of this compound gives the trans-3-hydroxy-4- (3,4-dimethoxyphenoxy) piperidine.  The neutral fumarate prepared therefrom with fumaric acid crystallizes from methanol ether; M.p.    173-175 ".    



   Example 19
Analogously to the procedure described in Example 14, 116.5 g (0.5 mol) of 3,4-epoxy-1-carbobenzyloxy-piperidine and 122 g (1 mol) of 3,4-dimethylphenol are converted into a mixture of Hydroxy-4- (3,4-dimethylphenoxy) - 1 carbobenzyloxy-piperidine and trans-4-hydroxy-3- (3,4-dimethylphenoxy) - 1-carbobenzyloxy-piperidine obtained as a yellowish oil. 

  The two isomers are separated by column chromatography on silica gel using benzene with a gradually increasing addition of ethyl acetate as the eluent, the first main fraction and main product being trans-3-hydroxy-4- (3,4-dimethylphenoxy) -l-carbobenzyloxy -piperidine and finally isolated after mixed fractions pure trans-4-hydroxy-3- (3,4-dimethyl-phenoxy) -l-carbobenzyloxy-piperidine.  Both isomers are obtained as pale yellow oils. 



   The hydrogenation of 71.8 g (0.2 mol) of trans-3-hydroxy-4- (3, 4-dimethylphenoxy) -1-carbobenzyloxy-piperidine carried out analogously to Example 14 yields trans-3-hydroxy-4- (3 , 4dimethylphenoxy) piperidine, which crystallizes from methanol ether; M.p.  125-127 '.     The acidic fumarate prepared with fumaric acid crystallizes from ethanol ether; M.p.  175-177 '.    



   The hydrogenation of 7.5 g (0.022 mol) of trans-4-hydroxy-3- (3,47dimethylphenoxy) -1-carbobenzyloxy-piperidine carried out analogously to Example 14 yields the trans-4-hydroxy-3 after crystallization from methanol ether - (3, 4-dimethylphenoxy) piperidine of mp.  93-95 ".     The hydrochloride prepared therefrom by reaction with ethereal hydrogen chloride solution crystallizes from methanol ether; M.p.  160-163.    

 

   Example 20
8.85 g (0.04 mol of the trans-3 hydroxy-4- (3,4-dimethylphenoxy) piperidine described in Example 19 are dissolved in 20 ml of formic acid and treated with 10 ml of a 3% aqueous formaldehyde solution.  The mixture is heated to 80 for 4 hours and then evaporated in a high vacuum after cooling.  The residue is dissolved in 100 ml of methanol and with an approx.  6-n.     Acidified solution of hydrogen chloride in ethanol.  The solvent is evaporated in a water jet vacuum, the oily residue is dissolved in 300 ml of water and extracted twice with 50 ml of methylene chloride.  The aqueous phase is concentrated with.  Sodium hydroxide solution made strongly alkaline, then extracted 3 times with 100 ml of methylene chloride. 

  The organic phase is washed once with water, dried over sodium sulfate and evaporated to dryness in a water jet vacuum.  The remaining oil is dissolved in an excess of ethanolic hydrogen chloride solution and the hydrochloride is precipitated with ether, giving amorphous trans3-hydroxy-4- (3, 4-dimethylphenoxy) - I -methyl -piperidine hydrochloride. 



   Example 21
Analogously to the procedure described in Example 14, an oily crude product is obtained from 15.0 g (0.064 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 16.5 g (0.12 mol) of m-chlorophenol , which is dissolved in benzene, filtered through silica gel and, after evaporation of the solvent, gives the trans-3-hydroxy-4- (m-chlorophenoxy) - 1-carboben- zyloxy-piperidine.  The hydrogenation carried out analogously to Example 14 with 0.039 mol of this compound yields crystalline trans-3-hydroxy-4- (m-chlorophenoxy) piperidine of mp.    109-111 '.     The acidic fumarate produced therefrom with fumaric acid crystallizes from methanol-acetone; M.p. 



      138-140.    



   Example 22
Analogously to the procedure described in Example 14, an oily crude product is obtained from 15.0 g (0.064 mol) of 3,4-epoxy-l-carbobenzyloxypiperidine and 21.0 g (0.12 mol) of 3,4-dichlorophenol. which, dissolved in benzene, is filtered through silica gel and gives trans-3-hydroxy-4- (3,4-dichlorophenoxy) -1-carbobenzyloxy-piperidine.  The hydrogenation carried out analogously to Example 14 with 0.036 mol of this product yields crystalline trans-3-hydroxy-4- (3, 4-di-chlorophenoxy) piperidine of mp.    196-198 ".     The acidic fumarate produced therefrom with fumaric acid crystallizes from methanol ether; M.p.    180-182 ".    



   Example 23
Analogously to the procedure described in Example 20, 5.2 g (0.025 mol) of the trans-3-hydroxy-4-phenylthio-piperidine described in Example 13 is converted into trans-3 hydroxy-4-phenylthio- by reaction with formaldehyde and formic acid. 1-methyl-piperidine obtained as a yellow oil.  The acidic fumarate produced therefrom with fumaric acid crystallizes from methanol ether; M.p.    150-152 ".    



   Example 24
In a suspension of 8.15 g (0.18 mol) of a 55% oily dispersion of sodium hydride in 100 ml of dimethylformamide is a solution of 45 g (0.12 mol) of the in the example within 30 minutes at 30-35 " 19 described trans-3-hydroxy-4- (3, 4-dimethyl-phenoxy) -1-carbobenzyloxy-piperidine entered in 100 ml of dimethylformamide.  The mixture is then heated to 50 and 22.5 g (0.15 mol) of methyl iodide are added dropwise.  The reaction mixture is then stirred for 3 hours at 60-70 "and for 15 hours at room temperature, then poured onto 600 ml of ice water and shaken 3 times with 150 ml of ethyl acetate each time. 

  The combined organic phases are washed with water, dried over sodium sulfate and first evaporated to dryness in a water jet vacuum, then in a high vacuum.  This gives trans-3-methoxy-4- (3, 4-dimetpyl-phen-oxy) -l-carbobenzyloxy-piperidine as a pale yellow oil.    



   36.9 g (0.1 mol) of trans-3-methoxy-4- (3,4-dimethylphenoxy) -1-carbobenzyloxypiperidine are dissolved in 800 ml of methanol and in the presence of 6 g of a 5% palladium -hydrogenated on carbon catalyst at normal pressure and room temperature.  After the hydrogen uptake has ended, the catalyst is filtered off over a layer of diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  Trans-3-methoxy-4- (3,4-dimethylphenoxy) piperidine is obtained as a yellowish oil.  The acidic fumarate prepared therefrom with fumaric acid crystallizes from methanol ether; M.p.    137-139 ".    



   Example 25
Analogously to the procedure described in Example 20, 4.7 g (0.02 mol) of the trans-3-methoxy-4- (3, 4-dimethylphenoxy) piperidine obtained according to Example 24 is converted into trans by reaction with formaldehyde and formic acid -3-methoxy-4- (3, 4-dimethylphenoxy) -1-methyl-piperidine obtained as a pale yellow oil.  The acidic fumarate obtained therefrom with fumaric acid crystallizes from methanol ether; M.p.  151-153 '.    



   Example 26
7.8 g (0.035 mol) of the trans-3 hydroxy-4- (3,4-dimethylphenoxy) piperidine described in Example 19 are dissolved in a suspension of 8 g of potassium carbonate in 150 ml of methanol and added dropwise with 6.3 g ( 0.053 mol) of propargyl bromide were added at room temperature.  The reaction mixture is stirred for a further 20 hours at this temperature, then filtered and the filtrate is evaporated in a water jet vacuum.  The oily residue is dissolved in 200 ml of toluene, 3 times with 150 ml of l-n.  Hydrochloric acid extracted, the combined aqueous phases are cooled with ice with conc.  Sodium hydroxide solution made alkaline and extracted twice with 200 ml of chloroform.  The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness in a water jet vacuum. 

  The oil obtained is dissolved in 50 ml of chloroform and filtered through a layer of silica gel.  Elution with chloroform gives crystalline trans-3-hydroxy4- (3, 4-dimethylphenoxy) -1-propargyl-piperidine of mp from the filtrate after removal of the solvent in a water jet vacuum. 



     105-107 ".    



   That from the base by treatment with an approx  6-n. 



  Solution of hydrogen chloride in ether prepared hydrochloride crystallized from methanol ether; M.p.    140-142 '.    



   Example 27
Analogously to the procedure described in Example 20, 4.9 g (0.02 mol) of the trans-4-hydroxy-3- (3, 4-dimethylphenoxy) piperidine obtained according to Example 19 is converted into trans by reaction with formaldehyde and formic acid -4-hydroxy-3- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine obtained, mp.  98-99 ".     By treating the base with an approx  6-n.     An amorphous hydrochloride is obtained by dissolving hydrogen chloride in ether. 

 

   Example 28
Analogously to the procedure described in Example 14c), the trans-3- is obtained from 30.0 g (0.12 mol) of 3,4-epoxy-l-carbobenzyloxypiperidine and 51.4 g (0.25 mol) of hydroquinone monobenzyl ether. Hydroxy-4- (4-benzyloxy-phen oxy) - 1-carbobenzyloxy-piperidine as an oily product. 



   The hydrogenation carried out analogously to Example 14 with 0.06 mol of this product gives the trans-3-hydroxy-4 (4-hydroxyphenoxy) piperidine, which is crystallized from methanol ether; M.p.  176-178 '.     By reaction with fumaric acid, a neutral fumarate of mp.    231-232 "received.   



   Example 29
Analogously to the procedure described in Example 14c), 23.3 g (0.1 mol) of 3,4-epoxy-1-carbobenzylylpiperidine and 28.9 g (0.195 mol) of 5,6,7, 8-tetrahydro-2naphthol the trans-3-hydroxy-4- (5,6,7,8-tetrahydro-2-naphthyloxy) -1-carbobenzyloxy-piperidine. 



   The hydrogenation carried out analogously to Example 14 with 0.08 mol of this product gives the trans-3-hydroxy-4 (5,6,7,8-tetrahydro-2-naphthyloxy) piperidine.     The base is crystallized from methanol ether, mp.  125-127 ", and by reaction with fumaric acid provides a neutral fumarate of mp. Crystallizing from methanol ether.    202-203 ".    



   Example 30
Analogously to the procedure described in Example 14, an oily crude product is obtained from 17.5 g (0.075 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 20.8 g (0.15 mol) of p-nitro-phenol, which is dissolved in benzene and filtered through a layer of silica gel.  Elution with a benzene / ethyl acetate mixture (1: 1) and evaporation of the solvent gives pure trans-3-hydroxy-4 (p-nitro-phenoxy) -1-carbobenzyloxy-piperidine.     4.1 g (0.01 mol) of this compound are dissolved in 15 ml of glacial acetic acid and added dropwise in 15 ml of a 40% solution of hydrobromic acid in glacial acetic acid.  In a slightly exothermic reaction, a white precipitate forms, which is filtered off after stirring for 3 hours at room temperature and the trans-3-hydroxy-4- (p-nitro-phenoxy) piperidine hydrobromide of mp.  248-250 ". 

  By treatment with an aqueous ammonia solution, the base is released from the hydrobromide, which forms an acidic fumarate which crystallizes with fumaric acid from methanol ether, mp. 



     179-180 '.    



   Example 31
Analogously to the procedure described in Example 14c), 17.5 g (0.075 mol) of 3,4-epoxy-1-carbobenzyloxy-piperidine and 16.8 g (0.15 mol) of p-fluorophenol, the trans -3-Hydroxy-4- (p-fluorophenoxy) -1-carbobenzyloxypiperidine as a yellowish oil. 



   The hydrogenation carried out analogously to Example 14 with 0.05 mol of this compound gives the trans-3-hydroxy-4 (p-fluorophenoxy) piperidine as crude base, which crystallizes from methanol ether, mp.    121-123 ".     The acidic fumarate prepared therefrom with fumaric acid crystallizes from methanol ether, mp.    159-161 ".    



   Example 32
In a suspension of 3.6 g (0.08 mol) of a 55% oily dispersion of sodium hydride in 50 ml of dimethylformamide, a solution of 21.3 g (0.05 mol) of the in 30 minutes at 30-35 " trans-4-hydroxy-3- (3,4-dimethyl-phenoxy) -1-carbobenzyloxypiperidine described in Example 19 entered in 50 ml of dimethylformamide.  The mixture is then heated to 50 and 9.94 g (0.07 mol) of methyl iodide are added dropwise.  The reaction mixture is then stirred for 3 hours at 60-70 "and for 15 hours at room temperature, then poured onto 600 ml of ice water and shaken 3 times with 150 ml of ethyl acetate each time. 

  The combined organic phases are washed once with water, dried over sodium sulfate and first evaporated to dryness in a water jet vacuum, then in a high vacuum.  Trans-4-methoxy-3- (3,4-dimethylphen oxy) -1-carbobenzyloxypiperidine is obtained as a pale yellow oil. 



   15.0 g (0.04 mol) of trans-4-methoxy-3- (3,4-dimethylphen oxy) -l-carbobenzyloxy-piperidine are dissolved in 180 ml of methanol and in the presence of 1.0 g of a 5% Palladium-on-carbon catalyst hydrogenated at normal pressure and room temperature.  After the hydrogen uptake has ended, the catalyst is filtered off over a layer of diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  Trans-4-methoxy-3- (3,4-dimethylphenoxy) piperidine is obtained as a yellowish oil.  By treating the base with an approx  6-n. 



  An amorphous hydrochloride is obtained by dissolving hydrogen chloride in ether. 



   Example 33
Analogously to the procedure described in Example 14c), 23.3 g (0.1 mol) of 3,4-epoxy-l-carbobenzyloxy-piperidine and 28.9 g (0.195 mol) of 5,6,7,8- Tetrahydro 1 -naphthol the trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1 - naphthyloxy) -l-carbobenzyloxy-piperidine as an oily product.  The hydrogenation carried out analogously to Example 14 with 26.6 g (0.07 mol) of this product yields trans-3 hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) piperidine, which consists of methanol Ether is recrystallized, mp. 



     168-169 "; by reaction with fumaric acid, a neutral fumarate of mp.    208-210 "received. 



   Example 34
Analogously to the procedure described in Example 14c), the trans is obtained from 50 g (0.21 mol) of 3,4-epoxy-1-carbobenzyloxypiperidine and 53.8 g (0.42 mol) of 2,3-dimethylphenol 3-Hydroxy-4- (2,3-dimethylphenoxy) - 1-carboben-zyloxy-piperidine as a brownish oil. 



   The hydrogenation carried out analogously to Example 14 with 50.8 g (0.143 mol) of this product gives trans-3-hydroxy-4 (2,3-dimethylphenoxy) piperidine.  The base is crystallized from methanol ether, mp.    127-129 "and, by reaction with fumaric acid, provides a neutral fumarate crystallizing from methanol ether, mp.    176-178 ".    



   Example 35
Analogously to the procedure described in Example 14c), the trans is obtained from 15.0 g (0.064 mol) of 3,4-epoxy-l-carbobenzyloxypiperidine and 15.5 g (0.12 mol) of 2,6-dimethylphenol. 3-Hydroxy-4- (2,6-dimethylphenoxy) -1-carbobenzyloxypiperidine as a yellow oil. 



   The hydrogenation carried out analogously to Example 14 with 8.3 g (0.023 mol) of this product yields crystalline trans-3 hydroxy-4- (2,6-dimethylphenoxy) piperidine.  The base can be crystallized from methanol ether, mp.    131-133 '; and by reaction with fumaric acid provides an acidic fumarate crystallizing from methanol ether, mp. 



     178-180 '.    



   Example 36
Analogously to the procedure described in Example 14c), 20-g (0.085 mol) of 3,4-epoxy-1-carbobenzyloxy-piperidine and 25.8 g (0.17 mol) of 4-tert. -Butylphenol the trans-3-hydroxy-4- (p-tert. -butylphenoxy) - 1 -car- bobenzyloxy-piperidine as a yellowish oil. 

 

   The hydrogenation carried out analogously to Example 14 with 20.0 g (0.052 mol) of this product gives trans-3-hydroxy-4 (p - rt. -butylphenoxy) -piperidine as a yellowish oil.  The base can be crystallized from methanol ether, mp.  138-140 ", and by treatment with fumaric acid gives an acidic fumarate crystallizing from methanol, mp.    192-194 ".    



   Example 37
Analogously to the procedure described in Example 3, trans-3-hydroxy is obtained from 25.0 g (0.114 mol) of 3,4-epoxy-1-carbobenzyloxypyrrolidine and 29.3 g (0.228 mol) of m-chlorophenol -4- (m-chlorophenoxy) -1-carbobenzyloxy-pyrrolidine as a yellow oil.  After the hydrogenation of 32.0 g (0.092 mol) of this compound, carried out analogously to Example 3, the trans-3-hydroxy-4- (m-chlorophenoxy) pyrrolidine is obtained as a yellowish oil.  The acidic fumarate produced therefrom crystallizes from methanol ether, mp.  128-129 '.    



   Example 38
Analogously to the procedure described in Example 3, the trans is obtained from 40.0 g (0.18 mol) of 3,4-epoxy-1-carbobenzyloxy-pyrrolidine and 44.7 g (0.366 mol) of 3,5-dimethylphenol -3-Hydroxy-4- (3,5-dimethylphenoxy) -1-car-bobenzyloxy-pyrrolidine as a yellow oil. 



   After the hydrogenation of 7.6 g (0.02 mol) of this compound, carried out analogously to Example 3, the trans3-hydroxy-4- (3,5-dimethylphenoxy) pyrrolidine is obtained as a yellow oil.  The acidic fumarate prepared therefrom crystallizes from methanol ether, mp.  178-179 '.    



   Example 39
Analogously to the procedure described in Example 14c), 16.2 g (0.07 mol) of 3,4-epoxy-1-carbobenzyloxypiperidine and 28.4 g (0.14 mol) of 2-bromo 4-methoxyphenol the trans-3-hydroxy-4- (2-bromo-4-methoxy-phen oxy) -l-carbobenzyloxy-piperidine as an oily product. 



   The hydrogenation carried out analogously to Example 14 with 17.6 g (0.04 mol) of this product gives the trans-3 hydroxy-4- (2-bromo-4-methoxyphenoxy) piperidine as the crystalline base of mp.  132-135 "(from methylene chloride).  The acidic fumarate formed therefrom by treatment with fumaric acid crystallizes from methanol ether, mp.  200-202 '.    



   Example 40
3.45 g (0.011 mol) of trans-4-hydroxy-5- (2,3-dimethylphen oxy) -1-methylsulfonyl-tetrahydro-1 H-azepine are dissolved in 75 ml of dry benzene and in a nitrogen atmosphere with 15 ml of one Treated 70% solution of sodium bis-2-methoxyethoxy aluminum hydride in benzene.  The reaction mixture is refluxed for 15 hours, then cooled to 0 "in an ice water bath and treated dropwise with 15 ml of water.  The precipitated aluminum salts are filtered off and washed with benzene.  The filtrate is evaporated to dryness in a water jet vacuum.  The crude 4-hydroxy-5- (2,3-dimethylphenoxy) hexahydro-l H-azepine obtained is treated by treatment with a 6-n. 

  Solution of hydrochloric acid in ether converted into the hydrochloride, crystallized from ether / ethyl acetate, mp.  113-115 '.    



   Analogously, the trans-4-hydroxy-5-phenoxy-hexahydro-1 H-azepine and its hydrochloride are obtained from 3.14 g (0.011 mol) of trans-4 hydroxy-5-phenoxy-1-methylsulfonyl-hexahydro-1 hazepine . 



   From 34.5 g (0.011 mol) of trans-4-hydroxy-5- (3,4-dimethylphenoxy) -1-methylsulfonyl-hexahydro-1 H-azepine, the trans 4-hydroxy-5- (3,4-dimethyl -phenoxy) -hexahydro- 1 H-azepine and its hydrochloride, from 3.9 g (0.011 mol) of trans-4-hydroxy-5- (3,4-dichlorophen oxy) - 1 -methylsulfonyl-hexyhydro-1 H-azepine the trans-4 hydroxy-5- (3,4-dichlorophenoxy) hexahydro-1 H-azepine and its hydrochloride, and from 3.9 g (0.011 mol) of trans-4-hydroxy-5- (p-trifluoromethyl phenoxy) - 1 -methylsulfonyl-hexahydro- 1 H-azepine the trans4-hydroxy-5- (p-trifluoromethyl-phenoxy) -hexahydro- 1 hazepine and its hydrochloride. 



   The starting materials can be prepared as follows: a) 15.9 g (0.05 mol) of endo-4- (p-toluenesulfonyloxy-1-azabicyclo [3. 2nd 1] octane hydrochloride of mp.  146-148 ', which according to W.  Kunz, dissertation from the University of Basel 1973, 6349, page 92, by implementing the there and in J.  Org. 



     Chem.  33,4376-4380 (1968) described endo-l-azabi cyclo [3. 2nd 1] octan-4-ol with the approx    1.2 times the molar amount of p-tolulsulfonyl chloride in abs.  Chloroform at room temperature with approx  48 hours of reaction, precipitation of the crude product with pentane and recrystallization from chloroform can be obtained, and 23.0 g (0.2 mol) of methanesulfonyl chloride are in 1400 ml of 0.75-n.  Sodium hydroxide solution stirred for 4 hours at room temperature and then heated to 90 "with stirring for 20 minutes.  After cooling, the reaction mixture is extracted four times with methylene chloride. 

  The combined extracts are 0.1-n.     Washed hydrochloric acid, dried over potassium carbonate and evaporated to give the 1-methylsulfonyl-2,3,6,7-tetrahydro-1 H-azepine.  95-96 "(from ethyl acetate-benzene). 



   b) 11.7 g (0.067 mol) of l-methanesulfonyl-2,3,6,74etra-hydro-I H-azepine are dissolved in 230 ml of methylene chloride and in portions with 23 g (0.13 mol) of m-chloro-perbenzoic acid treated.  A white suspension soon forms, which is further stirred for 24 hours at room temperature.  The precipitated m-chlorobenzoic acid is filtered off, the filtrate is saturated with aqueous sodium carbamate solution, then with aqueous iron (II) sulfate solution, then with 0.1 -n.  Sodium hydroxide solution and finally washed with water and dried over sodium sulfate.  When the solution is concentrated in a water jet vacuum, white crystals of 1-methanesulfonyl-hexahydro-3,4-epoxy-1 H-azepine are obtained, which are isolated by filtration, mp.    133-134 '.    



   c) 7.0 g (0.036 mol) of I-methylsulfonyl-hexahydro-3,4 epoxy-1H-azepine together with 8.9 g (0.073 mol) of 2,3-dimethylphenol with 36.6 ml of 2-n .  Sodium hydroxide solution (0.013 mol) dissolved in 200 ml of acetonitrile.  The reaction mixture is heated under reflux for 5 days, then cooled to room temperature and concentrated in a water jet vacuum.  The residue is then dissolved in 200 ml of methylene chloride, the organic phase is three times with 100 ml of 2-n.  Sodium hydroxide solution, then washed with water, dried over sodium sulfate and evaporated in a water jet vacuum.  The crude product obtained is purified by preparative thick-layer chromatography (silica gel plates 100 × 20 cm, layer thickness 1.5 mm). 

  Elution with a 3: 1 toluene / ethyl acetate mixture gives crystalline trans-4-hydroxy-5- (2,3-dimethylphenoxy) -1-methanesulfonyl-hexahydro-1 H-azepine, m.p.  112-115 '.    



   Analogously, using 6.9 g (0.073 mol) of 3,4-dimethylphenol, the trans-4-hydroxy-5- (3,4-dimethylphenoxy) -1-methylsulfonyl-hexahydro-1 H- azepine, using 11.9 g (0.073 mol) of 3,4-dichlorophenol the trans-4-hydroxy-5- (3,4-dichlorophenoxy) -1-methylsulfonyl-hexahydro-1 H-azepine, and using 12.0 g (0.073 mol) of p-trifluoromethyl-phenol, the trans-4 hydroxy-5- (p-trifluoromethyl-phenoxy) -1-methylsulfonyl hexahydro-1 H-azepine.    

 

   Example 41
Analogously to the procedure described in Example 20, 5.6 g (0.025 mol) of the trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine described in Example 34 is converted to trans-3 by reaction with formaldehyde and formic acid -Hydroxy-4- (2,3-dimethylphenoxy) - 1 -methyl-piperidine obtained as an amorphous foam.  By treating the base with an approx  6-n.     Solution of hydrogen chloride in ether gives an amorphous hydrochloride.   



   Example 42
Analogously to the procedure described in Example 20, 3.63 g (0.012 mol) of the trans-3-hydroxy-4- (2-bromo-4-methoxyphenoxy) piperidine described in Example 39 is converted into formaldehyde and formic acid the trans-3-hydroxy-4- (2-bromo-4-methoxy-phenoxy) 1-methyl-piperidine was prepared.  By treating the base with an approx  6-n.     A solution of hydrogen chloride in ether will get its hydrochloride. 



   Example 43
15.0 g (0.045 mol) of the trans3-hydroxy-4-phenoxy-1-carbobenzyloxy-piperidine described in Example 14 are combined with 28.34 g (0.13 mol) of dicyclohexylcarbodiimide and 3.7 ml (0.045 mol) of pyridine dissolved in 80 ml of dry dimethyl sulfoxide.  The mixture is cooled to 0 with an ice water bath and 2.6 g (0.023 mol) of trifluoroacetic acid are added.  The cooling bath is removed again and the reaction mixture is further stirred at room temperature for 4 hours in a nitrogen atmosphere.  The white suspension is diluted with 250 ml of ethyl acetate and a solution of 12.3 g (0.13 mol) of oxalic acid in 200 ml of methanol is added dropwise. 

  After the evolution of gas has ended, the reaction mixture is cooled to 0 "in an ice water bath, diluted with 400 ml of water and the precipitated dicyclohexylurea is separated off. The aqueous phase of the filtrate is extracted with 250 ml of ethyl acetate, the combined organic phases are dried over sodium sulfate and evaporated to dryness in a water jet vacuum .  The crude product obtained is dissolved in benzene and the solution is filtered through a layer of silica gel.  By eluting with a mixture of benzene and ethyl acetate (95: 5), 4-phenoxy-1-carbobenzyloxy-3-piperidone is obtained as a pale yellow oil. 



   14.0 g of this compound are dissolved in 150 ml of methanol, with 16.8 ml of a 2.5-n.  Hydrogen chloride solution in methanol and hydrogenated in the presence of 2.0 g of a 5% palladium-on-carbon catalyst at normal pressure and room temperature.  When the uptake of hydrogen has ended, the catalyst is filtered off using diatomaceous earth and the filtrate is evaporated in a water jet vacuum. 



  The amorphous crude product can be crystallized in an acetone-ether mixture and gives 4-phenoxy-3-piperidone hydrochloride monohydrate as white crystals, mp.  112-115 '.    



   Example 44
Analogously to the procedure described in Example 43, from 20.0 g (0.056 mol) of the trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1 described in Example 19, 1 carbobenzyloxypiperidine, 40.0 g ( 0.19 mol) of dicyclohexylcarbodiimide, 5.2 ml of pyridine and 4.2 g of trifluoroacetic acid in 130 ml of dry dimethyl sulfoxide, the 4- (3,4-dimethylphenoxy) - 1-carbobenzyloxy-3-piperidone as a yellow oil. 



   The hydrogenation carried out analogously to Example 43 with 9.3 g (0.026 mol) of this product yields crystalline 4- (3,4-dimethylphenoxy) -3-piperidone hydrochloride monohydrate, mp.  119-120 "(from methanol-acetone ether). 



   Example 45
Analogously to the procedure described in Example 43, 13.8 g (0.038 mol) of the trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1 carbobenzyloxypiperidine described in Example 34, 27.4 g ( 0.13 mol) of dicyclohexylcarbodiimide, 3.5 ml of pyridine and 1.9 ml of trifluoroacetic acid in 90 ml of dry dimethyl sulfoxide, the 4- (2,3-dimethylphen oxy) -1-carbobenzyloxy-3-piperidone as a colorless oil, which consists of ethyl acetate can be crystallized, mp.    108-111 ".    



     The hydrogenation carried out analogously to Example 46 with 4.75 g (0.013 mol) of this product yields crystalline 4- (2,3-dimethylphenoxy) -3-piperidone hydrochloride monohydrate after recrystallization of the crude product from methanol ether.    M.p.  110-112 '.    



   Example 46
Analogous to the procedure described in Example 43, from 28.3 g (0.08 mol) of the trans-4-hydroxy-3- (3,4-dimethylphenoxy) -1-carbobenzyloxypiperidine described in Example 19, 7.0 ml Pyridine, 4.2 ml of trifluoroacetic acid and 56.2 g (0.27 mol) of dicyclohexylcarbodiimide in 180 ml of dry dimethyl sulfoxide, the 3- (3,4-dimethylphenoxy) - 1-carbobenzyloxy-4-piperidone as a yellow oil.  A sample was crystallized from ethyl acetate for characterization.    M.p.  89-90 ".    



   The hydrogenation carried out analogously to Example 43 with 7.0 g (0.0198 mol) of this product gives crystalline 3- (3,4-dimethylphenoxy) -4-piperidone hydrochloride monohydrate of mp.  127-132 "(from ethyl acetate-petroleum ether). 



   Example 47
10.0 g (0.028 mol) of the 4- (3,4-dimethylphenoxy) -1-carbobenzyloxy-3-piperidone described in Example 44 are dissolved in 60 ml of dry tetrahydrofuran and added dropwise at room temperature in a nitrogen atmosphere with 112 ml of a 0 , 5-n.  Solution of potassium tri-sec. -butylborohydride (K-Selectride) (0.056 mol) in tetrahydrofuran. After the addition is complete, the reaction mixture is stirred at room temperature for 3 hours and then in a water jet vacuum to approx.    1A of the original volume was concentrated.  The solution is cooled to 0 "in an ice water bath, treated dropwise with 130 ml of water and extracted twice with 150 ml of methylene chloride.  The combined organic phases are with 0.1 -n.  Hydrochloric acid, then with 0.1 -n. 

  Sodium hydroxide solution and finally washed with water, dried over sodium sulfate and evaporated to dryness in a water jet vacuum.  The oily crude product is dissolved in toluene and the solution is filtered through a layer of silica gel.  By eluting with toluene-ethyl acetate mixture (5: 1), cis-3 hydroxy-4- (3,4-dimethylphenoxy) -1-carbobenzyloxy-perridine is obtained as a pale yellow oil. 



   6.0 g (0.0168 mol) of this product are dissolved in 120 ml of methanol and hydrogenated in the presence of 0.6 g of a 5% palladium-on-carbon catalyst at normal pressure and room temperature.  When the uptake of hydrogen has ended, the catalyst is filtered off using diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  The crude base obtained, the cis-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine, crystallizes from methanol ether, mp.    140-143 '.    

 

  The neutral fumarate prepared therefrom with fumaric acid crystallizes from methanol ether, mp.  186-190 ".    



   Example 48
Analogously to the procedure described in Example 47, 8.0 g (0.022 mol) of the 4- (2,3-dimethylphenoxy) -1-carbobenzyloxy-3-piperidone described in Example 47 are obtained by selective reduction with potassium tri-sec . butyl borohydride is the cis-3-hydroxy-4- (2,3-dimethylphenoxy) -l-carbobenzyloxy-piperidine as a yellowish oil.    



   The hydrogenation carried out analogously to Example 47 with 3.7 g (0.01 mol) of this product gives cis-3-hydroxy-4 (2,3-dimethylphenoxy) piperidine as a colorless oil.  The neutral fumarate prepared therefrom with fumaric acid crystallizes from methanol ether; M.p.  188-189 '.      



   Example 49
6.64 g (0.03 mol) of the trans-3 described in Example 4
Hydroxy-4- (2,3-dimethyl-phenoxy) -piperidine are in
100 ml of ethyl formate dissolved and during 1 1A
Cooked under reflux for hours.  The cooled solution is evaporated to dryness in a water jet vacuum, the white, solid residue obtained is dissolved in 100 ml of methyl chloride, this and the organic phase solution with 50 ml of 1-n. 



  Washed hydrochloric acid, dried over sodium sulfate and evaporated to dryness in a water jet vacuum, with trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-formyl-pipe ridine as crystals of mp.    140-141 ". 



   In an analogous manner, 7.06 g (0.03 mol) of the 4-trans described in Example 4 are obtained
Hydroxy-5- (2,3-dimethyl-phenoxy) hexahydro-1 H-azepine is the 4-trans-hydroxy-5- (2,3-dimethyl-phenoxy) -1-formyl hexahydro-1 H-azepine.    



   7.5 g (0.03 mol) of the above l-formyl compound are dissolved in
100 ml of dry tetrahydrofuran dissolved and added dropwise in an inert nitrogen atmosphere at 0 "to a suspension of 2.0 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran.  The reaction mixture is stirred for 5 hours at room temperature, then cooled again to 0 "in an ice bath and successively with 2 ml of water, 2 ml of 2N.  Sodium hydroxide solution and 6 ml of water treated.  The precipitated salts are filtered off and the filtrate is evaporated to dryness in a water jet vacuum.  The colorless, oily residue is dissolved in 20 ml of chloroform and filtered through a layer of silica gel and the layer is washed (eluted) with further chloroform. 

  The combined filtrates are evaporated in a water jet vacuum, crystalline trans-3-hydroxy-4- (2,3-dimethyl-phenoxy) -1-methyl-piperidine of mp.    105-107 ".  The acidic fumarate prepared from the base by treatment with fumaric acid crystallizes from methanol ether, mp.    150-152 ".    



   The trans-4-hydroxy-5 is obtained in an analogous manner from 7.9 g (0.03 mol) of trans-4-hydroxy-5- (2,3-dimethyl-phenoxy) -1-formyl-hexahydro IH-azepine - (2,3-dimethyl-phenoxy) -l-methyl-hexahydro-1 H-azepine. 



   Example 50
Analogously to the procedure described in Example 49, 5.5 g (0.25 mol) of the cis-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine described in Example 48 are converted into 100 ml of ethyl formate receive the cis 3-hydroxy-4- (2,3-dimethyl-phenoxy) -1-formyl-piperidine as a pale yellow oil. 



   The reduction carried out in an analogous manner as in Example 49 with 3 g of lithium aluminum hydride in 100 ml of tetrahydrofuran gives the cis-3-hydroxy-4- (2,3-dimethyl-phenoxy) -l-methyl-piperidine as a colorless oil, which consists of methylene chloride crystallized, mp.    80-82 ".     The neutral fumarate prepared from the base by treatment with fumaric acid crystallizes from methanol / ether, mp.    159-161 ".    



   Example 51
Analogously to the procedure described in Example 49, 5.2 g (0.023 mol) of the cis-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine described in Example 47 is converted into the cis 3 - by reaction in 100 ml of ethyl formate. Hydroxy-4- (3, 4-dimethylphenoxy) - l-formyl-piperidine obtained as a yellowish oil. 



   The reduction of this product (0.023 mol) carried out in analogy to Example 49 with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran gives the cis-3-hydroxy-4 (3,4-dimethylphenoxy) -l-methylpiperidine, which crystallizes from methylene chloride, M.p.    127-129 ".     The fumarate prepared from the base by treatment with fumaric acid crystallized from ethanol / ether, mp.    157-159 ".    



   Also analogously to Example 46, 6.1 g (0.025 mol) of the trans-3-hydroxy-4- (1-naphthyloxy) piperidine and 100 ml described in Example 10 are obtained
Formic acid ethyl ester the trans-3-hydroxy-4- (naphthyl oxy) - 1 -formyl-piperidine, and by reducing this product (0.025) with 3 g lithium aluminum hydride in 150 ml tetrahydrofuran the trans-3-hydroxy-4- (1- naphthyloxy) -1-methyl-piperidine as a pale yellow oil.  That from the base with
Hydrochloride prepared in ether hydrochloride is amorphous. 



   Example 52
Analogously to Example 20, the corresponding l-methyl derivatives, namely from 9.12 g of trans-3-hydroxy-4- (m-chlorophenoxy) piperidine (Example 21), are obtained using in each case 0.04 mol of the compounds below. the trans-3-hydroxy-4- (m-chlorophenoxy) -l-methyl-piperidine, from 8.36 g of trans-3-hydroxy-4-phenylthio-piperidine (example
13) the trans-3-hydroxy-4-phenylthio-1-methylpiperidine, from 9.88 g of trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) piperidine ( Example 33) the trans-3-hydroxy-4- (5,6,7,8 tetrahydro-1-naphthyloxy) -1-methyl-piperidine, from 8.44 g of trans-3-hydroxy-4- (p-fluor -phenoxy) -piperidine (Example 31) the trans-3-hydroxy-4- (p-fluorophenoxy) -lmethyl-piperidine,

   from 10.60 g of trans-3-acetoxy-4- (3,4-dimethylphenoxy) -piperidine (Example 9) the trans-3-acetoxy-4- (3,4-dimethylphenoxy) -1-methyl- piperidine, from 10.44 g of trans-3-hydroxy-4- (p-trifluoromethyl-phenoxy) piperidine (Example 36) the trans-3-hydroxy-4- (p-trifluoromethyl-phenoxy) -1-methyl-piperidine , from 9.40 g of trans-4-hydroxy-5- (3,4-dimethylphenoxy) -hexa- hydro-1 H-azepine (Example 40) the trans-4-hydroxy-5- (3,4-dimethylphenoxy) - 1-methyl-hexahydro- 1 H-azepine and its hydrochloride,

   from 11.04 g of trans-4-hydroxy-5- (3,4-dimethylphenoxy) hexa hydro-1 H-azepine (example 40) the trans-4-hydroxy-5- (3,4 dichlorophenoxy) - 1 - methyl-hexahydro-1 H-azepine and its hydrochloride and from 11.0 g of trans-4-hydroxy- (p-trifluoromethyl-phenoxy) -hexahydro-lH-azepine (Example 40) the trans-4-hydroxy-5 (p -trifluoromethyl-phenoxy) - 1 -methyl-hexahydro- 1 H-azepine and its hydrochloride. 



   Example 53
Analogously to Example 43, the 4- (m chlorophenoxy) - is obtained from 16.3 g (0.045 mol) of trans-3-hydroxy-4- (m-chlorophenoxy) -t-carbobenzyloxypiperidine (Example 21). 1-carbobenzyloxy-3-piperidone, and from 14.4 g (0.04 mol) of the latter the 4- (m-chlorophenoxy-3piperidone and its hydrochloride monohydrate, from 17.0 g (0.045 mol) of trans- 3-Hydroxy-4- (l-naphthyloxy) -l-carbobenzyloxy-piperidine (Example 10) the 4- (1-naphthyl-oxy-l-carbobenzyloxy-3-piperidone, and from 15.0 g (0.04 mol ) the latter the 4- (1-naphthyloxy) -3-piperidone and its hydrochloride monohydrate,

   from 17.15 g (0.045 mol) of trans-3-hydroxy-4- (5,6,7,8-tetra hydro-1-naphthyloxy) -1-carbobenzyloxy-piperidine (Example 33) the 4- (5.6 , 7,8-tetrahydro-1-naphthyloxy) - 1-carbobenzyl-oxy-3-piperidone and from 15.16 g (0.04 mol) of the latter the 4- (5,6,7,8-tetrahydro-1 -naphthyloxy) -3-piperidone and its hydrochloride monohydrate from 15.5 g of trans-3-hydroxy-4- (p-fluorophenoxy) -1-carbobenzyloxy-piperidine (Example 31) the 4- (p-fluoro- phenoxy) - 1 - carbobenzyloxy-3-piperidone,

   and from 13.72 g (0.04 mol) of the latter be 4- (p-fluoro-phenoxy) -3-piperidone and
Hydrochloride monohydrate and from 16.0 g of trans-4-hydroxy-3- (3, 4-dimethylphenoxy) -1-carbobenzyloxy-piperidine (Example 19) the 3- (3,4-dimethylphenoxy) -l -carbobenzyloxy-4-piperidone, and from 14.12 g (0.04 mol) of the latter the 3- (3,4-dimethyl-phenoxy) -4piperidone and its hydrochloride monohydrate. 



   Example 54
Analogously to Example 47, the cis-3-hydroxy- is obtained from 10.2 g (0.028 mol) of 4- (m-chlorophenoxy) -1-carbobenzyloxy-3-piperidone (Example 53) by selective reduction and subsequent hydrogenolysis (Example 53). 4- (m-chlorophenoxy) piperidine, from 10.5 g (0.028 mol) of 4- (1-naphthyloxy) -l-carbobenzyloxy-3-piperidone (Example 53) the cis-3-hydroxy-4- (1- naphthyloxy) piperidine, from 10.6 g (0.028 mol) of 4- (5,6,7,8-tetrahydro-1-naphthyloxy) -
I-carbobenzyloxy-3-piperidone (Example 53) the cis-3 hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) piperidine, and from 9.6 g (0.028 mol) 4- ( p-Fluorophenoxy) -1-carbobenzyloxy-3-piperidone (Example 53) the cis-3-hydroxy-4- (p-fluorophenoxy) piperidine. 



   Example 55
Analogously to Example 20, using 0.02 mol of the following compounds, 10 ml of formic acid and 5 ml of a 35% aqueous formaldehyde solution, the corresponding l-methyl derivatives, namely from 4.56 g of cis-3-hydroxy-4- ( m-chlorophenoxy) piperidine (Example 54) the cis-3-hydroxy-4- (m-chlorophenoxy) -1-methyl-piperidine, from 4.86 g of cis-3-hydroxy-4- (1 -naphthyloxy) -piperidine (Example 54) the cis-3-hydroxy-4- (l -naphthyloxy) -l -methylpiperidine, from 4.94 g of cis-3-hydroxy-4- (5,6,7, 8-tetrahydro-1-naphthyloxy) piperidine (Example 54) the cis-3-hydroxy-4- (5,6,7,8 tetrahydro-1-naphthyloxy) - 1-methyl-piperidine,

   and from 4.22 g of cis-3-hydroxy-4- (p-fluorophenoxy) piperidine (Example 54) the cis-3-hydroxy-4- (p-fluorophenoxy) -1-methylpiperidine. 



   Example 56
Analogously to Example 24, etherification and subsequent hydrogenolysis using 1.35 g (0.03 mol) of a 55% oily dispersion of sodium hydride in 20 ml of dimethylformamide, 0.02 mol of the following starting materials in 20 ml of dimethylformamide and 3, 55 g (0.025 mol) of methyl iodide the corresponding end products, namely from 7.1 g of trans-3-hydroxy-4- (2,3-dimethyl-phenoxy) -1-carbobenzyloxy-piperidine (Example 34) the trans-3- Methoxy-4 (2,3-dimethylphenoxy) piperidine, from 7.1 g of cis-3-hydroxy- (3,4-dimethylphenoxy) -1-carbobenzyloxypiperidine (Example 47) the cis-3-methoxy 4- (3,4-dimethylphenoxy) piperidine, and from 7.1 g of cis-3-hydroxy-4- (2,3-dimethylphenoxy) -1-carbobenzyloxy-piperidine (Example 48) the cis- 3-methoxy-4- (2,3dimethylphenoxy) piperidine. 



   Example 57
Analogously to Example 20, using 4.70 g (0.02 mol of the following compounds from Example 56), 10 ml of formic acid and 5 ml of a 35% aqueous formaldehyde solution, the corresponding l-methyl derivatives, namely from trans-3 - Methoxy-4- (2,3-dimethyl-phenoxy) -piperidine the trans-3-methoxy-4- (2,3-dimethyl-phenoxy) -1-methylpiperidine, from cis-3-methoxy-4- (3, 4-dimethyl-phenoxy) -piperidine is cis-3-methoxy-4- (3, 4-dimethyl-phenoxy) -1-methyl-piperidine, and from cis-3-methoxy-4- (2,3-dimethyl- phenoxy) piperidine the cis-3-methoxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine. 



   Example 58
In a suspension of 2.8 g (0.062 mol) of a 55% oily dispersion of sodium hydride in 50 ml of dimethylformamide is a solution of 15.0 g (0.04 mol) of the in the example at 30-35 "within 30 minutes 19 trans-3-hydroxy-4- (3, 4-dimethyl-phenoxy) -1-carbobenzyloxy-piperidine described in 100 ml of dimethylformamide.  The mixture is then heated to 50 and 7.16 g (0.055 mol) of 1-chloro-3-fluorobenzene are added dropwise.  The reaction mixture is then stirred at 60-70 "for 4% hours and then at room temperature for 15 hours, cooled in an ice-water bath and mixed with 250 ml of water. 

  The mixture is extracted three times with 250 ml of ethyl acetate, the combined organic phases are washed twice with water, dried over magnesium sulfate and evaporated to dryness in a water jet vacuum, then in a high vacuum.  The remaining oil is dissolved in 100 ml of toluene and filtered through a layer of silica gel.  Elution with toluene / ethyl acetate mixture (4: 1) gives the trans-3- (3 chlorophenoxy) -4- (3, 4-dimethylphenoxy) -1-carbobenzyloxypiperidine as a pale yellow oil. 



   5.4 g (0.011 mol) of this compound are dissolved in 120 ml of methanol, with 3.3 ml of a 2.5-n.  added methanolic hydrogen chloride solution and hydrogenated in the presence of 1.8 g of a 5% palladium-on-carbon catalyst at normal pressure and room temperature.  When the uptake of hydrogen has ended, the catalyst is filtered off through diatomaceous earth and the filtrate is evaporated in a water jet vacuum.  The base is released from the crude hydrochloride by treatment with aqueous ammonia solution and extracted with methylene chloride.  After evaporation of the methylene chloride solution dried over sodium sulfate, the trans-3- (3-chlorophenoxy) -4- (3,4-dimethylphenoxy) piperidine is obtained as a pale yellow oil.  The acidic fumarate prepared with fumaric acid crystallizes from methanol ether, mp.  148-150 '.    



   Example 59
Tablets weighing 100 mg containing 20 mg of active substance are produced in the following composition in the usual way:
Composition trans-3-hydroxy-4- (2,3-dimethyl-phenoxy) piperidine fumarate (2: 1) (neutral) 27 mg wheat starch 50 mg lactose 43 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 mg
135 mg
Manufacturing
The trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine.    



  fumarate (2: 1) is mixed with part of the wheat starch, milk sugar and colloidal silica and the mixture is passed through a sieve.  Another part of the wheat starch is gelatinized with a multiple of the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed. 

 

   The plastic mass is passed through a sieve of approx.  3 mm mesh size pressed, dried and the dry granules obtained again passed through a sieve.  Then the remaining wheat starch, talc and magnesium stearate are mixed in and the mixture is pressed into tablets of 135 mg weight with a cross notch. 



   Example 60
Analogously to the procedure described in Example 59, tablets weighing 100 mg containing 20 mg of trans-3-hydroxy-4- (3,4-dimethyl-phen oxy) -1-methyl-piperidine hydrochloride are prepared as the active substance forth.  


    

Claims (17)

 PATENT CLAIMS 1. Derivatives of perhydro-aza-heterocycles of the formula EMI1.1  in which X represents the oxo radical or hydrogen and the radical OR, wherein R1 represents hydrogen or an optionally substituted aliphatic, an optionally substituted araliphatic or an optionally substituted aromatic hydrocarbon radical or an acyl radical, R2 represents hydrogen or an optionally substituted aliphatic hydrocarbon radical, Y represents oxygen or is sulfur, ni and in each case stand for the values 1 to 3, where nl + n2 is at most four, and Ar represents an optionally substituted aromatic hydrocarbon radical, and their acid addition salts.  2. Compounds of formula I according to claim 1, in which X represents the oxo radical or hydrogen and the radical ORI, wherein Rl is hydrogen, lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N-mono-lower alkylcarbamoyl-lower alkyl, N, N-di-lower-alkyl-carbamoyl-lower alkyl or cyan-lower alkyl, or Phenyl or phenyl-lower alkyl or phenyloxy-lower alkyl optionally branched on the a-carbon atom, where in each case phenyl can be substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkoxycarbonyl, carbamoyl, N-mono-lower alkyl-carbamoyl, N, N-di-lower alkylcarbamoyl or cyano or in which RI is acyl , where acyl represents the group -C (= O) -R, where R is lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl, or phenyl or phenyl-lower alkyl,  where phenyl can in each case be substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, R2 is hydrogen, lower alkyl or propargyl, Y has the meaning given in claim 1 and Ar is phenyl, naphthyl, tetrahydronaphthyl or anthryl, in each case phenyl or an aromatic Ring of naphthyl or anthryl is optionally substituted by lower alkyl, hydroxy, lower alkoxy, halogen, trifluoromethyl, lower alkoxycarbonyl, carbamoyl, N-mono-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, nitro or cyano, these substituents each being 1, 2 or 3 times present and can either be the same or different, and nl, n2 and ni + n2 have the meaning given in claim 1, and their acid addition salts.  3. Compounds of the formula I according to claim 1, in which X is the oxo radical or hydrogen and the radical OR, in which R1 is hydrogen or lower alkyl having up to 4 carbon atoms, and optionally N-mono-lower alkyl- or N, N-di-lower-alkyl-substituted carbamoyl-lower alkyl, or cyano-lower alkyl, or in the lower alkyl part preferably branched phenyl-lower alkyl, carbamoylphenyl-lower alkyl or carbamoylphenyloxy-lower alkyl or acyl, where acyl represents the group -C (= O) -R, where R is lower alkyl or halogen-lower alkyl, each having up to 4 carbon atoms in the lower alkyl parts , or phenyl or phenyl-lower alkyl, where phenyl can be substituted by lower alkyl or lower alkoxy, each with up to 4 carbon atoms in lower alkyl, halogen and / or trifluoromethyl,  R2 is hydrogen or lower alkyl having up to 4 carbon atoms or propargyl, and in which Y has the meaning given in claim 1 and Ar is phenyl, naphthyl or tetrahydronaphthyl, phenyl, naphthyl or the aromatic ring of tetrahydronaphthyl optionally being by lower alkyl, hydroxy, Lower alkoxy, lower alkoxycarbonyl, N-mono-lower alkyl carbamoyl or N, N-di-lower alkyl carbamoyl is substituted, where lower alkyl has up to 4 carbon atoms in each case, or is substituted by halogen, trifluoromethyl, carbamoyl, nitro or cyano, these substituents being in each case 1- or 2-fold present and can either be the same or different, and nl, n2 and al + n2 have the meaning given in claim 1, and their acid addition salts.  4. Compounds of formula I according to claim 1, in which X represents the oxo radical or hydrogen and the radical OR, wherein Rl is hydrogen, lower alkyl, cyano-lower alkyl, or carbamoyl-lower alkyl, each having up to 4 carbon atoms in the lower alkyl part or phenyl, which is optionally in the below is substituted for Ar, or means acyl, where acyl represents the group -C (= O) -R, where R is lower alkyl having up to 4 C atoms, R2 is hydrogen or lower alkyl having up to 4 C atoms or propargyl, and Ar denotes phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, which are optionally substituted at most twice by lower alkyl, lower alkoxy, each having up to 4 carbon atoms, halogen, trifluoromethyl, carbamoyl, nitro or cyano,  wherein the substituents mentioned are aromatically bonded and in each case once or, in the case of lower alkyl, lower alkoxy and halogen, can also be present twice and may be identical or different and Y, ni, n2 and n + n2 have the meaning given in claim 1, and their acid addition salts .  5. Compounds of formula I according to claim 1, in which X represents the oxo radical or hydrogen and the radical OR, wherein Rl is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl or propargyl, and Ar phenyl, naphthyl or 5,6,7,8 -Tetrahydro-naphthyl, where phenyl, preferably at most twice, can be substituted by lower alkyl, lower alkoxy or halogen, or by trifluoromethyl, where the substituents mentioned can be the same or different, and Y, nl, n2 and nl + n2 the im Claim 1 have meaning given, and their acid addition salts.  6. trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine and its pharmaceutically acceptable acid addition salts according to claim 1.  7. Trans-3-hydroxy-4- (3,4-dimethyl-phenoxy) -1-methyl-piperidine and its pharmaceutically acceptable acid addition salts according to claim 1.    8. trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine and its pharmaceutically acceptable acid addition salts according to claim 1.  9. Trans-3-hydroxy-4- (2,3-dimethyl-phenoxy) -1-methyl-piperidine and its pharmaceutically acceptable acid addition salts according to claim 1.  10. Cis-3-hydroxy-4- (3, 4-dimethylphenoxy) piperidine and cis-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine and their pharmaceutically acceptable acid addition salts according to claim 1.  11. Cis-3-hydroxy-4- (3,4-dimethyl-phenoxy) - 1-methyl-piperidine and cis-3-hydroxy-4- (2,3-dimethyl-phenoxy) - 1-methyl-piperidine and their pharmaceutical acceptable acid addition salts according to claim 1.  12. 4- (3,4-dimethyl-phenoxy) -3-piperidone and 4- (2,3-dimethyl-phenoxy) -3-piperidone and their pharmaceutical  acceptable acid addition salts according to claim 1.  13. Compounds of the formula I according to claim 1, in which X is hydrogen and ORI, in which Rl has the meaning given in claim 1, and R2, Ar, Y, nl, n2 and nl and n have the meaning given in claim 1, and their acid addition salts.  14. Compounds of formula I according to claim 1, in which X represents the oxo radical and R2, Ar, Y, ni, n2 and ni and n2 have the meaning given in claim 1, and their acid addition salts.  15. Pharmaceutical composition, characterized by a content of a compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier.  16. Pharmaceutical composition according to claim 15, characterized in that it contains a compound according to one of claims 2 to 5, 13 and 14 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier.  17. Pharmaceutical composition according to claim 15, characterized in that it contains a compound according to one of claims 6 to 12 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier.  The present invention relates to new derivatives of perhydro-aza-heterocycles and their acid addition salts and pharmaceutical preparations which contain the new compounds.  The compounds according to the invention correspond to the formula EMI2.1  where X represents the oxo radical or hydrogen and the radical ORI, where R represents hydrogen or an optionally substituted aliphatic, an optionally substituted araliphatic or an optionally substituted aromatic hydrocarbon radical or an acyl radical, R2 represents hydrogen or an optionally substituted aliphatic hydrocarbon radical, Y represents oxygen or sulfur, ni and n each represent the values 1 to 3, where nl + n2 is at most four, and Ar represents an optionally substituted aromatic hydrocarbon radical.  Aliphatic hydrocarbon radicals R1 and R2 are primarily lower alkyl, but can also be lower alkenyl or lower alkynyl.  Araliphatic hydrocarbon radicals are in particular phenyl-lower alkyl, also phenyl-lower alkenyl or phenyl-lower alkynyl.  Aromatic hydrocarbon radicals are in particular phenyl, and also naphthyl, such as 1- or 2-naphthyl, hydrogenated Naphthyl such as 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetra hydro-2-naphthyl, anthryl such as 1-2- or 9-anthryl, 9,10 dihydro-9, 1 0-ethanone anthracenyl such as 9.1 0-dihydro-9, 10-ethanone anthracene-l-yl or 9.1 0-dihydro-9, 1 0-ethenoane thracenyl such as 9.1 0-dihydro-9, 1 0-ethenoanthracene 1 -yl, -2-yl or -9-yl. Substituents in the phenyl part of phenyl-lower alkyl, phenyl-lower alkenyl and phenyl-lower alkynyl, or in an aromatic ring of naphthyl of the type indicated or in one or two aromatic rings of anthryl, 9,10-dihydro-9,10-ethanoanthracenyl or 9,10 dihydro-9, 1 0-äthenoanthracenyl each of the above type are, for example optionally, such as halogen, substituted lower alkyl, such as lower alkyl or trifluoromethyl, optionally etherified or esterified hydroxy, such as Hydroxy, lower alkoxy, methylenedioxy or halogen, and / or optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl, amidated carboxy, e.g. optionally N-substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, further e.g. Nitro or cyan, where the radicals indicated are each 1-, 2- or 3-fold and can be either identical or different from one another and substituted radicals can have one or more substituents in any of the positions suitable for substitution.  Substituents of lower alkyl, as well as lower alkenyl or lower alkynyl are e.g. optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy, phenyloxy and / or halogen, or optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl, amidated carboxy, e.g. Carbamoyl, N-lower alkyl carbamoyl or N, N-di lower alkyl carbamoyl, or cyan.  In connection with the present invention, radicals and compounds denoted by preferably contain up to 7, in particular up to 4, acyl radicals up to 5 carbon atoms.  The general terms used in connection with the present invention have e.g. the following meanings: Lower alkyl can be unbranched or, especially at the a-carbon atom, branched and is e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. Butyl.  Lower alkenyl contains one or more double bonds and is e.g. Allyl, 1- or 2-methylallyl or 3,3-dimethylallyl, while lower alkynyl e.g. Propargyl means.  Phenyl lower alkyl is e.g. Benzyl, 1- or 2-phenylethyl, while phenyl-lower alkenyl e.g. Cinnamyl, and phenyl lower alkynyl e.g. Is 3-phenylpropargyl, the radical R e.g. can also be styryl or phenylethynyl.  Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy, furthermore n-pentyloxy or neopentyloxy.    Halogen is especially chlorine or bromine, but can also be fluorine and iodine.  Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl, while N-lower alkyl and N, N-di-lower alkyl carbamoyl, e.g. Is N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-Nmethyl-carbamoyl or N, N-diethylcarbamoyl.  Lower alkoxy lower alkyl is e.g. Methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, I-methoxy-2-propyl, l-ethoxy-2-propyl or l-ethoxy-2-butyl, where lower alkoxy is preferably from the linking carbon atom of the lower alkyl part by at least 2, usually 2- 3 carbon atoms is separated. ** WARNING ** End of CLMS field could overlap beginning of DESC **.