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  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
  • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
  • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/62—Carboxylic acid esters

Definitions

• the present invention relates to processes for the preparation of (R)-l- , (3,5-bis(trifluoromethyl)phenyl)ethan-l-ol and esters thereof which are useful as intermediates in the preparation of certain therapeutic agents.
• the present invention provides a process for the preparation of (R)-l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-ol which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
• the (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol prepared by the present invention may be utilized in the synthesis of (2R, 2-alpha-R, 3a)-2-[l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-l,4-oxazine of the formula:
• the present invention employs processes for the preparation of an enantiomerically enriched ester in which a mixture of the enantiomers of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol is subjected to an enantioselective conversion in the presence of a racemization catalyst and an acyl donor upon which the ester is formed and an acyl donor residue is obtained.
• General processes for the preparation of esters are disclosed by Backvall, et al., J. Am. Chem. Soc, 121, 1645-1650 (1999).
• the subject invention provides a process for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol and esters thereof via a very simple, short and highly efficient synthesis.
• novel process of this invention involves the synthesis of (R)-l- (3,5-bis(trifluoromethyl)phenyl)ethan-l-ol and esters thereof.
• present invention is concerned with novel processes for the preparation of a compound of the formula:
• the present invention is directed to processes for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
• R is hydrogen, C ⁇ _20 alkyl, C2-20 alkenyl, Ci_20 alkoxy, aryl, or Ci-20 alkyl-aryl; which comprise subjecting a compound of the formula:
• R is hydrogen, Ci_20 alkyl, C2-20 alkenyl, C ⁇ _20 alkoxy, aryl, or Cl-20 alkyl-aryl; which comprises reduction of a ketone of the formula:
• Another embodiment of the invention is directed to a process for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
• R is hydrogen, Ci_20 alkyl, C2-20 alkenyl, Ci-20 alkoxy, aryl, or C ⁇ _20 alkyl-aryl; followed by cleavage of the ester to give the compound of the formula:
• Another embodiment of the invention is directed to processes for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
• R is hydrogen, C ⁇ _20 alkyl, C2-20 alkenyl, Ci_20 alkoxy, aryl, or
• Another embodiment of the invention is directed to processes for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
• R is hydrogen, Cl-20 alkyl, C2-20 alkenyl, C ⁇ _20 alkoxy, aryl, or
• Another embodiment of the invention is directed to processes for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
• the enantioselective conversion of the mixture of enantiomers of l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-ol may be carried out with the known asymmetrical acylation catalysts, for example as described by Garrett et al., J. Am.Chem. Soc, 120, 7479-7483 (1998) and references cited therein, and by Gregory C. Fu, Chemical Innovation, 3-5 ( anuary 2000).
• An aspect of this invention is that wherein the enantioselective conversion is an enzymatic conversion, such as enantioselective conversion carried out in the presence of an enantioselective enzyme.
• Suitable enzymes that may be used in the processes of the present invention are for example the known enzymes with hydrolytic activity and a high enantioselectivity in such reactions that are also active in an organic environment, for example enzymes with lipase (i.e. esterase) activity or, when an amide is used as acyl donor, enzymes with amidase activity and lipase (i.e.
• esterase activity for example originating from Pseudomonas, in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia; Chromobacterium, in particular Chromobacterium viscosum; Bacillus, in particular Bacillus thermocatenulatus, Bacillus licheniformis; Alcaligenes, in particular Alcaligenes faecalis; Aspergillus, in particular Aspergillus niger, Candida, in particular Candida antarctica, Candida rugosa, Candida lipolytica, Candida cylindracea; Geotrichum, in particular Geotrichum candidum; Humicola, in particular Humicola lanuginosa;
• Penicillium in particular Penicillium cyclopium, Penicillium roquefortii, Penicillium camembertii; Rhizomucor, in particular Rhizomucor javanicus, Rhizomucor miehei; Mucor, in particular Mucor javanicus; Rhizopus, in particular Rhizopus oryzae, Rhizopus arrhizus, Rhizopus delemar, Rhizopus niveus, Rhizopus japonicus, Rhizopus javanicus; Porcine pancreas lipase, Wheat germ lipase, Bovine pancreas lipase, Pig liver esterase.
• an enzyme originating from Pseudomonas cepacia, Pseudomonas sp., Burkholderia cepacia, Porcine pancreas, Rhizomucor miehei, Humicola lanuginosa, Candida rugosa or Candida antarctica or subtilisin is used.
• an R-selective enzyme is used, for example from Candida antarctica.
• Such enzymes may be obtained by methods that are well known in the art. In particular, many enzymes are produced on a technical scale and are commercially available.
• the enzyme preparations employed in the present invention are not limited by purity constraints and can be both a crude enzyme solution or a purified enzyme, or it can also consist of (permeabilised and/or immobilised) cells that have the desired activity, or of a homogenate of cells with such an activity.
• the enzyme may also be used in an immobilised form or in a chemically modified form.
• the invention is in no way limited by the form in which the enzyme is used for the present invention.
• the enantioselective enzyme is Novozym435® ⁇ Candida antartic ⁇ ).
• racemization catalysts examples include redox catalysts as occurring in transfer hydrogenations.
• the racemization catalyst and the acylation catalyst are preferably chosen so that they are mutually compatible, which means that they do not or minimally deactivate each other.
• One skilled in the art may readily establish the acylation/ racemization catalyst combination that is suitable for the specific system.
• the acylation catalyst and/or the racemization catalyst may be used in heterogenized form.
• racemization catalysts examples are catalysts based on a transition metal compound.
• transition metal compounds are described for example in Comprehensive Organometallic Chemistry 'The synthesis, Reactions and Structures of Organometallic Compounds ' ' Volumes 1 - 9, Editor: Sir Gerissay Wilkinson, FRS, deputy editor: F. Gordon A. Stone, FRS, Executive editor Edward W. Abel, preferably volumes 4, 5, 6 and 8 and in Comprehensive Organometallic Chemistry 'A review of the literature 1982 - 1994', Editor-in-chief: Edward W. Abel, Geoffrey Wilkinson, F. Gordon A.
• Stone preferably volume 4 (Scandium, Yttrium, Lanthanides and Actinides, and Titanium Group), volume 7 (Iron, Ruthenium, and Osmium), volume 8 (Cobalt, Rhodium, and Iridium), volume 9 (Nickel, Palladium, and Platinum), volume 11 (Main-group Metal Organometallics in Organic Synthesis) and volume 12 (Transition Metal Organometallics in Organic Synthesis).
• Preferred transition metal compounds are of the general formula:
• n is an integer selected from 1, 2, 3 and 4; p, q and r are independently an integer selected from 0, 1, 2, 3 and 4;
• M is a transition metal, selected from iron, cobalt, nickel, rhenium, ruthenium, rhodium, iridium, osmium, palladium, platinum or samarium, or a mixture thereof, in particular palladium, ruthenium, iridium or rhodium, most preferably ruthenium or iridium;
• X is an anion selected from hydride, halogenide, carboxylate, alkoxy, hydroxy or tetrafluoroborate;
• S is a spectator ligand, a neutral ligand that is difficult to exchange, such as that selected from an olefin, a diene, or an aromatic compound selected from: benzene, toluene, xylene, cumene, cymene, naphthalene, anisole, chlorobenzene, indene, cyclopentadienyl derivatives, tetraphenyl cyclopentadienone, dihydroindene, tetrahydronaphthalene, gallic acid, benzoic acid and phenylglycine, or wherein the aromatic compound is covalently bonded to the ligand;
• L is a neutral ligand that is relatively easy to exchange with another ligand, such as that selected from the group consisting of nitrile or a co-ordinating solvent, in particular acetonitrile, dimethyl sulphoxide (DMSO), methanol, water, tetrahydrofuran, dimethyl formamide, pyridine and N-methylpyrrolidinone.
• nitrile or a co-ordinating solvent in particular acetonitrile, dimethyl sulphoxide (DMSO), methanol, water, tetrahydrofuran, dimethyl formamide, pyridine and N-methylpyrrolidinone.
• the racemization catalyst may be a transfer hydrogenation catalyst, such as a racemization catalyst which comprises a transition metal chosen from the group of Ru, Rh, Ir, Co, in particular wherein the racemization catalyst comprises a transition metal which is Ru.
• transition metal compounds include those which are selected from the group consisting of: [RuCl 2 (n 6 -benzene)] 2 , [RuCl 2 (n 6 -cymene)] 2 , [RuCl 2 (n 6 -mesitylene)] 2 , [RuCl 2 (n 6 - hexamethylbenzene)] 2 , [RuCl 2 (n 6 - 1 ,2,3 ,4-tetramethylbenzene)] 2 , [RuCl 2 (n 6 - 1,3,5- triethylbenzene)] 2 , [RuCl 2 (n 6 -l,3,5-tri ⁇ spropylbenzene)] 2 , [RuCl 2 (n 6 - tetramethylthiophene)] 2 , [RuCl 2 (n 6 -methoxybenzene)] 2 , [RuBr 2 (n 6 -benzene)] , [Rul 2 (n 6 -benzene
• the transition metal compound may be converted to a transition metal complex by for example exchanging the neutral ligand with another ligand, or complexing the transition metal compound with a ligand.
• the catalyst on the basis of the transition metal compound and the ligand can be added in the form of separate components of which one is the transition metal compound and the other is the ligand, or as a complex that contains the transition metal compound and the ligand.
• Suitable racemization catalysts are obtained for example by complexing the transition metal compound with for example a primary or secondary amine, alcohol, diol, amino alcohol, diamine, mono-acylated diamine, mono-acylated amino alcohol, monodiamine, monoamino alcohol, amino acid, amino acid amide, amino-thioether, phosphine, bisphosphine, aminophosphine, preferably an aminoalcohol, monoacylated diamine, monotosylated diamine, amino acid, amino acid amide, amino thioether or an aminophosphine.
• a primary or secondary amine alcohol, diol, amino alcohol, diamine, mono-acylated diamine, mono-acylated amino alcohol, monodiamine, monoamino alcohol, amino acid, amino acid amide, amino-thioether, phosphine, bisphosphine, aminophosphine, preferably an aminoalcohol, monoacylated diamine, monotosylated diamine, amino acid, amino acid
• ligands are described in EPO Patent Publication EP 0916637, in Tetrahedron: Asymmetry 10 (1999) 2045-2061, and in Molecules (2000), 5, 4-18. Complexing does not necessarily take place with the optically active ligand, but optionally with the racemate corresponding to the optically active ligands.
• the ligands are preferably used in quantities that vary between 0.5 and 8 equivalents relative to the metal, in particular between 1 and 3 equivalents. In the case of a bidentate ligand use is preferably made of 0.3-8, in particular 0.5-3 equivalents.
• An example of preferred ligands for inclusion in the racemization catalyst is the class of amino acid amides such as compounds of the formula:
• R 1 and R each independently represent hydrogen, C ⁇ _9 alkyl, aryl or Ci-9 alkyl-aryl, which is unsubstituted or substituted with C ⁇ _9 alkyl, hydroxy, C ⁇ _9 alkoxy or C ⁇ _6 alkyl-sulfonyl;
• R and R each independently represent hydrogen, Ci_9 alkyl, aryl or Ci-9 alkyl-aryl, which is unsubstituted or substituted with Ci_9 alkyl, hydroxy, C ⁇ _9 alkoxy or C ⁇ _6 alkyl-sulfonyl, or R 1 and R 2 form a ring together with the N and C atom to which they are attached.
• a preferred ligand is (R,S)- -methyl phenylglycinamide.
• activation of catalysts for example catalysts obtained by complexing of the transition metal compound and the ligand, can be effected by treating the transition metal compound or the complex of the transition metal compound and the ligand in a separate step with a base, for example KOH, KOtBu, or NaOH, and subsequently isolating it by separating the base, or by activating the transition metal compound or the complex of the transition metal compound and the ligand in situ, when the acylation/racemization takes place, with a mild base, for example a heterogeneous base, in particular KHCO 3 or K 2 CO 3 , or a homogeneous base, in particular an organic amine, for example triethylamine.
• a base for example KOH, KOtBu, or NaOH
• racemization catalyst and acylation catalyst are not particularly critical and are for example less than 5, preferably less than 1 mole , calculated relative to the substrate.
• the optimum quantities of both catalysts are linked to each other; the quantity of acylation catalyst is preferably adapted so that the overall reaction continues to proceed efficiently, that is to say, that the racemization reaction does not proceed much slower than the acylation reaction and thus the e.e. of the remaining substrate does not become too high.
• the optimum ratio between racemization catalyst and acylation catalyst for a given reaction/catalyst system may readily be established by one skilled in the art.
• the acyl donor may be an activated form of a carboxylic acid, for example esters or amides or anhydrides.
• the acyl donor residue is removed from the reaction mixture. In the present invention it is preferred that the acyl donor residue is removed via distillation under reduced pressure.
• the acyl donor is chosen such that the acyl donor itself is (relatively) not volatile under the reaction conditions while its acyl donor residue is volatile, and oxidation of the substrate is prevented as much as possible under the reaction conditions.
• acyl donors are carboxylic acid esters of an alcohol with l-4C-atoms and a carboxylic acid with 4-20C-atoms, for instance isopropyl butyric acid ester.
• Suitable acyl donors include esters of C ⁇ -20 alkyl carboxylic acids, preferably isopropyl acetate, isopropenyl acetate, isobutyl acetate, vinyl acetate, ethyl acetate, isopropyl laureate, isopropenyl laureate or other readily available esters of C ⁇ -20 alkyl carboxylic acids and C ⁇ _7 alkyl alcohols.
• Preferred acyl donors include isopropyl acetate, isopropenyl acetate, isobutyl acetate, vinyl acetate, ethyl acetate, isopropyl laureate and isopropenyl laureate.
• the acyl donor is isopropenyl acetate.
• the acyl donor residue is preferably removed from the reaction mixture on a continuous basis, for example by preferentially transferring the acyl donor residue to another phase relative to the acyl donor and the other reaction components. This can be achieved by physical and by chemical methods, or by a combination thereof.
• Examples of physical methods by which the acyl donor residue can irreversibly be removed from the phase in which the enzymatic reaction occurs are selective crystallisation, extraction, complexing to form an insoluble complex, absorption or adsorption; or by such a choice of the acyl donor that the acyl donor residue is sufficiently volatile relative to the reaction mixture, or is converted in situ into another compound that is sufficiently volatile relative to the reaction mixture to remove the acyl donor residue irreversibly from the reaction mixture; examples of the latter are the application of isopropyl acetate as acyl donor resulting in volatile isopropyl alcohol as acyl donor residue, and the application of isopropenyl acetate as acyl donor, resulting, via isopropenyl alcohol, in volatile acetone as acyl donor residue.
• a reduced pressure In order to remove the acyl donor residue use can be made of a reduced pressure, depending on the boiling point of the reaction mixture.
• the pressure (at a given temperature) is preferably chosen in such a way that the mixture refluxes or is close to refluxing.
• the boiling point of a mixture can be lowered by making an azeotropic composition of the mixture. Examples of chemical methods of removal are covalent bonding or chemical or enzymatic derivatization.
• Another aspect of this invention is that wherein the acyl donor is chosen so that the acyl donor residue is converted in situ into another compound.
• the (R,S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol that is used as substrate (substrate alcohol) can be formed beforehand from the corresponding ketone l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one in a separate step (that principally does not need to be stereoselective at all) with the aid of a reducing ancillary reagent, the reduction preferably being catalysed by the racemization catalyst, and a cheap and preferably volatile alcohol being used as reducing ancillary reagent (non- stereoselective transfer hydrogenation).
• the (R,S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol may optionally be formed in situ from the corresponding ketone l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-one with the aid of a reducing ancillary reagent.
• This provides flexibility to employ substrate ketone or substrate alcohol or mixtures of both as substrate. The choice can depend on the availability and the simplicity of the synthesis. If the alcohol is formed in situ from the ketone, a hydrogen donor is also added as ancillary reagent.
• ancillary reagent preferably a secondary alcohol is added to the reaction mixture that promotes the conversion of the ketone to the substrate alcohol and is not converted by the acylation catalyst.
• the ancillary reagent is preferably chosen so that it is not also removed from the reaction mixture by the same irreversible removal method by which the acyl donor residue is removed, that this ancillary reagent is not acylated by the acylation catalyst, and has sufficient reduction potential, relative to the substrate ketone, for the creation of a redox equilibrium.
• Reducing agents other than alcohols may also be used as ancillary reagents.
• Compounds suitable for use as ancillary reagents may readily be determined by one skilled in the art.
• the product ester of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol obtained may subsequently be isolated from the reaction mixture using common practice isolation techniques, depending on the nature of the ester, for instance by extraction, distillation, chromatography or crystallization. If the product is isolated by crystallization further enantiomeric enrichment may be obtained. If desired, the mother liquor (which may contain the alcohol, ester and/or ketone involved in the reaction) may be recirculated to the racemization catalyst, non stereoselective transfer hydrogenation or to the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester.
• the solids will be removed from the mother liquor and, according to common practice, if necessary a purge will be built in to prevent built up of impurities.
• the ester in the mother liquor will first be saponified. This is especially desirable if saponification of the ester under the reaction conditions of the non-stereoselective transfer hydrogenation respectively the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester, is rather slow.
• an enantiomerically enriched ester of (R)- 1 -(3 ,5-bis(trifluoromethyl)phenyl)ethan- 1 -ol can be obtained with enantiomeric excess (e.e.) larger than 95%, preferably larger than 98%, more preferably larger than 99%, optionally after (re)crystallization.
• the enantiomerically enriched ester obtained can subsequently be used as such, or the enantiomerically enriched ester may be subsequently converted by a known procedure into the corresponding enantiomerically enriched alcohol (R)-l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-ol.
• This can for example be effected by means of catalytic conversion, for example catalysis by an acid, base or enzyme.
• an enantioselective enzyme When an enantioselective enzyme is used the enantiomeric excess of the product alcohol can be increased further by this.
• the enantioselective esterification according to the invention has been carried out with the aid of an enzyme, the same enzyme can very suitably be used for the conversion of the enantiomerically enriched ester into the enantiomerically enriched alcohol.
• the cleavage of the alcohol from the ester of l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol can be achieved in the absence of water, for instance by solving the isolated ester of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol in for instance methanol and transesterification into the methyl ester thereby liberating the l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol, adding the desired solvent and removing the methanol for instance by distillation.
• the acyl donor can be freely chosen in such a way that the physical or chemical properties of the acyl donor and the acyl donor residue are optimal for the irreversible removal of the acyl donor residue and the treatment of the reaction mixture.
• enantiomerically enriched alcohol (R)-l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-ol with an enantiomeric excess (e.e.) larger than 95%, preferably larger than 98%, more preferably larger than 99% can be obtained, optionally after recrystallization and/or conversion with the aid of an enantioselective enzyme.
• the concentration at which the reaction is carried out is not particularly critical.
• the reaction can be carried out without a solvent.
• a solvent may be used.
• the reaction can suitably be carried out at greater concentrations, for example at a substrate concentration greater than 0.4 M, in particular greater than 0.8 M.
• the substrate (eventually substrate mixture) concentration is greater than 1M.
• the (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
• the present invention is directed to a process for purification or enhancing the enantiomeric purity of enantiomerically enriched (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which comprises: contacting enantiomerically enriched (R)-l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-ol with an acyl donor in the presence of an enzyme, a transfer hydrogenation catalyst and a base, to give an ester of (R)-l-(3,5-bis(trifluoromethyl)- phenyl)ethan- 1 -ol) ; followed by cleavage of the ester to give (R)-l-(3,5-bis(trifluoro- methyl)phenyl)ethan- 1 -ol .
• Another aspect of this alternate embodiment is directed to (R)-l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol which is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, preferably greater than 95%, more preferably greater than 98%, particularly greater than 99% and especially greater than 99.5% (enantiomeric excess).
• R is hydrogen, Cl-20 alkyl, C2-20 alkenyl, C ⁇ _20 alkoxy, aryl, or Cl-20 alkyl-aryl.
• the starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds.
• bromination of 1,3- bis(trifluoromethyl)benzene gives 3,5-bis(trifluoromethyl)bromobenzene.
• Treatment of 3,5-bis(trifluoromethyl)bromobenzene with magnesium, followed by reaction with acetic anhydride provides l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one.
• the rate and selectivity of the bromination is highly dependent on the agitation of the two phase reaction. Slower stirring increases the amount of bis- bromination and slows the overall rate of reaction.
• the rate of bromination is also dependent on the ratio of acetic to sulfuric acid.
• the assay yield of l,3-bis(trifluoromethyl)bromobenzene was 93.7% (137.3 g, 469 mmol), which contained 0.6% l,3-bis(trifluoromethyl)benzene, 1.0% l,2-dibromo-3,5-bis(trifluoromethyl)benzene, and 0.3% l,4-dibromo-3,5-bis-
• Example preparation 100 ⁇ L sample quenched into 3.5 mL of 1:1 THF:2N HC1, then diluted to 100 mL in 65:35 acetonitrile:pH 6 buffer).
• Grignard formation was considered complete when the bromide level is less that 1 mol%.
• THF 10 mL was used as rinse. This solution was then added to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15 °C over 1 hr.
• the resulting heterogeneous reaction mixture was degassed by five vacuum (reflux)/nitrogen purge cycles at 25°C.
• the temperature of the reaction mixture was increased to 84 °C, to perform the transfer hydrogenation until 95% of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one was converted to (R,S)-l-(3,5-bis(trifluoro-methyl)phenyl)ethan-l-ol.
• the isopropanol and acetone were removed by distillation under reduced pressure.
• the temperature of the distillation mixture was decreased to 70 °C. From now, the temperature of the reaction mixture was maintained at 70°C and at this temperature the vacuum was slowly decreased to 100 mbar.
• the resulting heterogeneous mixture was degassed by one vacuum/nitrogen purge cycle.
• the reaction mixture was aged for another 4 hours, before the enzymatic acylation was continued by the addition of a second amount of isopropenyl acetate (100.9 g, 1.009 mol).
• the pressure was slowly reduced to approximately 200 mbar in order to distill the formed acetone and a small amount of isopropenyl acetate.
• the resulting heterogeneous reaction mixture was degassed by five vacuum (reflux)/nitrogen purge cycles at 25°C.
• the temperature of the reaction mixture was increased to 84 °C, to perform the transfer hydrogenation until 95% of l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one was converted to (R,S)-l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-ol.
• the isopropanol and acetone were removed by distillation under reduced pressure.
• the temperature of the reaction mixture was decreased to 70 °C. From now, the temperature of the reaction mixture was maintained at 70°C and at this temperature the vacuum was slowly decreased to 100 mbar.
• the resulting heterogeneous mixture was degassed by one vacuum/nitrogen purge cycle.
• the reaction mixture was aged for another 4 hours, before the enzymatic acylation was continued by the addition of a second amount of isopropenyl acetate (100.9 g,
• the obtained mother liquor (inclusive wash solvent) from the procedure above was collected and used as follows.
• a three neck round bottom flask was charged with the mother liquor and the heptane was removed by distillation under reduced pressure (>100 mbar). From the residue 20 % of the total amount was drained.
• l-(3,5-bis(trifluoromethyl)phenyl)- ethan-1-one 220.0 g, 0,86 mol was added to replenish the total amount of bis(trifluoromethyl)-phenyl derivatives to 1 mol [the bis(trifluoromethyl)phenyl derivatives are l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-one, l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-ol and l-(3,5-bis(trifluoromethyl)-phenyl)ethyl acetate].
• the temperature of the reaction mixture was increased to reflux, to perform the transfer hydrogenation until 95% of l-(3,5-bis(trifluoromethyl)- phenyl)ethan-l-one was converted to (R,S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l- ol.
• Methanol, isopropanol and acetone were removed by distillation under reduced pressure.
• the temperature of the distillation mixture was decreased to 70 °C. From now, the temperature of the reaction mixture was maintained at 70°C and at this temperature the vacuum was slowly decreased to 100 mbar. Distillation was continued at approximately 100 mbar until almost all isopropanol was removed.
• the reaction mixture was aged for another 4 hours, before the enzymatic acylation was continued by the addition of a second amount of isopropenyl acetate (100.9 g, 1.009 mol).
• the pressure was slowly reduced to approximately 200 mbar in order to distill the formed acetone together with a small amount of isopropenyl acetate.
• the applied vacuum during distillation was limited to 100 mbar to avoid sublimation of (R,S)-l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-ol.
• Novozym435® 400 mg
• isopropenyl acetate 6 g, 0.06 mol
• the kinetic resolution was continued for 2 hours.
• the remaining isopropenyl acetate and acetone was removed by distillation under reduced pressure.
• 5 ml toluene was added and distilled under reduced pressure.
• the applied vacuum during all distillations was limited to 100 mbar.
• the resulting heterogeneous reaction mixture was degassed by five vacuum (reflux)/nitrogen purge cycles at 25°C.
• the temperature of the heterogeneous solution was increased to 70°C, to perform the aselective transfer hydrogenation for 2 hours.
• the acetone and isopropanol were distilled under reduced pressure.
• the allowed vacuum during the distillation was limited to 100 mbar, to avoid sublimation of (R,S)-l-(3,5- bis(trifluoromethyl)-phenyl)ethan-l-ol.
• 100 ml oxygen free toluene was added and 90 ml toluene was distilled under reduced pressure at 70°C.
• reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above.
• specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

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