PROCESS FOR THE PREPARATION OF (1R)-1-[3,5-B!S(TRIFLUOROMETHYL)
PHENYL] ETHANOL
INTRODUCTION TO THE INVENTION The present invention relates to a process for the preparation of preparation of the (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol compound of Formula I. This compound is an intermediate in the synthesis of compounds possessing pharmacological activity, such as aprepitant.

Aprepitant is a substance P (neurokinin-1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name EMEND™ as 80 mg or 125 mg capsules.
International Application Publication No. WO 00/1202326 A1 discloses the preparation of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol by treating 1-(3,5-bis (trifluoromethyl) phenyl) ethan-1-one with rhodium or a ruthenium catalyst and a ligand in the presence of 2-propanol.

U.S. Patent Application Publication No. 2004/0191880 A1 discloses the preparation of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol by enantioselective reduction of a prochiral aromatic ketone 3,5-bis (trifluoromethyl) acetophenone by using lactobacillus enzyme Lactobacillus Kefiri DSM20587 to afford (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol.
Joseph F. Payack et al, Journal of the American Chemical Society, Vol. 125 (8), 2003, pages 2129-35 discloses the preparation of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol by reduction of 1-(3,5-Bis«trifluoromethylphenyl) ethanone using a BH3-PhNEt2 complex in the presence of methyltertiarybutyl ether at -10 to 0° C to afford 97% of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol with 93% enantiomeric excess ("e.e.") which on recrystallization resulted in >99% e.e.
SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of preparation of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol compound of Formula I, an intermediate used in the preparation of aprepitant, an embodiment of the process comprising the steps of:
a) reacting (±)-1-[3,5-bis (trifluoromethyl) phenyljethanol compound of Formula III with a suitable acetylating agent in the presence of a suitable enzyme;
b) separating the (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate compound of Formula IVa; and
c) hydrolyzing (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate compound of Formula IVa using a suitable acid to afford the compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of (1R)-1-[3,5-bis
(trifluoromethyl) phenyl] ethanol compound of Formula I, an intermediate useful in the
preparation of aprepitant.
As an embodiment of present invention, there is provided a process for the
synthesis of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol of Formula I, which process
comprises the steps of:

suitable organic solvent to afford a mixture of the compound (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate of Formula (IVa) and the compound (1S)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol of Formula (IVb).
Suitable acetylating reagents include but are not limited to methyl acetate, vinyl acetate, vinyl laurate, vinyl butyrate, isopropenyl acetate, acetic anhydride, butyric anhydride and the like.
Suitable enzymes include but are not limited to lipases such as Candida antarctica lipase-type B (CAL-B), Lipase-A-Amano-6, Pseudomonas alcaligens, Candida rugosa, Rhizopus japanicus, Mucor javanicus, Pseudomonas fluorescence and the like.
The reaction can be conducted in the presence of a base. Suitable bases include but are not limited to organic bases such as methylamine, dimethylamine, triethylamine, pyridine, 2,6-lutidine, ammonium hydroxide and the like; and mixtures thereof or their combination with water in various proportions.
Suitable organic solvents can include but are not limited to; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof or their combinations with water in various proportions without limitation.
The temperatures for the process of present invention are usually about 0 °C to about 40 °C, but any temperature can be chosen as long as the stability of the compound of Formula III and the enzyme used are not compromised.
Step b) involves separating the (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate compound of Formula IVa from the mixture comprising the compound (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate of Formula (IVa) and the compound (1S)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol of Formula (IVb), using suitable techniques.

Suitable techniques include crystallization, chromatographic purification and the like.
The suitable solvents that can be used for separation by crystallization include but are not limited to: ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof or their combinations with water in various proportions without limitation.
The chromatographic separations include column chromatography, flash chromatography, separation by high performance liquid chromatography (HPLC) and other separation techniques known in the art.
Purification by means of chromatography can be performed with a packed bed column chromatography or fluidized bed chromatography technique and the like, which comprises filling the column with a suitable pre-equilibrated mixture of compounds, coated or immobilized on the adsorbent or inert particles. Inert particles may be resin or glass beads or sand or any other particulate material, and the mixture of compounds as a liquid or mobile phase is passed through the column.
Inert particles used herein to prepare the substrate include but are not limited to: resins such as porous copolymers of methacrylic acid crosslinked with divinylbenzene like DUOLITE™ AP143/1083 (cholestyramine resin USP), AMBERLITE™ IRP-64 and IRP-88 (a porous copolymer of methacrylic acid crosslinked with divinylbenzene); polymethacrylate based polymers; copolymers of polyacrylate, methacrylate and other derivatives thereof having either hydroxyl groups alone or a combination of hydroxy! and halogen atoms such as chloride, fluoride or bromide; copolymers of polymethacrylate with surface grafted moieties such as hydroxyl containing geminal or vicinal di hydroxyl groups and/or having substituted halogen atoms selected from chlorine, fluorine or bromine; resins based on polymethacrylate matrix or its combination with other acrylate polymers, prepared by cross-linking of monomers, with or without grafted moieties that are aliphatic or aromatic containing hydroxyl groups with or without substituted halogen

atoms from chlorine, fluorine or bromine; such as cross-linked carbohydrate materias such as agarose, agar, cellulose, dextran, chitosan, carrageenan, alginate and the like; silica; glass; plastics; porous metalloid oxides, porous metallic oxides; metal pyrophosphate, metal metaphosphate or a combination thereof such that metaphosphate is in combination with metals like magnesium, alkaline earth metals, manganese, iron, copper, zinc, aluminum, zirconium, aluminum, calcium, magnesium and the like.
The chromatographic separations using silica gel in the adsorption steps can be identical or different ones may be used. Selection of silica gel depends upon the properties of the silica gel (pore size, grain size, surface area, polarity of the surface), type of material to be purified, level and nature of impurities present, type of medium, and the mobile phase.
Chromatography apparatus comprises a chromatography column having a column housing defining a bed space to contain in use a bed of particulate chromatography medium, through which in use a process liquid containing components to be separated is passed, to separate the components chromatographically resulting in the desired purity of the components.
Chromatographic separation member including a substrate carrying on at least one surface a thin layer of a chromatographically active capture material and to a method for separating, or removing, one or more components from a fluid which may contain a mixture of components utilizing the chromatographic separation member.
These processes involve easy adsorption and washing operations without the need of any additional pre-purification while maintaining satisfactory fast rates of recovery and good durability of the adsorbent, that is, inert particles.
The purification can be done by using columns of defined dimensions depending upon the amount of sample to be purified, flow rate of the mobile phase and the nature of the sample containing the mixture of wanted precursor and unwanted isomer in a suitable solvent system.
Step c) involves hydrolyzing the (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate compound of Formula IVa using a suitable acid to afford the compound of Formula I.

Suitable acids include but are not limited to inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and the like.
The present process of present invention is simple, eco-friendly process resulting in high yields and a high purity compound of Formula I.
Certain specific aspects and embodiments of the invention are further described in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1 PREPARATION OF (1R)-1-[3,5-BIS (TRIFLUOROMETHYL) PHENYL] ETHYL ACETATE (FORMULA (IVa))
2 L of toluene and 100 g of (±)-1-(3,5-bistrifluoromethyl)phenylethanol of Formula III were charged in a clean and dry round bottom flask at about 30-32° C followed by stirring for about 15 minutes to get a clear solution. 4.1 g of 2,6-lutidine was charged followed by charging of vinyl acetate (200 mL) and the mixture was stirred for about 15 minutes. The resultant mass was heated to about 40 °C followed by charging of the enzyme Candida antarctica lipase-type B (CAL-B), in the form of the commercial product Novozyme® 435 manufactured by Novozymes AS, Bagsvaerd, Denmark and having > 10,000 U/g of the recombinant enzyme adsorbed on a macroporous acrylic resin polymeric matrix (5 g). The suspension was stirred for about 72 hours and reaction progress was monitored by high performance liquid chromatography (HPLC). After completion of the reaction, the enzyme was filtered followed by concentration of the filtrate at about 65 °C. 500 mL of water was charged to the residue followed by stirring for about 20 minutes. Organic and aqueous layers were separated followed by separation of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethyl acetate of Formula IVa and (1S)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol of Formula IVb using column chromatography on silica gel of 60-120 mesh and elution with a mixture of 10% ethyl acetate and 90% n-hexane (9 litres), to afford 45 g of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethyl acetate of Formula IVa, with a chiral purity of 98.5% e.e. and 45 g of (1S)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol of Formula IVb.

EXAMPLE 2 PREPARATION OF (1R)-1-[3,5-BIS (TRIFLUOROMETHYL) PHENYL] ETHANOL (FORMULA I)
8 g of (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethyl acetate of Formula IVa, a mixture of 80 mL of demineralised water and 80 mL of methanol were charged in a clean and dry round bottom flask followed by charging of 8 mL of aqueous hydrochloric acid (concentration 36.5 %). Resultant mixture was stirred for about 10 minutes followed by heating to about 70 °C for about 8 hours. After the completion of reaction, the mass was cooled to about 35 °C followed by extraction of the mass with 3x80 mL of dichloromethane. Organic and aqueous layers were separated and the organic layer was washed with 3x80 mL of water followed by drying the organic layer over anhydrous sodium sulphate. Organic layer was distilled at about 45°C under vacuum to afford 6 g of the title compound with purity: 94.6 %, and S-isomer content: 5.037% by chiral HPLC.
CLAIMS:
1. A process for preparing (1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethanol
comprising the steps of:
reacting (±)-1-[3,5-bis (trifluoromethyl) phenyl]ethanol with an acetylating agent in the presence of an enzyme to form (1R)-1-[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate; and
hydrolyzing (1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethyl acetate with an acid.
2. The process of claim 1, wherein an acetylating agent comprises methyl acetate, vinyl acetate, vinyl laurate, vinyl butyrate, isopropenyl acetate, acetic anhydride, or butyric anhydride.
3. The process of claim 1, wherein an acetylating agent comprises vinyl acetate.
4. The process of any one of claims 1-3, wherein an enzyme comprises Candida antarctica lipase-type B.
5. The process of any one of claims 1-4, wherein an enzyme comprises Candida antarctica lipase-type B adsorbed on a polymeric matrix.

6. The process of any one of claims 1-5, further comprising purifying (1R)-1-
[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate, before hydrolyzing.
7. The process of any one of claims 1-5, further comprising purifying (1R)-1-
[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate by chromatography, before hydrolyzing.
8. The process of any one of claims 1-5, further comprising purifying (1R)-1-
[3,5-bis(trifluoro-methyl)phenyl] ethyl acetate by column chromatography on silica gel,
before hydrolyzing.
9. The process of claim 8, wherein (1R)-1-[3,5-bis(trifluoro-methyl)phenyl]
ethyl acetate is eluted from a column using a mixture of 10% ethyl acetate and 90% n-
hexane, by volume 9 litres.
10. The process of any one of claims 1-9, wherein (1R)-1-[3,5-
bis(trifluoromethyl)phenyl] ethyl acetate is hydrolyzed with an inorganic acid.