WO2011040717A2

WO2011040717A2 - Method for preparing intermediate of sitagliptin using chiral oxirane

Info

Publication number: WO2011040717A2
Application number: PCT/KR2010/006346
Authority: WO
Inventors: Nam Du Kim; Ji Yeon Chang; Jae Hyuk Jung; Hyun Seung Lee; Dong Jun Kim; Young Kil Chang; Gwan Sun Lee
Original assignee: Hanmi Holdings Co., Ltd.
Priority date: 2009-10-01
Filing date: 2010-09-16
Publication date: 2011-04-07
Also published as: KR20110036308A; WO2011040717A3; TW201118101A; AR079102A1; KR101253106B1

Abstract

Disclosed is: a novel, simple and low-cost method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, which is used as a key intermediate in the preparation of sitagliptin.

Description

METHOD FOR PREPARING INTERMEDIATE OF SITAGLIPTIN

USING CHIRAL OXIRANE

FIELD OF THE INVENTION

The present invention relates to a method for preparing 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin. BACKGROUND OF THE INVENTION

Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved by the US Food and Drug Admimstration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes in October 2006 and is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent) or JANUMET™ (as an oral combination of sitagliptin/Metformin).

Various methods for preparing sitagliptin phosphate have been developed. For example, WO 2004/085661 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using a platinum-based catalyst, Pt0₂. WO 2005/097733 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively employing a rhodium-based catalyst, [Rh(cod)Cl]₂ with a chiral diphosphine ligand.

The document [J. Am. Chem. Soc, 2009, 131, p.l 1316-11317] discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using a ruthenium-based catalyst, Ru(OAc)₂ with a chiral diphosphine ligand, and WO 2009/064476 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using Ru(OAc)₂ and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent such as NaBH₄.

On the other hand, there has been developed a method for preparing sitagliptin phosphate by using 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, (3S)-3-hydroxy-4- (2,4,5-trifluorophenyl)-butyric acid in particular, as a key intermediate. For example, WO 2004/087650 discloses a method for preparing sitagliptin phosphate from (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid through the five- step processes shown in Reaction Scheme 1 :

Reaction Scheme 1

wherein, Bn is benzyl.

WO 2004/087650 also discloses a method for preparing (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key sitagliptin intermediate, comprising the steps of: conducting a stereoselective reduction of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutyrate in the presence of (S)-BINAP-RuCl₂-Et₃N under a high hydrogen pressure, and hydrolyzing the resulting compound, as shown in Reaction Scheme 2:

Reaction Scheme 2

Yield : 83% Ee : 94%ee wherein, Me is methyl and BINAP is 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl. Further, WO 2009/045507 discloses methods for preparing methyl (S)- and (R)- enantiomers of 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyrate, a key sitagliptin intermediate, via the stereoselective enzymatic reduction of methyl 4-(2,4,5- trifluorophenyl)-3-oxobutyrate using an enzyme, as shown in Reaction Schemes 3 and 4:

Reaction Scheme 3

Yield : 86%<

Ee : 96.6%ee

wherein, KRED-NADH- 110™ is a trade name of the ketoreductase enzyme (Codexis, Redwood City, CA) and A-KRED-NADH is a recycle mixture containing KRED-NADH.

However, the above methods must be carried out under a high hydrogen pressure in the presence of a ruthenium catalyst, or using a ketone reducing enzyme to obtain (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid having a chiral center at the 3- position.

The present inventors have therefore endeavored to develop a novel method for preparing sitagliptin which is free from the above-mentioned problems associated with the conventional methods and unexpectedly found that (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid can be prepared by a simple and low-cost method using (2S)-2-(2,4,5-trifluorobenzyl)-oxirane prepared from the commercially available (S)- epichlorohydrin.

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a novel method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid, which is a key intermediate in the synthesis of sitagliptin.

It is another object of the present invention to provide (2S)-2-(2,4,5- trifluorobenzyl)-oxirane and 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile which are used in the preparation of 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid.

In accordance with an aspect of the present invention, there is provided a method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)butyric acid of formula (la), comprising the steps of:

subjecting 2-(2,4,5-trifluorobenzyl)-oxirane of formula (Ila) to β-hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia); and

hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base:

Preferably, the 2-(2,4,5-trifluorobenzyl)-oxirane is (2S)-2-(2,4,5-trifluorobenzyl)- oxirane of formula (lib):

In accordance with an aspect of the present invention, there is provided (2S)-2- (2,4,5-trifluorobenzyl)-oxirane of formula (lib) and 4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile of formula (Ilia), which are used in the preparation of 3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is characterized in that 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin, is prepared by using a chiral oxirane with a high yield and at a low cost.

The inventive method comprises the steps of: subjecting 2-(2,4,5- trifluorobenzyl)-oxirane of formula (11a) to β-hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia); and hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid of formula (la).

Preferably, the inventive method comprises the steps of: subjecting (2S)-2-(2,4,5- trifluorobenzyl)-oxirane of formula (lib) to β-hydrocyanation in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula

(Illb) (step 1); and hydrolyzing the (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid of formula (lb) (step 2):

The method for preparing (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid using (2S)-2-(2,4,5-trifluorobenzyl)-oxirane as a starting material according to the present invention is shown in Reaction Scheme 5, but not limited thereto.

Reaction Scheme 5

(Illb) (lb)

Hereinafter, description of the preparation method illustrated in Reaction Scheme 5 by each step will be given in detail.

The (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb) is prepared by subjecting (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) to β- hydrocyanation in the presence of a catalyst.

Particularly, (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) is dissolved in a solvent and conducted a β-hydrocyanation by adding sodium cyanide in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb).

The (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is a novel compound and may be prepared by treating a 2,4,5-trifluorobenzene halide as a starting material with a (S)- epihalohydrin (Route 1); or by treating the 2,4,5-trifluorobenzene halide with a allyl halide (Route 2) as shown in Reaction Scheme 6: Reaction Scheme 6

wherein, m-CPBA is m-chloroperoxybenzoic acid.

Route 1

The method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 1 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating a (S)-epihalohydrin using the Grignard reagent in the presence of a copper halide to obtain (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol; and conducting an epoxidation reaction of the (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2- propanol in the presence of a strong base.

Particularly, the 2,4,5 -trifluorobenzene halide is treated with magnesium (Mg) and organic alkyl halide (e.g., 1,2-dibromoethane); Mg and I₂; or isopropyl magnesium chloride (z^'-PrMgCl) to obtain a Grignard reagent.

Examples of the 2,4,5-trifluorobenzene halide include 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.

Next, (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol is prepared by arylating the (S)-epihalohydrin using the Grignard reagent. Preferably, the Grignard reagent is mixed with a catalytic amount of the copper halide, and then the (S)-epihalohydrin is added thereto slowly at a low temperature to obtain (2S)-3-(2,4,5-trifluorophenyl)-l- halo-2-propanol.

Examples of the copper halide include CuBr, Cul, and a mixture thereof, preferably Cul.

The oxirane such as (S)-epihalohydrin comprises (S) and (R) isomer which are commercially available. Examples for the (S)-epihalohydrin include (S)- epichlorohydrin.

Then, (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by dissolving (2S)-3- (2,4,5-trifluorophenyl)-l-halo-2-propanol into a solvent and conducting an epoxidation reaction of a strong base.

Examples of the solvent include tetrahydrofuran, diethylether, and the like.

Examples of the strong base include a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof, preferably sodium hydroxide.

Route 2

The method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 2 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating an allyl halide with the Grignard reagent to obtain 3- (2,4,5-trifluorophenyl)-l-propene; conducting an epoxidation reaction of 3-(2,4,5- trifluorophenyl)-l-propene using an oxidant to obtain a racemic 2-(2,4,5- trifluorobenzyl)-oxirane; and carrying out selective hydrolytic kinetic resolution (HKR) of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen.

Particularly, a Grignard reagent is prepared using a 2,4,5-trifluorobenzene halide. The methods for preparing the 2,4,5-trifluorobenzene halide and the Grignard reagent using the same are the same as described above.

Then, an allyl halide is arylated using the Grignard reagent at a low temperature to obtain 3-(2,4,5-trifluorophenyl)-l-propene.

Examples for the allyl halide include allyl bromide and the like.

Next, a reacemic 2-(2,4,5-trifluorobenzxyl)-oxirane is prepared by dissolving 3-

(2,4,5-trifluorophenyl)-l-propene in a solvent and adding an oxidant thereto to induce an epoxidation.

Examples of the solvent include tetrahydrofuran, diethylether, and the like.

Examples of the oxidant include m-ClC^CCbH, CH₃C0₃H, CF₃C0₃H, H₂0₂, and a mixture thereof, preferably m-ClC₆H₄C0₃H.

Then, optionally (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by conducting a selective HKR of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen of formula (IV):

The method for preparing the desired chiral oxirane via selective HKR of the terminal oxirane has been disclosed in the documents [see Tetrahedron Asymmetry, 2003, 14, 1407-1446, and J Am. Chem. Soc, 2002, 124, 1307-1315].

The β-hydrocyanation of the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is conducted in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or d to C₆ alcohol {e.g., methanol, ethanol, and isopropanol), preferably DMF.

The β-hydrocyanation is conducted in the presence of a catalyst such as H4CI, citric acid, acetic acid, formic acid, maleic acid, or a mixture thereof, preferably NH₄CI.

The 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, preferably (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid is prepared by hydrolyzing (3S)-4-(2,4,5- trifluorophenyl)-3-hydroxybutane nitrile obtained in Step 1 in the presence of a strong base and H₂0₂.

Examples of the strong base include an alkali metal hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH) or a mixture thereof, preferably sodium hydroxide. Preferably, the strong base is used in a form of aqueous solution.

The method according to the present invention makes it possible to easily prepare 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key intermediate in the synthesis of sitagliptin, with a high yield and a low cost, which is suitable for mass production of sitagliptin.

Further, the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane and 4-(2,4,5-trifluorophenyl)- 3 -hydroxy butane nitrile which are used in preparing (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid as a intermediate, are novel compound. Accordingly, the present invention provides the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane and 4-(2,4,5- trifluorophenyl)-3-hydroxybutane nitrile. The following preparative examples and examples illustrate the embodiments of the present invention in more detail. However, the following preparative examples and examples of the present invention are merely examples, and the present invention is not limited thereto. Preparation Example 1: Preparation of (2S)-2-(2,4,5-trifluorobenzyI)-oxirane

Step 1: preparation of (2S)-3-(2A5-trifluorophenyl -chloro-2-prepanol Magnesium (Mg) (1.26 g) was added to tetrahydrofuran (THF) (10 ml) and a drop of 1 ,2-dibromomethane was added thereto. To the resulting mixture, 2,4,5- trifluorobenzene bromide (0.55 g) was added slowly, and then stirred for 30 min. To the reaction mixture thus obtained, 2,4,5-trifluorobenzene bromide (9.0 g) in THF (50 ml) was added dropwise over 30 min and then stirred at room temperature for 1 hr. Cul (0.72 g) was added thereto and the temperature of the resulting reaction mixture was lowered to 0 ^°C. To the cooled reaction mixture, (S)-epichlorohydrin (4.1 ml) in THF (40 ml) was added dropwise over 30 min, and then stirred for 2 hrs at room temperature. Saturated NH4CI (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0₄, and filtered off MgS0₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.

Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl -oxirane (2S)-3-(2,4,5-Trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and an aqueous solution of NaOH (2.3 g) was added thereto dropwise. The resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0₄, and filtered off MgSO₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (6.8 g, yield: 80 %).

'H-NMR(300MHz, CDC1₃) : δ 7.17-7.05 (2H, m), 6.96-6.88 (2H, m), 3.16-3.13 (1H, m) 3.14 (1H, dd, J=4.68, 14.7), 2.82-2.77 (2H, m), 2.54-2.47 (1H, m).

Preparation Example 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane

Step 1 : Preparation of (2SV3-(2.4,5-trifluorophenvn-l-chloro-2-propanol

2N -PrMgCl in THF (26 ml) was added to 2,4,5-trifluorobenzene bromide (9.55 g) in THF (30 ml) dropwise at -15 ^°C for lhr. Cul (0.72 g) was added thereto at -15 ^°C and raised the temperature of the resulting mixture to -10 ^°C. To the resulting mixture, (S)-epichlorohydrin (4.1 ml) in THF (40 ml) was added dropwise over 30 min and then stirred at 0 ^°C for 1 hr. Saturated N¾C1 (50 ml) and ethyl acetate (50 ml) were added to the resulting reaction mixture to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0₄, and filtered off MgS0₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.

Step 2: preparation of (2S -2-(2,4,5-trifluorobenzylVoxirane

(2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and NaOH (2.3 g) was added thereto dropwise. The resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0₄, and filtered off MgS0₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (7.6 g, yield: 85 %).

Preparation Example 3: Preparation of 2-(2,4,5-trifluorobenzyl)-oxirane

Step 1: Preparation 3-(2A5-trifluorophenyl -l-propene

Mg (1.26 g) was added to THF (30 ml) and a drop of 1 ,2-dibromomethane (0.2 g) was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (3.6 g) was added slowly and then stirred for 30 min. To the reaction mixture thus obtained, 2,4,5-trifluorobenzene bromide (25 g) in THF (60 ml) was added dropwise over 60 min and then stirred at room temperature for 1 hr. The temperature of the resulting mixture was lowered to -10 ^°C . To the cooled mixture, allyl bromide (18.0 g) in THF (60 ml) was added dropwise over 20 min and then stirred for 1 hrs. The temperature of the resulting mixture was increased to room temperature and then stirred for 1 hr. Dichloromethane (MC) (300 ml) was added to the resulting mixture to induce phase separation. The organic layer was isolated, washed with 2 M NH₄CI (150 ml) and water (150 ml) successively, dried over MgS0₄, and filtered off MgS0₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.

Step 2: Preparation of 2-(2,4,5-trifluorobenzyl^')-oxirane

3-(2,4,5-Trifiuorophenyl)-l-propene obtained in step 1 was dissolved in dichloromethane (300 ml) and m-chloroperoxybenzoic acid (m-CPBA) (35 g) was added thereto dropwise. The resulting mixture was stirred for 17 hr and then saturated NaHC0₃ (300 ml) was added thereto to induce phase separation. The organic layer was isolated, washed with 1 N NaOH (300 ml) and brine (100 ml) successively, dried over MgS0₄, and filtered off MgS0₄. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (19.1 g, yield: 75 %).

Preparation Example 4: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane

(S,S)-Co-salen (302 mg), 2-(2,4,5-trifluorobenzyl)-oxirane (18.8 g), acetic acid

(AcOH) (120 uL) and THF(1 mL) were mixed in a reactor at room temperature. The temperatue of the resulting mixture was lowered to 0 ^°C and H₂0 (1.0 ml) was added thereto. The mixture thus obtained was stirred at room temperature for 24 hrs and condensed under a reduced pressure to remove THF. The residue was subjected to column chromatography to obtain the title compound (7.71 g, yield: 41 %).

Preparation Example 5: Preparation of (3S)-4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile

To a solution of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (5.30 g) in MeOH (25 ml), NaCN (2.07 g) in water (10 ml) and NH₄C1 (1.96 g) were added successively and warmed up to 50 ^°C . The resulting mixture was stirred for 3 hrs and condensed under a reduced pressure to remove the solvent. The residue was mixed with water (25 ml) and ethyl acetate (25 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (25 ml) twice, dried over MgS0₄, filtered off MgS0₄, and condensed under a reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to obtain the title compound (5.59 g, yield: 92 %).

'H-NMR(300MHz, CDC1₃) : δ 7.19-7.08 (2H, m), 6.99-6.90 (2H, m), 4.24-4.15 (1H, m), 2.96-2.83 (2H, m), 2.65-2.48 (2H, m)

Example 1: Preparation of (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid

(3S)-4-(2,4,5-Trifluorophenyl)-3-hydroxybutane nitrile (5.59 g) obtained in Preparation Example 5 was dissolved in MeOH (20 ml) in a reactor at room temperature and 30 % H₂0₂ (5.31 mL) and NaOH (2.60 g) were added thereto successively. The resulting mixture was warmed up 70 ^°C and refluxed for 6 hrs with stirring. The temperature of the resulting mixture was lowered to 0 ^°C and 2N HCl (aq) (28.0 mL) was added slowly thereto. The mixture thus obtained was extracted with ethyl acetate (30 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (30 ml) twice, dried over MgS0₄, filtered off MgS0₄, and condensed under a reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to obtain the title compound (5.48 g, yield: 90 %).

'H-NMR(300MHz, CDC1₃) : δ 7.27-7.07 (2H, m), 6.96-6.86 (2H, m), 6.0 (1H, br), 4.30-4.22 (m, 1H), 2.79 (2H, d, J=6.3), 2.61-2.44 (m, 2H)

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)butyric acid of formula (la), comprising the steps of:

subjecting 2-(2,4,5-trifluorobenzyl)-oxirane of formula (Ila) to β- hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile of formula (Ilia); and

F (Ilia).

2. The method of claim 1, wherein the 2-(2,4,5-trifluorobenzyl)-oxirane is (2S)-2- (2,4,5-trifluorobenzyl)-oxirane of formula (lib):

3. The method of claim 1, wherein the catalyst is selected from the group consisting of NH4CI, citric acid, acetic acid, formic acid, maleic acid, and a mixture thereof.

4. The method of claim 1, wherein the β-hydrocyanation is conducted by using sodium cyanide.

5. The method of claim 1, wherein the strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof.

6. The method of claim 1, wherein the 2-(2,4,5-trifluorobenzyl)-oxirane is prepared by a method comprising the steps of:

preparing a Grignard reagent using a 2,4,5-trifluorobenzene halide;

arylating a (S)-epihalohydrin in the presence of a copper halide to obtain (2S)-3- (2,4,5-trifluorophenyl)-l-halo-2-propanol using the Grignard reagent; and

conducting an epoxidation reaction of the (2S)-3-(2,4,5-trifluorophenyl)-l-halo- 2-propanol in the presence of a strong base.

7. The method of claim 6, wherein the 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.

8. The method of claim 6, wherein the copper halide is selected from the group consisting of CuBr, Cul, and a mixture thereof.

9. The method of claim 6, wherein the strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof.

10. The method of claim 1, wherein 2-(2,4,5-trifluorobenzyl)-oxirane is prepared by a method comprising the steps of:

preparing a Grignard reagent using a 2,4,5-trifluorobenzene halide;

arylating an allyl halide with the Grignard reagent to obtain 3-(2,4,5- trifluorophenyl)- 1 -propene; conducting an epoxidation reaction of the 3-(2,4,5-trifluorophenyl)-l-propene using an oxidant to obtain a racemic 2-(2,4,5,-tifluorobenzyl)-oxirane; and

carrying out selective hydrolytic kinetic resolution of the racemic 2-(2,4,5,- tifluorobenzyl)-oxirane.

11. The method of claim 10, wherein the 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.

12. The method of claim 10, wherein the oxidant is selected from the group consisting of m-ClCetL_tCOsH, CH3CO3H, CF3CO3H, H₂0₂, and a mixture thereof.

13. The method of claim 10, wherein the selective hydrolytic kinetic resolution is conducted using (S,S)-Co-salen of formula (IV):

(IV).

14. (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib):

F (lib).

15. 4-(2,4,5-Trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia):

(Ilia).