KR101253106B1 - Method for preparing intermediate of sitagliptin using chiral oxirane - Google Patents

Abstract

The present invention relates to 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy-4- (2, The present invention relates to a method for producing 4,5-trifluorophenyl) -butyric acid, and an intermediate of cytagliptin can be prepared easily and economically by the production method of the present invention.

Citagliptin, Intermediates, Manufacturing Method

Description

Method for preparing cytagliptin intermediate using chiral oxysilane {METHOD FOR PREPARING INTERMEDIATE OF SITAGLIPTIN USING CHIRAL OXIRANE}

The present invention relates to 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy-4- (2, A method for producing 4,5-trifluorophenyl) -butyric acid.

Cytagliptin phosphate selectively inhibits the second generation of dipeptidyl peptidase IV (DPP-4) to maintain incretin concentrations. In the monohydrate form, it was approved by the FDA in October 2006 as a dietary and exercise therapy adjunct to patients with type 2 protein, and currently in Korea or the United States as a single agent oral with Januvia ^TM or metpolmin. It is marketed as Janumet ^™ as a composite formulation for the present invention.

Such citagliptin phosphate is manufactured by various methods. For example, International Patent Publication No. WO2004 / 085661 discloses a theta after stereoselectively reducing enamine using a platinum catalyst (PtO ₂ ). A method of making gliptin is disclosed.

As another example, International Patent Publication No. WO2005 / 097733 discloses the preparation of cytagliptin through a process of stereoselectively reducing enamine using a rhodium catalyst ([Rh (cod) Cl] ₂ ) and a chiral diphosphine ligand. A method is disclosed.

As another example, J. Am . Chem . Soc ., 2009, 131 , p.11316-11317 includes a ruthenium catalyst (Ru (OAc) ₂ ) and a chiral diphosphine ligand to stereoselectively select enamines. A method for producing cytagliptin through reduction is disclosed, and WO 2009/064476 discloses a ruthenium catalyst (Ru (OAc) ₂ ), a chiral diphosphine ligand, or a chiral acid and borohydride (e.g., For example, a method of preparing cytagliptin through a process of stereoselectively reducing enamine using NaBH ₄ ) is disclosed.

Other 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid There is a method for preparing cytagliptin phosphate using as an intermediate.

As an example, WO 2004/087650 discloses cytagles through five steps from (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid as shown in Scheme 1 below. A method of preparing liptin phosphate is disclosed.

Wherein Bn represents benzyl.

Further, the International Patent Publication No. WO2004 / 087650 discloses to methyl 4 as shown in scheme 2 (2,4,5-trifluorophenyl) -3-oxo-butyrate to _{(S) -BINAP-RuCl 2 ·} Et 3 N Stereoselective reduction with hydrogen at high pressure in the presence of a catalyst, followed by hydrolysis to yield (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl)-the main intermediate of cytagliptin. A method of making butyric acid is disclosed.

In another example relating to the preparation of intermediates for cytagliptin, WO 2009/045507 discloses methyl 4- (2,4,5-trifluorophenyl) -3-oxobutyrate as enzymes, as shown in Schemes 3 and 4. By stereoselective reduction using methyl (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyrate or methyl (3R) -3-hydride as the major intermediate of cytagliptin A process for preparing oxy-4- (2,4,5-trifluorophenyl) -butyrate is disclosed.

However, these methods utilize high pressure hydrogen in the presence of a ruthenium catalyst in the preparation of (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, the main intermediate of cytagliptin. Alternatively, a chiral center was introduced at position 3 of (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid using ketone reductase.

Accordingly, the inventors have intensively studied the preparation of cytagliptin and the easy preparation of the intermediate thereof, and as a result, commercially available chiral oxysilane (2S)-made from (S) -epichlorohydrin is commercially available. (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid inexpensively and easily by using 2- (2,4,5-trifluorobenzyl) -oxysilane It has been found that the present invention can be made and the present invention has been completed.

Accordingly, an object of the present invention is to provide 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy-4, which is a major intermediate in the preparation of cytagliptin. It is to provide a method for producing-(2,4,5-trifluorophenyl) -butyric acid.

Another object of the present invention is (2S) -2- (2,4,5-trifluorobenzyl, which is used to prepare 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid. ) -Oxysilane and 4- (2,4,5-trifluorophenyl) -3-hydroxybutanenitrile.

In order to achieve the above object,

2- (2,4,5-trifluorobenzyl) -oxysilane of formula (2a) was subjected to nitrilation in the presence of a catalyst to 4- (2,4,5-trifluorophenyl) -3- Preparing hydroxybutanenitrile; And

Hydrolysis of the prepared 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile in the presence of a strong base, 3-hydroxy-4- (2, Provided are methods for preparing 4,5-trifluorophenyl) -butyric acid:

Preferably the 2- (2,4,5-trifluorobenzyl) -oxysilane is (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of formula 2b:

In addition, the present invention provides (2S) -2- (2,4,5-tri of Formula 2b used in the preparation of 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid. Fluorobenzyl) -oxysilane and 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile of Formula 3a are provided.

According to the preparation method of the present invention, 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy, which is a major intermediate of cytagliptin easily and economically Since 4- (2,4,5-trifluorophenyl) -butyric acid can be produced efficiently, industrial application is easy.

Hereinafter, the present invention will be described in more detail.

The present invention relates to 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, in particular (3S) -3-hydroxy-4- (2,4,5), which is a major intermediate of cytagliptin. -Trifluorophenyl) -butyric acid is produced easily and efficiently at low cost using chiral oxysilane.

That is, in the preparation method according to the present invention, 4- (2,4, Preparing 5-trifluorophenyl) -3-hydroxybutanenitrile, and hydrolyzing 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile prepared in the presence of a strong base To prepare 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid of Chemical Formula 1a.

Preferably, (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of formula (2b) is subjected to nitrilation in the presence of a catalyst to (3S) -4- (2,4 of formula (3b). Preparation of, 5-trifluorophenyl) -3-hydroxybutanenitrile (step 1), and (3S) -4- (2,4,5-trifluorophenyl) -3-hydrate prepared above Hydrolysis of oxybutannitrile in the presence of a strong base to prepare (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid of formula 1b (step 2) :

(2b)

Scheme 5 below, for example, sequentially proceeds with nitrilation and hydrolysis of (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane in chiral oxysilane (3S) -3- A method of preparing hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid is shown. Hereinafter, each step will be described in more detail with reference to Scheme 5 below.

(Step 1)

Step 1 is carried out by nitriding the (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of formula (2b) in the presence of a catalyst (3S) -4- (2, To prepare 4,5-trifluorophenyl) -3-hydroxybutanenitrile, specifically, (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of Chemical Formula 2b. (3S) -4- (2,4,5-trifluorophenyl) -3-hydroxybutanenitrile of formula 3b by dissolving in a solvent and then nitriding by adding sodium cyanide in the presence of a catalyst. Can be.

The (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane is a novel compound, starting from 2,4,5-trifluorobenzene halide as shown in Scheme 6 below. It can be prepared by the method of route 1 using (S)-epihalohydrin and route 2 using allyl halide.

Route 1

Method for preparing (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane according to route 1, comprising preparing Grignard reagent from 2,4,5-trifluorobenzene halide In addition, the Grignard reagent prepared above was subjected to arylation with (S) -epihalohydrin in the presence of a copper halide catalyst (2S) -3- (2,4,5-trifluoro Preparing phenyl) -1-halo-2-propanol, and (2S) -3- (2,4,5-trifluorophenyl) -1-halo-2-propanol prepared in the presence of a strong base Epoxidation.

Specifically, first, the 2,4,5-trifluorobenzene halide is used an organic halogenated alkyl such as magnesium (Mg) and 1,2-dibromoethane or magnesium and I ₂ , or isopropyl magnesium Prepared with Grignard reagent using chloride ( i- PrMgCl).

In this case, as the 2,4,5-trifluorobenzene halide, 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, or the like may be used.

Subsequently, a catalytic amount of copper halide was added dropwise to the prepared Grignard reagent, and (2S) -3- (2,4,5-tri was reacted by slowly dropping (S) -epihalohydrin at a low temperature. Prepare fluorophenyl) -1-halo-2-propanol.

As the copper halide, CuBr, CuI or a mixture thereof may be used, and more preferably CuI may be used.

Oxylanes such as (S) -epihalohydrin include the (S) or (R) isomers, each of which is readily available commercially. Specifically, (S) -epichlorohydrin may be used as the (S) -epihalohydrin.

Subsequently, the prepared (2S) -3- (2,4,5-trifluorophenyl) -1-halo-2-propanol was dissolved in a solvent, followed by addition of a strong base to carry out epoxidation reaction (2S) -2. Prepare-(2,4,5-trifluorobenzyl) -oxysilane.

Tetrahydrofuran, diethyl ether and the like can be used as the solvent.

As the strong base, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide can be used, and more preferably sodium hydroxide.

Route 2

A process for preparing (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane according to route 2 includes the steps of preparing a Grignard reagent from a 2,4,5-trifluorobenzene halide. Preparing a 3- (2,4,5-trifluorophenyl) -1-propene by arylating the prepared Grignard reagent with allyl halide, and preparing the prepared 3- (2,4, Epoxidation of 5-trifluorophenyl) -1-propene with an oxidizing agent to produce racemic 2- (2,4,5-trifluorobenzyl) -oxysilane, and (S, S The hydrodynamic kinetic resolution (HKR) of the racemic 2- (2,4,5-trifluorobenzyl) -oxysilane prepared above using) -Co-salen ( Preparing 2S) -2- (2,4,5-trifluorobenzyl) -oxysilane.

Specifically, first, a Grignard reagent is prepared from the 2,4,5-trifluorobenzene halide.

The 2,4,5-trifluorobenzene halide and the method for preparing Grignard reagent therefrom are the same as described above.

Subsequently, allylhalide is slowly added dropwise to the prepared Grignard reagent at a low temperature to be arylated to prepare 3- (2,4,5-trifluorophenyl) -1-propene.

As the allyl halide, allyl bromide may be used.

Subsequently, the obtained 3- (2,4,5-trifluorophenyl) -1-propene is dissolved in a solvent and then an oxidizing agent is added to carry out the epoxidation reaction to thereby racemic 2- (2,4,5- Prepare trifluorobenzyl) -oxysilane.

In this case, tetrahydrofuran, diethyl ether, or the like may be used as the solvent.

In addition, the oxidizing agent may be used m- ClC ₆ H ₄ CO ₃ H, CH ₃ CO ₃ H, CF ₃ CO ₃ H, H ₂ O ₂ , or a mixture thereof, more preferably m -ClC ₆ H ₄ CO ₃ H.

Then, (2S) -2- (2 by selectively HKR racemic 2- (2,4,5-trifluorobenzyl) -oxysilane using (S, S) -Co-salen of formula (4) Prepare 4,5-trifluorobenzyl) -oxysilane:

A method for obtaining the desired chiral oxysilane by selectively HKR the terminal oxysilane is described in Tetrahedron. Asymmetry , 2003, 14 , 1407-1446, and J. Am . Chem . Soc. , 2002, 124 , 1307-1315).

The nitrile reaction for (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane prepared by the above method is dimethylformamide (DMF), dimethyl cellulose oxide (DMSO), or carbon number. It is implemented in solvent, such as alcohol of 1-6 (for example, methanol, ethanol, isopropanol, etc.), More preferably, it is dimethylformamide.

As the catalyst used in the nitriding reaction, NH ₄ Cl, citric acid, acetic acid, formic acid, maleic acid, or a mixture thereof may be used, and more preferably NH ₄ Cl.

(Step 2)

Step 2 is hydrolysis of (3S) -4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile prepared in Step 1 in the presence of a strong base to form 3-hydroxy-4- (2 Preparing 4,5-trifluorophenyl) -butyric acid, preferably (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, specifically (3S) -3-hydroxy-4- (2,4 by hydrolysis of (3S) -4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile in the presence of a strong base and hydrogen peroxide Prepare, 5-trifluorophenyl) -butyric acid.

As the strong base, hydroxides of alkali metals such as sodium hydroxide (NaOH), potassium hydroxide (KOH) and lithium hydroxide (LiOH) can be used, and more preferably sodium hydroxide. It is preferable to use the said strong base as aqueous solution.

By the above preparation method, 3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid, which is the main intermediate of cytagliptin, preferably (3S) -3-hydroxy-4 -(2,4,5-trifluorophenyl) -butyric acid can be produced in good yield in a simple and economic manner.

Furthermore, in the production method according to the present invention, (2S) -2- (2,4) which is an intermediate in the preparation of (3S) -3-hydroxy-4- (2,4,5-trifluorophenyl) -butyric acid , 5-trifluorobenzyl) -oxysilane and 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile are themselves novel compounds. Accordingly, the present invention provides the above (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane and 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile. to provide.

Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Manufacturing example  1: (2S) -2- (2,4,5- Trifluorobenzyl ) - Oxirane  Produce

Step 1: Preparation of (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol

Magnesium (Mg) (1.26 g) was added to 10 ml of tetrahydrofuran (THF) solvent, and a drop of 1,2-dibromoethane was added dropwise, followed by 2,4,5-trifluorobenzene bromide (0.55 g). Was slowly added dropwise and stirred for 30 minutes. To the resulting reaction mixture was slowly added dropwise a solution of 2,4,5-trifluorobenzene bromide (9.0 g) dissolved in 50 ml of THF over 30 minutes. After stirring the resulting reaction mixture at room temperature for 1 hour, CuI (0.72 g) was added and the reaction temperature was lowered to 0 deg. To the cooled reaction mixture, (S) -epichlorohydrin (4.1 ml) diluted in 40 ml of THF solvent was slowly added dropwise over 30 minutes, warmed to room temperature and stirred for 2 hours. 50 ml of saturated NH ₄ Cl and 50 ml of ethyl acetate were added to the resulting reaction mixture, and the organic layer was separated. By washing the separated organic layer with saturated brine 50 ml, dried with MgSO ₄ filtered off the MgSO _4, remove the organic solvent in the remainder under reduced pressure to give the title compound.

Step 2: Preparation of (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane

After dissolving (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol prepared in step 1 in 50 ml of methanol, the reaction mixture was added dropwise with NaOH (2.3 g). Was prepared. After stirring the obtained reaction mixture for 1 hour, methanol was removed under reduced pressure, 50 ml of water and 50 ml of ethyl acetate were added, and the organic layer was separated. The separated organic layer washed with saturated brine and dried with MgSO _4, the title compound (6.8 g, yield: 80%) was filtered to remove MgSO _4, remove the organic solvent in the remainder under reduced pressure to give the.

¹ H-NMR (300 MHz, CDCl ₃ ): 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).

Manufacturing example  2: (2S) -2- (2,4,5- Trifluorobenzyl ) - Oxysilane  Produce

Step 1: Preparation of (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol

To a solution of 2,4,5-trifluorobenzene bromide (9.55 g) dissolved in 30 ml of THF, 26 ml of 2N i -PrMgCl (in THF) was slowly added dropwise over 60 minutes at a reaction temperature of -15 ° C. CuI (0.72 g) was added at -15 ° C to prepare a reaction mixture, and the reaction temperature was raised to -10 ° C. To the reaction mixture was slowly added dropwise (S) -epichlorohydrin (4.1 ml) diluted in 40 ml of THF solvent over 30 minutes and stirred at 0 ° C. for 1 hour. 50 ml of saturated NH ₄ Cl and 50 ml of ethyl acetate were added to the resulting reaction mixture, and the organic layer was separated. By washing the separated organic layer with saturated brine 50 ml, dried with MgSO ₄ to remove the MgSO ₄ by filtration, remove the organic solvent in the remainder under reduced pressure to give the title compound.

Step 2: Preparation of (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane

After dissolving (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol obtained in step 1 in 50 ml of methanol, NaOH (2.3 g) was added dropwise to the reaction mixture. Was prepared. After stirring the obtained reaction mixture for 1 hour, methanol was removed under reduced pressure, 50 ml of water and 50 ml of ethyl acetate were added, and the organic layer was separated. The separated organic layer washed with saturated brine, dried with MgSO _4, filtered to remove MgSO _4, and by removing the organic solvent in the remainder under reduced pressure to give the title compound (7.6 g, yield: 85%) was obtained.

Manufacturing example  3: 2- (2,4,5- Trifluorobenzyl ) - Oxirane  Produce

Step 1: Preparation of 3- (2,4,5-trifluorophenyl) -1-propene by arylation reaction

Mg (3.9 g) was added to 30 ml of THF solvent, 0.2 g of 1,2-dibromoethane was added dropwise, followed by slowly dropping 2,4,5-trifluorobenzene bromide (3.6 g) for 30 minutes. Stirred. To the reaction mixture was slowly added dropwise a solution of 2,4,5-trifluorobenzene bromide (25 g) dissolved in 60 ml of THF over 60 minutes. The resulting reaction mixture was stirred at room temperature for 1 hour, and then the reaction temperature was lowered to -10 ° C. To the cooled reaction mixture, allyl bromide (18.0 g) diluted in 60 ml of THF solvent was slowly added dropwise over 20 minutes, followed by stirring for 1 hour, and the temperature was raised to room temperature, followed by stirring for 1 hour. 300 ml of dichloromethane (MC) was added dropwise to the resulting reaction mixture to separate the organic layer. The separated organic layer was washed with 150 ml of 2 M NH ₄ Cl, washed successively with 150 ml of water, and then dried over MgSO ₄ . MgSO ₄ was filtered off and the organic solvent in the residue was removed under reduced pressure to afford the title compound.

Step 2: Preparation of 2- (2,4,5-trifluorobenzyl) -oxysilane by epoxidation reaction

The reaction mixture was prepared by dissolving 3- (2,4,5-trifluorophenyl) -1-propene obtained in step 1 in 300 ml dichloromethane and slowly dropwise adding m-CPBA (35 g). Stir for hours. 300 ml of saturated NaHCO ₃ was slowly added dropwise to the reaction mixture, and the organic layer was separated. The separated organic layer washed with 1 N NaOH 300 ml, and then was removed by and washed with brine 100 ml, dried over MgSO _4, filtered and the MgSO _4. The organic solvent in the residue was removed under reduced pressure to give the title compound (19.1 g, yield: 75%).

Manufacturing example  4: (2S) -2- (2,4,5- Trifluorobenzyl ) - Oxirane  Produce

(S, S) -Co-salen (302 mg), 2- (2,4,5-trifluorobenzyl) -oxysilane (18.8 g), AcOH (120 μL) and THF (1 mL) at room temperature ) Was added and mixed to prepare a reaction mixture. After the reaction temperature of the prepared reaction mixture was lowered to 0 ° C., H ₂ O (1.0 ml) was added dropwise at once, stirred at room temperature for 24 hours, and then THF was removed under reduced pressure. The residue was separated by column to give the title compound (7.71 g, yield: 41%).

Manufacturing example  5: (3S) -4- (2,4,5- Trifluorophenyl ) -3- Of hydroxybutanenitrile  Produce

(2S) -2- (2,4,5-trifluorobenzyl) -oxysilane (5.30 g) in a solution of 25 mL of MeOH, NaCN (2.07 g) and NH ₄ Cl dissolved in 10 mL of water (1.96 g) was added sequentially and the temperature was raised to 50 ° C. After stirring for 3 hours, the solvent in the reaction mixture was removed under reduced pressure distillation, 25 ml of water and 25 ml of ethyl acetate were added to separate an organic layer. Washed twice with saturated brine. The separated organic layer was 25 mL, which was then dried with MgSO _4, filtered to remove MgSO _4, remove the organic solvent in the remainder under reduced pressure. The obtained residue was separated by column to give the title compound (5.59 g, yield: 92%).

¹ H-NMR (300 MHz, CDCl ₃ ): 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: (3S) -3-hydroxy-4- (2,4,5- Trifluorophenyl Preparation of Butyric Acid

After dissolving (3S) -4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile (5.59 g) prepared in Preparation Example 5 in a reactor at room temperature in 30 mL of MeOH, % H ₂ O ₂ (5.31 mL) and NaOH (2.60 g) were added sequentially to prepare a reaction mixture, and the internal temperature was raised to about 70 ° C. After the reaction mixture was stirred at reflux for 6 hours at a temperature, the reaction temperature was lowered to 0 ° C. and 2N HCl (aq) (28.0 mL) was added slowly. To the reaction the resultant mixture into the organic layer was separated and ethyl acetate 30mL, washed twice The separated organic layer with saturated brine 30mL, dried with MgSO _4, filtered to remove MgSO _4, remove the organic solvent in the remainder under reduced pressure It was. The obtained residue was separated by column to give the title compound (5.48 g, yield: 90%).

¹ H-NMR (300 MHz, CDCl ₃ ): 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)

Claims (15)

2- (2,4,5-trifluorobenzyl) -oxysilane of formula (2a) was subjected to nitrile reaction in the presence of NH ₄ Cl to form 4- (2,4,5-trifluorophenyl)- Preparing 3-hydroxybutanenitrile, and Hydrolysis of the prepared 4- (2,4,5-trifluorophenyl) -3-hydroxybutannitrile in the presence of a strong base, 3-hydroxy-4- (2, Method for preparing 4,5-trifluorophenyl) -butyric acid: <Formula 1a>

&Lt; EMI ID =

<Formula 3a>

The method of claim 1, The 2- (2,4,5-trifluorobenzyl) -oxysilane is characterized in that (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of formula 2b Way: (2b)

delete The method of claim 1, Said nitrile reaction is carried out using sodium cyanide. The method of claim 1, The strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and mixtures thereof. The method of claim 1, 2- (2,4,5-trifluorobenzyl) -oxysilane, Preparing a Grignard reagent from a 2,4,5-trifluorobenzene halide, The Grignard reagent prepared above was arylated with (S) -epihalohydrin in the presence of a halogenated copper catalyst to give (2S) -3- (2,4,5-trifluorophenyl) -1-halo- Preparing 2-propanol, and (2S) -3- (2,4,5-trifluorophenyl) -1-halo-2-propanol prepared by the preparation method comprising the step of epoxidation in the presence of a strong base. Manufacturing method. The method of claim 6, The 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride and mixtures thereof Manufacturing method. The method of claim 6, The halogenated copper catalyst is selected from the group consisting of CuBr, CuI and mixtures thereof. The method of claim 6, The strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and mixtures thereof. The method of claim 1, 2- (2,4,5-trifluorobenzyl) -oxysilane, Preparing a Grignard reagent from a 2,4,5-trifluorobenzene halide; Preparing a 3- (2,4,5-trifluorophenyl) -1-propene by arylating the prepared Grignard reagent with allyl halide; The 3- (2,4,5-trifluorophenyl) -1-propene prepared above was epoxidized using an oxidizing agent to racemic 2- (2,4,5-trifluorobenzyl) -oxysilane. Preparing a; And A process for producing the racemic 2- (2,4,5-trifluorobenzyl) -oxysilane prepared by the preparation method comprising the step of selectively hydrolyzing. 11. The method of claim 10, The 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride and mixtures thereof Manufacturing method. 11. The method of claim 10, The oxidizing agent is selected from the group consisting of m- ClC ₆ H ₄ CO ₃ H, CH ₃ CO ₃ H, CF ₃ CO ₃ H, H ₂ O ₂ and mixtures thereof. 11. The method of claim 10, The kinetic hydrolysis reaction is carried out using (S, S) -Co-salen of the following formula (4): &Lt; Formula 4 >

(2S) -2- (2,4,5-trifluorobenzyl) -oxysilane of formula (2b) (2b)

4- (2,4,5-trifluorophenyl) -3-hydroxybutanenitrile of Formula 3a: <Formula 3a>