A method for preparing aminoacetonitrile compounds and intermediates thereof

Abstract

The present invention discloses a method for preparing an aminoacetonitrile compound and an intermediate thereof, belonging to the technical field of pharmaceutical synthesis. The aminoacetonitrile compound is a compound of formula (I). The method for preparing the compound of formula (I) of the present invention uses 1-(tert-butyldimethylsilyloxy)-2-acetone as a starting material 1, and obtains a high-purity chiral intermediate 2 under the action of a chiral catalyst. The chiral intermediate 2 is subjected to a condensation reaction with p-trifluoromethylthiobenzoyl chloride to obtain an intermediate 3, which is then subjected to a deprotection and substitution reaction to obtain the compound of formula (I). Finally, the compound of formula (I) is recrystallized from a solvent to obtain a fine product. In the method for preparing the compound of formula (I) of the present invention, a chiral catalyst is used to efficiently obtain the key chiral intermediate, avoiding the chiral resolution process. The reagents used are all low-toxic or non-toxic, environmentally friendly, and the reaction conditions are simple. The prepared compound of formula (I) has a high yield and purity, and the product quality is stable, making it suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an aminoacetonitrile compound and an intermediate thereof. Background Art

[0002] The compound of formula (I) is an aminoacetonitrile anthelmintic developed by Novartis Animal Health, primarily used to treat and control intestinal worm infections in sheep. It was first approved for marketing in Europe in 2009 and subsequently launched in countries such as Australia, Brazil, and New Zealand. The structure of the compound of formula (I) is as follows:

[0003] .

[0004] The compound of formula (I) has achieved good clinical therapeutic effects, but existing synthesis processes use chemical resolution methods to resolve the chiral isomers of the compound of formula (I). For example, patent WO2008 / 096231 A1 discloses a method for preparing the compound of formula (I) that first synthesizes the racemic compound and then uses a preparative liquid phase to separate the isomers to obtain the compound of formula (I). Patent CN101056849A discloses a method for synthesizing the compound of formula (I) that uses a preparative liquid phase to separate the isomers. Although this patent discovers that the inferior isomer can be converted to the target isomer under certain conditions, the final product is still a racemate, requiring preparative liquid phase separation and purification. The above-mentioned disclosed synthesis methods reveal that this step limits the potential for improving the yield and reducing the cost of synthesizing the compound of formula (I).

[0005] In view of the disadvantage of low selectivity for the synthesis of optical isomers of the compound of formula (I) in the existing process, the present invention innovatively uses a chiral catalyst to directly and highly selectively synthesize the target optical isomer, thereby significantly improving the yield. In particular, by recrystallizing the crude compound of formula (I), impurities are easily controlled, making it suitable for industrial production. Summary of the Invention

[0006] In view of the above technical background, the present invention provides a method for efficiently synthesizing aminoacetonitrile compounds and intermediates thereof. The aminoacetonitrile compounds are compounds of formula (I), and their structures are as follows:

[0007] .

[0008] The present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a method for preparing an intermediate of a compound of formula (I), wherein the intermediate is a chiral intermediate 2, comprising the following steps: dissolving 1-(tert-butyldimethylsilyloxy)-2-propanone as a starting material 1 in isopropanol, adding a chiral catalyst, a phase transfer catalyst, an ammonia source, and trimethylsilyl cyanide to react to obtain chiral intermediate 2. The reaction scheme is as follows:

[0010] .

[0011] Furthermore, the chiral catalyst consists of a monovalent copper salt and a ligand.

[0012] Furthermore, the monovalent copper salt is selected from one or both of cuprous bromide and cuprous chloride, and preferably the monovalent copper salt is cuprous bromide.

[0013] Furthermore, the ligand is selected from one or both of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, and the preferred ligand is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

[0014] Furthermore, the phase transfer catalyst is one or more of benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium bromide; preferably, the phase transfer catalyst is benzyltriethylammonium chloride.

[0015] Furthermore, the ammonia source is selected from one or more of ammonia solution, ammonia water, and tert-butylsulfenamide, and preferably the ammonia source is one or two of ammonia solution and tert-butylsulfenamide.

[0016] Furthermore, the ammonia solution is an organic solution of ammonia.

[0017] Furthermore, the organic solution of ammonia is selected from ammonia / methanol solution and ammonia / ethyl acetate solution.

[0018] Furthermore, the molar ratio of the 1-(tert-butyldimethylsilyloxy)-2-propanone, monovalent copper salt, ligand, phase transfer catalyst, ammonia source, and trimethylsilyl cyanide is 1:(0.01-2):(0.01-2):(0.5-1):(0.7-30):(1-1.5), and the preferred molar ratio is 1:0.05:0.05:1:5:1.2.

[0019] Furthermore, the weight-to-volume ratio of the 1-(tert-butyldimethylsilyloxy)-2-propanone to isopropanol is 5.3:13.2.

[0020] In a second aspect, the present invention provides a method for preparing a compound of formula (I), comprising the following steps:

[0021] (1) Chiral intermediate 2 reacts with trifluoromethylthiobenzoyl chloride to obtain intermediate 3. The reaction scheme is as follows.

[0022] .

[0023] (2) Intermediate 3 reacts with a deprotecting agent to obtain intermediate 4. The reaction scheme is as follows:

[0024] .

[0025] (3) Intermediate 4 undergoes substitution reaction with 3-chloro-4-trifluoromethylbenzonitrile to obtain a crude compound of formula (I). The reaction scheme is as follows:

[0026] .

[0027] (4) The crude compound of formula (I) is dissolved in isopropanol solvent, heated until clear and then cooled to allow the compound of formula (I) to precipitate. The solution is filtered, washed with water, and dried to obtain the fine compound of formula (I).

[0028] Furthermore, the molar ratio of trifluoromethylthiobenzoyl chloride to chiral intermediate 2 in step (1) is (1.1-2):1.

[0029] Furthermore, the deprotecting agent in step (2) is selected from one or more of tetrabutylammonium fluoride, tetraethylammonium fluoride, cesium fluoride, and potassium carbonate / methanol, and preferably the deprotecting agent is tetrabutylammonium fluoride or cesium fluoride.

[0030] Furthermore, the molar ratio of the intermediate 3 in step (2) to the deprotecting agent is 1:(0.8-10).

[0031] Furthermore, the molar ratio of 3-chloro-4-trifluoromethylbenzonitrile to intermediate 4 in step (3) is (3-1):1.

[0032] Beneficial effects:

[0033] (1) The present invention directly and selectively synthesizes the target optical isomer intermediate by using a suitable chiral catalyst, avoiding the chiral resolution process and significantly improving the yield.

[0034] (2) The reagents used in the present invention are non-toxic or low-toxic, the reaction conditions are mild, and the method is environmentally friendly.

[0035] (3) The present invention adopts solvent recrystallization to prepare the fine compound of formula (I), thereby achieving controllable process impurities of the compound of formula (I), ensuring product safety and meeting pharmaceutical specifications. DETAILED DESCRIPTION

[0036] To make the objectives, technical solutions, and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other implementations obtained by those of ordinary skill in the art without inventive effort are within the scope of protection of the present invention.

[0037] The starting materials and reaction reagents used in the specific examples of the present invention are all commercially available. Experimental methods in the examples of the present invention where specific conditions are not specified are generally carried out under conventional conditions or under conditions recommended by the raw material or product manufacturers. The reaction schemes in the following examples are as follows:

[0038] .

[0039] Example 1

[0040] 1-(tert-Butyldimethylsilyloxy)-2-propanone (30.1 g, 0.16 mol) was added to 300 mL of isopropanol, followed by cuprous bromide (1.2 g, 8 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (5.0 g, 8 mmol), benzyltriethylammonium chloride (36.5 g, 0.16 mol), 7M ammonia / methanol solution (114.3 mL, 0.8 mol), and trimethylsilyl cyanide (18.8 g, 0.19 mol). The mixture was stirred at 30°C for 8 h. After completion of the reaction, the mixture was filtered, the filter cake was washed once with methanol, and the filtrate was concentrated under reduced pressure to obtain a viscous oil. The oil was then extracted three times with 300 mL of ethyl acetate and water. The organic phases were combined and dried under reduced pressure to obtain 30.2 g of chiral intermediate 2 in an 88.2% yield.

[0041] Chiral intermediate 2 (21.4 g, 0.1 mol) was dissolved in 150 mL of dichloromethane, and triethylamine (12.1 g, 0.12 mol) was added. p-Trifluoromethylthiobenzoyl chloride (26.5 g, 0.11 mol) was added under ice bath, and the reaction was restored to room temperature for 2 h. After the reaction was completed, 200 mL of water was added to quench the reaction. The layers were separated, and the aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 37.8 g of intermediate 3 with a yield of 90.4%.

[0042] Intermediate 3 (41.8 g, 0.1 mol) was dissolved in 200 mL of methanol, and cesium fluoride (45.6 g, 0.3 mol) was added. The reaction was carried out at room temperature for 2 h. After completion, the oil was dried under reduced pressure to obtain an oil. 150 mL of dichloromethane and 300 mL of water were added to the oil, and the layers were separated. The aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 27.8 g of intermediate 4 with a yield of 91.3%.

[0043] Intermediate 4 (30.4 g, 0.1 mol) was dissolved in 200 mL of N,N-dimethylformamide, and 3-chloro-4-trifluoromethylbenzonitrile (20.6 g, 0.1 mol) was added. NaH (6 g, 0.15 mol) was added in batches at 0-10°C. After completion, the temperature was raised to 30°C and the reaction was continued for 2 h. 200 mL of water was added to quench the reaction. The mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed four times with saturated brine. The organic phase was dried under reduced pressure to obtain 44.1 g of a crude compound of formula (I) with a yield of 93.1%.

[0044] To the crude compound of formula (I) was added 353 mL of isopropanol, the temperature was raised to reflux to dissolve the product, the temperature was kept stirring for 30 min, the temperature was lowered to room temperature, crystallized for 4 h, filtered, and the filter cake was washed with water to obtain 40.7 g of the dried fine product of formula (I), with a yield of 92.4%.

[0045] Example 2

[0046] 1-(tert-Butyldimethylsilyloxy)-2-propanone (37.7 g, 0.2 mol) was added to 300 mL of isopropanol, followed by cuprous bromide (0.28 g, 2 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.25 g, 2 mmol), benzyltriethylammonium chloride (22.8 g, 0.1 mol), 7M ammonia / methanol solution (857.1 mL, 6 mol), and trimethylsilyl cyanide (19.8 g, 0.2 mol). The reaction was stirred at 30°C for 9 h. After completion of the reaction, the mixture was filtered, the filter cake washed once with methanol, and the filtrate was concentrated under reduced pressure to yield a viscous oil. The oil was then extracted three times with 300 mL of ethyl acetate and water. The organic phases were combined and dried under reduced pressure to yield 37.6 g of chiral intermediate 2 in an 87.8% yield.

[0047] Chiral intermediate 2 (21.4 g, 0.1 mol) was dissolved in 150 mL of dichloromethane, and triethylamine (15.1 g, 0.15 mol) was added. p-Trifluoromethylthiobenzoyl chloride (48.1 g, 0.2 mol) was added under ice bath, and the reaction was restored to room temperature for 2 h. After the reaction was completed, 200 mL of water was added to quench the reaction. The layers were separated, and the aqueous phase was extracted twice with 150 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 38.2 g of intermediate 3 with a yield of 91.4%.

[0048] Intermediate 3 (41.8 g, 0.1 mol) was dissolved in 200 mL of methanol, and tetrabutylammonium fluoride (20.9 g, 0.08 mol) was added. The reaction was carried out at room temperature for 2 h. After completion, the oil was dried under reduced pressure to obtain an oil. 150 mL of dichloromethane and 300 mL of water were added to the oil, and the layers were separated. The aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 27.4 g of intermediate 4 with a yield of 90.2%.

[0049] Intermediate 4 (30.4 g, 0.1 mol) was dissolved in 180 mL of N,N-dimethylformamide, and 3-chloro-4-trifluoromethylbenzonitrile (30.8 g, 0.15 mol) was added. NaH (8.0 g, 0.2 mol) was added in batches at 0-10°C. After completion, the temperature was raised to 30°C and the reaction was continued for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added twice and extracted. The organic phases were combined and washed four times with saturated brine. The organic phase was dried under reduced pressure to obtain 43.9 g of a crude compound of formula (I) with a yield of 92.9%.

[0050] 878 mL of isopropanol was added to the crude compound of formula (I), and the temperature was raised to reflux to dissolve the product. The mixture was stirred for 30 min at this temperature, cooled to room temperature, and crystallized for 4 h. The mixture was filtered and the filter cake was washed with water to obtain 38.9 g of the fine compound of formula (I) with a yield of 88.2%.

[0051] Example 3

[0052] 1-(tert-Butyldimethylsilyloxy)-2-propanone (37.7 g, 0.2 mol) was added to 500 mL of isopropanol, followed by cuprous chloride (39.56 g, 0.4 mol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (231.4 g, 0.4 mol), benzyltriethylammonium bromide (54.4 g, 0.2 mol), aqueous ammonia (138.5 mL, 1.8 mol), and trimethylsilyl cyanide (19.8 g, 0.2 mol). The reaction was stirred at 30°C for 6 h. After completion of the reaction, the mixture was filtered, the filter cake was washed once with methanol, and the filtrate was concentrated under reduced pressure to obtain a viscous oil. The oil was extracted three times with 300 mL of ethyl acetate and water. The organic phases were combined and dried under reduced pressure to obtain 38.2 g of chiral intermediate 2 in an 89.3% yield.

[0053] Chiral intermediate 2 (21.4 g, 0.1 mol) was dissolved in 200 mL of dichloromethane, and triethylamine (30.3 g, 0.3 mol) was added. p-Trifluoromethylthiobenzoyl chloride (36.1 g, 0.15 mol) was added under ice bath, and the reaction was restored to room temperature for 2 h. After the reaction was completed, 200 mL of water was added to quench the reaction, and the layers were separated. The aqueous phase was extracted twice with 150 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 38.3 g of intermediate 3 with a yield of 91.5%.

[0054] Intermediate 3 (41.8 g, 0.1 mol) was dissolved in 500 mL of methanol, and tetraethylammonium fluoride (185.2 g, 1 mol) was added. The reaction was carried out at room temperature for 2 h. After completion, the oil was dried under reduced pressure to obtain an oil. 150 mL of dichloromethane and 300 mL of water were added to the oil, and the layers were separated. The aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 27.1 g of intermediate 4 with a yield of 89.1%.

[0055] Intermediate 4 (30.4 g, 0.1 mol) was dissolved in 180 mL of N,N-dimethylformamide, and 3-chloro-4-trifluoromethylbenzonitrile (41.1 g, 0.2 mol) was added. NaH (4.4 g, 0.11 mol) was added in batches at 0-10°C. After completion, the temperature was raised to 30°C and the reaction was continued for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added twice and extracted twice. The organic phases were combined and washed four times with saturated brine. The organic phase was dried under reduced pressure to obtain 43.2 g of a crude compound of formula (I) with a yield of 91.3%.

[0056] To the crude compound of formula (I) was added 173 mL of isopropanol, the temperature was raised to reflux to dissolve the product, the temperature was kept stirring for 30 min, the temperature was lowered to room temperature, crystallized for 4 h, filtered, and the filter cake was washed with water to obtain 40.0 g of the dried fine product of formula (I), with a yield of 92.6%.

[0057] Example 4

[0058] 1-(tert-Butyldimethylsilyloxy)-2-propanone (37.7 g, 0.2 mol) was added to 200 mL of isopropanol, and cuprous chloride (1.9 g, 0.02 mol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.5 g, 0.02 mol), benzyltriethylammonium bromide (54.4 g, 0.2 mol), tert-butylsulfenamide (17.0 mg, 0.14 mol) and trimethylsilyl cyanide (29.7 g, 0.3 mol) were added in sequence. The mixture was stirred at 30 ° C for 6 h, and 4M hydrochloric acid isopropanol solution (100 mL, 0.4 mol) was added. Stirring was continued for 1 h. After the hydrochloric acid reaction was completed, the mixture was filtered, the filter cake was washed once with methanol, and the filtrate was concentrated under reduced pressure to obtain a viscous oil. 300 mL of ethyl acetate was added to the oil, and water was added for extraction three times. The organic phases were combined and dried under reduced pressure to obtain 37.4 g of chiral intermediate 2 with a yield of 87.3%.

[0059] Chiral intermediate 2 (21.4 g, 0.1 mol) was dissolved in 200 mL of dichloromethane, and triethylamine (20.2 g, 0.2 mol) was added. p-Trifluoromethylthiobenzoyl chloride (36.1 g, 0.15 mol) was added under ice bath, and the reaction was restored to room temperature for 2 h. After the reaction was completed, 200 mL of water was added to quench the reaction, and the layers were separated. The aqueous phase was extracted twice with 150 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 38.3 g of intermediate 3 with a yield of 91.6%.

[0060] Intermediate 3 (41.8 g, 0.1 mol) was dissolved in 300 mL of methanol, and potassium carbonate (41.4 g, 0.3 mol) was added. The reaction was carried out at room temperature for 2 h. After completion, the mixture was dried under reduced pressure to obtain a viscous material. 150 mL of dichloromethane and 500 mL of water were added to the viscous material, and the layers were separated. The aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain 27.3 g of intermediate 4 with a yield of 89.8%.

[0061] Intermediate 4 (30.4 g, 0.1 mol) was dissolved in 180 mL of N,N-dimethylformamide, and 3-chloro-4-trifluoromethylbenzonitrile (61.6 g, 0.3 mol) was added. NaH (4.4 g, 0.15 mol) was added in batches at 0-10°C. After completion, the temperature was raised to 30°C and the reaction was continued for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added twice and extracted. The organic phases were combined and washed four times with saturated brine. The organic phase was dried under reduced pressure to obtain 42.8 g of a crude compound of formula (I) with a yield of 90.6%.

[0062] To the crude compound of formula (I) was added 428 mL of isopropanol, the temperature was raised to reflux to dissolve the product, the temperature was kept stirring for 30 min, the temperature was lowered to room temperature, crystallized for 4 h, filtered, and the filter cake was washed with water to obtain 39.5 g of the fine product of formula (I) with a yield of 92.4%.

[0063] Comparative Example 1

[0064] .

[0065] 1-(tert-Butyldimethylsilyloxy)-2-propanone (200 g, 1.0 eq) was added to 500 mL of methanol, and ammonium chloride (170.6 g, 3.0 eq) and 7 M ammonia / methanol solution (1.52 L, 10 eg) were added to the reaction system, and the temperature was raised to 25 ° C. and stirred for 30 minutes. Then, sodium cyanide (78.25 g, 1.5 eg) was added to the reaction system in batches. After the addition was completed, the reaction solution was clarified and then stirred at 25 ° C for 20 hours. The reaction was tracked by thin layer chromatography (TLC). After 20 hours, the reaction was completed. The filter cake was filtered and washed with methanol (50 mL). It was concentrated under reduced pressure at 45 ° C to obtain a brown viscous oil. Ethyl acetate (1 L) was then added to the brown oil and stirred at 25°C for 1 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). The organic phases were combined and concentrated under reduced pressure at 45°C to obtain compound 2 (220 g, yield 96.6%, R:S=50.9:49.1).

[0066] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A method for preparing an intermediate of a compound of formula (I), wherein the intermediate is a chiral intermediate 2, characterized in that: The following steps are involved: 1-(tert-butyldimethylsilyloxy)-2-propanone is used as the starting material 1 and dissolved in isopropanol. A chiral catalyst, a phase transfer catalyst, an ammonia source, and trimethylsilyl cyanide are added to react to obtain a chiral intermediate 2. The reaction scheme is as follows: The chiral catalyst is composed of a monovalent copper salt and a ligand; the ligand is selected from one or two of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthene.

2. The preparation method according to claim 1, characterized in that The monovalent copper salt is selected from cuprous bromide and cuprous chloride; the phase transfer catalyst is one or more of benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium bromide.

3. The preparation method according to claim 2, characterized in that The monovalent copper salt is cuprous bromide; the ligand is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; and the phase transfer catalyst is benzyltriethylammonium chloride.

4. The preparation method according to claim 1, characterized in that The ammonia source is selected from one or more of an organic ammonia solution, ammonia water, and tert-butylsulfenamide.

5. The preparation method according to claim 1, characterized in that The molar ratio of the 1-(tert-butyldimethylsilyloxy)-2-propanone, monovalent copper salt, ligand, phase transfer catalyst, ammonia source and trimethylsilyl cyanide is 1:(0.01-2):(0.01-2):(0.5-1):(0.7-30):(1-1.5).

6. A method for preparing a compound of formula (I), comprising the following steps: (1) The chiral intermediate 2 described in claim 1 is subjected to a condensation reaction with p-trifluoromethylthiobenzoyl chloride to obtain intermediate 3. The reaction scheme is as follows: ； (2) Intermediate 3 reacts with a deprotecting agent to obtain intermediate 4. The reaction scheme is as follows: ； (3) Intermediate 4 undergoes substitution reaction with 3-chloro-4-trifluoromethylbenzonitrile to obtain a crude compound of formula (I). The reaction scheme is as follows: ； (4) The crude compound of formula (I) is dissolved in isopropanol solvent, heated until the solution is clear, and then cooled to precipitate the compound of formula (I). The solution is filtered, washed with water, and dried to obtain the fine product of the compound of formula (I).

7. The preparation method according to claim 6, characterized in that The molar ratio of the intermediate 2 to trifluoromethylthiobenzoyl chloride in step (1) is 1:(1.1-2).

8. The preparation method according to claim 6, characterized in that The deprotecting agent in step (2) is selected from one or more of tetrabutylammonium fluoride, tetraethylammonium fluoride, cesium fluoride, and potassium carbonate.

9. The preparation method according to claim 6, characterized in that The molar ratio of the intermediate 3 to the deprotecting agent in step (2) is 1:(0.8-10).

10. The preparation method according to claim 6, characterized in that The molar ratio of the intermediate 4 to 3-chloro-4-trifluoromethylbenzonitrile in step (3) is 1:(1-3).

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