Preparation method of aminoacetonitrile compound and intermediate thereof

Abstract

The invention discloses a preparation method of an aminoacetonitrile compound and an intermediate thereof, and belongs to the technical field of medicine synthesis. The aminoacetonitrile compound is a compound as shown in a formula (I). The preparation method of the compound of the formula (I) comprises the following steps: taking 1-(tert-butyldimethylsiloxy)-2-acetone as a starting material 1, obtaining a high-purity chiral intermediate 2 under the action of a chiral catalyst, carrying out condensation reaction on the chiral intermediate 2 and p-trifluoromethylthiobenzoyl chloride to obtain an intermediate 3, and carrying out deprotection and substitution reaction to obtain the compound of the formula (I). And finally recrystallizing with a solvent to obtain a refined product of the compound shown in the formula (I). In the preparation method of the compound as shown in the formula (I), the key chiral intermediate is efficiently obtained by adopting the chiral catalyst, a chiral resolution process is avoided, the used reagents are low in toxicity or non-toxic, environment-friendly and simple in reaction condition, and the prepared compound as shown in the formula (I) is relatively high in yield and purity, stable in product quality and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically 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, mainly used to treat and control intestinal worm infections in sheep. It was first approved for marketing in Europe in 2009, and subsequently marketed in Australia, Brazil, New Zealand and other countries. 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 the existing synthesis process uses a chemical separation method for 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), first synthesizing a racemic compound, and then using 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), which uses a preparative liquid phase to separate the isomers. Although the patent found that the inferior isomer can be converted into the target isomer under certain conditions, the final product is still a racemate, which requires preparative liquid phase separation and purification. The above-mentioned public synthesis method reveals that this step limits the room for improving the yield and reducing the cost of synthesizing the compound of formula (I).

[0005] In view of the disadvantage that the existing process has low selectivity for synthesizing the optical isomers of the compound of formula (I), the present invention innovatively uses a chiral catalyst to directly and highly selectively synthesize the target optical isomer, thereby greatly improving the yield. In particular, by recrystallizing the crude product of the 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, wherein the aminoacetonitrile compounds are compounds of formula (I), and their structures are as follows:

[0007] .

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

[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: using 1-(tert-butyldimethylsilyloxy)-2-acetone as a starting material 1 and dissolving it in isopropanol, adding a chiral catalyst, a phase transfer catalyst, an ammonia source and trimethylsilyl cyanide to react to obtain a chiral intermediate 2, and 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] Further, the ligand is selected from one or two 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-acetone, 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 is reacted 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 route is as follows:

[0024] .

[0025] (3) The intermediate 4 undergoes a 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 the solution is clear and then cooled to precipitate the compound of formula (I), which is filtered, washed with water and dried to obtain a fine product of the 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, in step (2), the molar ratio of the intermediate 3 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 highly selectively synthesizes the target optical isomer intermediate by using a suitable chiral catalyst, thus avoiding the chiral resolution step and greatly improving the yield.

[0034] (2) The reagents used in the present invention are non-toxic or low-toxic, the reaction conditions are mild, and they are 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 purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0037] The starting materials, reaction reagents, etc. used in the specific examples of the present invention are all commercially available. The experimental methods in the examples of the present invention that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the raw material or commodity manufacturer. 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 the 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 30.2 g of chiral intermediate 2 with a yield of 88.2%.

[0041] The 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, and the liquids 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 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 mixture was dried under reduced pressure to obtain an oily substance. 150 mL of dichloromethane and 300 mL of water were added to the oily substance, and the phases 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] The 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 mixture was reacted for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added and extracted twice. The organic phases were combined and then washed with saturated brine for 4 times. 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, the filter cake was washed with water, and 40.7 g of the fine compound of formula (I) was dried, 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 mixture was stirred at 30°C for 9 h. After the 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 37.6 g of chiral intermediate 2 with a yield of 87.8%.

[0047] The 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. Then, p-trifluoromethylthiobenzoyl chloride (48.1 g, 0.2 mol) was added under an 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 38.2 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 mixture was dried under reduced pressure to obtain an oily substance. 150 mL of dichloromethane and 300 mL of water were added to the oily substance, and the phases 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] The 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 carried out for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added and extracted twice. The organic phases were combined and then washed with saturated brine for 4 times. 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] To the crude compound of formula (I) was added 878 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, the filter cake was washed with water, and 38.9 g of the fine compound of formula (I) was dried, 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), ammonia water (138.5 mL, 1.8 mol), and trimethylsilyl cyanide (19.8 g, 0.2 mol). The mixture was stirred at 30°C for 6 h. After the 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 38.2 g of chiral intermediate 2 with a yield of 89.3%.

[0053] The 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. Then, p-trifluoromethylthiobenzoyl chloride (36.1 g, 0.15 mol) was added under an 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 mixture was dried under reduced pressure to obtain an oily substance. 150 mL of dichloromethane and 300 mL of water were added to the oily substance, and the phases 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] The 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 carried out for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added and extracted twice. The organic phases were combined and then washed with saturated brine for 4 times. 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, the filter cake was washed with water, and 40.0 g of the refined compound of formula (I) was dried, 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-dimethyloxanthene (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, 4M hydrochloric acid isopropanol solution (100 mL, 0.4 mol) was added, and stirring was continued for 1 h. After the hydrochloric acid reaction was completed, the mixture was filtered, and the filter cake was washed once with methanol. 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] The 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 an 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 substance. 150 mL of dichloromethane and 500 mL of water were added to the viscous substance, and the phases were separated. 100 mL of dichloromethane was added to the aqueous phase and extracted twice. 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] The 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 carried out for 2 h. 200 mL of water was added to quench the reaction. 100 mL of ethyl acetate was added and extracted twice. The organic phases were combined and then washed with saturated brine for 4 times. 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, the filter cake was washed with water, and 39.5 g of the fine compound of formula (I) was dried, 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 the mixture was stirred for 30 min. Then, sodium cyanide (78.25 g, 1.5 eg) was added to the reaction system in batches. After the addition, the reaction solution was clarified, and then stirred for 20 h at 25°C. The reaction was tracked by thin layer chromatography (TLC). After 20 h, the reaction was completed. The mixture was filtered, and the filter cake was washed with methanol (50 mL). The mixture 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 is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope 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-acetone 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 route 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 ammonia solution, ammonia water, and tert-butylsulfenamide.

5. The preparation method according to claim 2, characterized in that: The molar ratio of the 1-(tert-butyldimethylsilyloxy)-2-acetone, 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 the intermediate 3. The reaction scheme is as follows: ； (2) Intermediate 3 reacts with a deprotecting agent to obtain intermediate 4. The reaction route is as follows: ; (3) The intermediate 4 undergoes a 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), which is filtered, washed with water and dried to obtain a 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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