A Preparation Method of a Key Intermediate of Montelukast Sodium

Abstract

The present invention relates to a preparation method of montelukast sodium intermediate, belonging to the field of pharmaceutical chemistry. In the present invention, crotonic acid is used as the starting material, and ethyl 3-butenoate is generated through esterification rearrangement reaction. The double bond of ethyl 3-butenoate undergoes epoxidation reaction with m-chloroperoxybenzoic acid to obtain an epoxy compound. The epoxy compound reacts with thiourea to obtain a cyclic sulfur compound. The cyclic sulfur compound undergoes ring opening with a cuprous salt reagent and cyclopropylmagnesium bromide, and finally, it is further hydrolyzed under alkaline conditions to obtain 1-mercaptomethylcyclopropylacetic acid. This method has cheap and easily available starting materials, reducing the material cost; in the reaction process, the use of highly toxic cyanide reagents or extremely explosive diazomethane is avoided, improving the production safety, and the technological process is simple and easy to implement; the number of reaction steps is reduced, the production cost can be greatly reduced, which is beneficial to industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a key intermediate of montelukast sodium for preventing and treating asthma. Background Art

[0002] Montelukast sodium [trade name Singulair] is a leukotriene receptor antagonist developed by Merck & Co., Inc. in the United States. It is an anti-inflammatory and anti-asthmatic and anti-allergic drug with high efficiency, low toxicity and good safety. It was first launched in Finland and Mexico in February 1998, and then launched in the UK and the US in April and October of the same year respectively, and entered the Chinese market in 2002. According to the recommendations of the "Guidelines for the Prevention and Treatment of Bronchial Asthma" (2008 edition) in China, leukotriene regulators are the only long-term control drugs that can be used alone in addition to inhaled corticosteroids, and can be used as an alternative treatment for mild asthma and a combination treatment for moderate and severe asthma. Its chemical name is: sodium 1-[[[1-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropaneacetate, and its structural formula is as follows:

[0003]

[0004] The 1-mercaptomethylcyclopropaneacetic acid described in Formula 6 is a key precursor compound for the formation of montelukast sodium and an important intermediate for the synthesis of montelukast sodium. Its chemical properties are active, the mercapto group is easily oxidized, and the synthesis is difficult, which has always been the focus and hotspot of synthetic chemists.

[0005]

[0006] Among many methods for preparing 1-mercaptomethylcyclopropaneacetic acid, most patents use diethyl malonate and 1,2-dihaloethane as raw materials to first generate 1,1-cyclopropanedicarboxylic acid diester under alkaline conditions, then reduce the diester to obtain cyclopropylpropanediol, and then protect the hydroxyl group to obtain cyclopropylpropanediol monoester or six-membered cyclic sulfite. Cyclopropylpropanediol monoester or six-membered cyclic sulfite is further introduced with -CN and -SR groups through a series of reactions, and finally the product 1-mercaptomethylcyclopropaneacetic acid is obtained by hydrolysis. For example, the World Patent WO2008058118 reported a synthesis method of 1-mercaptomethylcyclopropaneacetic acid, and its specific process is as follows:

[0007]

[0008] These methods inevitably use highly toxic cyanide reagents, which cause great environmental pollution, have long routes and low yields, and are very unsatisfactory for the pharmaceutical industry.

[0009] In addition, World Patent WO2008035086 reported a synthesis method. Using itaconic anhydride as the raw material, through aminolysis, cyclization, reduction, esterification substitution hydrolysis and other reactions, 1-mercaptomethylcyclopropylacetic acid was obtained. The advantage of this route is that the synthesis route is relatively short. However, diazomethane, which is extremely explosive, was used in the reaction process, posing safety hazards such as explosion and is not suitable for large-scale industrial production.

[0010]

[0011] Chinese Patent CN103288695A disclosed a relatively novel synthesis method. Using 1,4-butanediol as the raw material, through multi-step conversions such as selective protection of alcohol hydroxyl groups, oxidation, alkylation, cyclopropanation, etc., 1-mercaptomethylcyclopropylacetic acid was obtained. The synthesis route of this method is too long (9-step reaction) and the total yield is very low, which is not suitable for industrial production.

[0012]

[0013] The methods described in the above inventions either cannot avoid the use of highly toxic substances such as cyanide or extremely explosive diazomethane, or the synthesis route is relatively long, so they are extremely unsuitable for large-scale industrial production. Summary of the Invention

[0014] Object of the Invention: Aiming at the disadvantages and deficiencies in the prior art, to provide a method for preparing the key intermediate 1-mercaptomethylcyclopropylacetic acid of montelukast sodium without using dangerous materials such as sodium cyanide and diazomethane.

[0015] The technical solution adopted in the present invention is as follows:

[0016] The first step: Using crotonic acid 1 as the starting material, through esterification rearrangement reaction to generate ethyl 3-butenoate 2;

[0017] The second step: The double bond of ethyl 3-butenoate 2 undergoes epoxidation reaction with m-chloroperoxybenzoic acid to obtain an epoxy compound 3;

[0018] The third step: The compound 3 reacts with thiourea to obtain a cyclic sulfur compound 4;

[0019] The fourth step: The compound 4 reacts with cuprous salt and cyclopropylmagnesium bromide successively to obtain a compound 5;

[0020] The fifth step: The compound 5 is further hydrolyzed under alkaline conditions to obtain the target compound 1-mercaptomethylcyclopropylacetic acid.

[0021] The reaction route of this method is as follows:

[0022]

[0023] Furthermore, in the first step, the molar ratio of crotonic acid 1 to thionyl chloride is 1:1;

[0024] Further, slowly drop thionyl chloride into the crotonic acid 1 solution. After dropping, raise the temperature to 70 - 80 °C for reaction until no more gas is generated to obtain the crotonyl chloride solution;

[0025] Further, drop the crotonyl chloride solution into the mixed solution containing ethanol, n-pentane and triethylamine under low temperature conditions. After dropping, raise the temperature for reaction;

[0026] Furthermore, react the above reaction solution at 25 - 40 °C;

[0027] Further preferably, the molar ratio of ethyl 3-butenoate 2 to m-chloroperoxybenzoic acid in the second step is 1:1.5;

[0028] Further, control the epoxidation reaction temperature at -5 - 15 °C;

[0029] Furthermore, in the third step, compound 3 reacts with thiourea to obtain the cyclic sulfur compound 4, and control the reaction temperature at 15 - 30 °C;

[0030] Further, the feeding ratio of compound 3 to thiourea is 1:1 - 2;

[0031] Further, in the fourth step, the molar ratio of compound 4 to cyclopropylmagnesium bromide is 1:1;

[0032] Further, in the fourth step, the molar amount of the cuprous salt added does not exceed 30% of compound 4;

[0033] Further, in the fourth step, the cuprous salt is cuprous bromide or cuprous iodide;

[0034] Furthermore, in the fifth step, control the temperature at 15 - 30 °C for hydrolysis of compound 5 under alkaline conditions to obtain the target compound 1-mercaptomethylcyclopropylacetic acid;

[0035] Further, the alkaline condition in the fifth step can be NaOH, KOH, K 2 CO 3 。

[0036] Beneficial effects: The present invention provides a new preparation route for the intermediate of montelukast sodium, providing a feasible method for this important intermediate; compared with the prior art, the starting materials of this method are cheap and easily available, reducing the material cost; the use of highly toxic cyanide reagents or extremely explosive diazomethane is avoided during the reaction process, improving production safety, and the process flow is simple and easy to implement; in addition, the reaction steps are reduced, the production cost can be greatly reduced, which is conducive to industrial production. Specific embodiments

[0037] The following further elaborates the present invention in detail with reference to specific embodiments.

[0038] Example 1: Preparation of 1-mercaptomethylcyclopropylacetic acid

[0039] Preparation of Compound 2

[0040]

[0041] Add crotonic acid 1 (20.0 g, 232.32 mmol) into a 500 mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer. Connect a dropping funnel containing thionyl chloride (16.85 mL, 232.32 mmol) to the reaction flask. Under nitrogen protection, slowly drop thionyl chloride at a rate of about 3 - 5 drops per second, and finish dropping in about 0.5 h. Slowly heat the reaction system to 80 °C and react until no more gas escapes (the reaction solution is light yellow). Then distill the product under atmospheric pressure to obtain 21.88 g of colorless liquid crotonyl chloride.

[0042] Take another 1000 mL four-necked flask, add ethanol (18.32 mL, 313.97 mmol), 400 mL of n-pentane and triethylamine (20.70 mL, 209.31 mmol) in sequence, add a thermometer and mechanical stirring, and cool the reaction in a cold trap to 0 °C. At 0 °C, slowly drop the crotonyl chloride prepared above into the system. White precipitate can be observed to precipitate in the system during the dropping process. After dropping for about 0.5 h, place the reaction in a 30 °C water bath, stir and heat up, and the solid gradually dissolves at this time. After holding the reaction at 30 °C for 3 h, add saturated sodium bicarbonate solution to the reaction mixture and continue stirring for 10 min. Then pour the reaction mixture into a separating funnel and let it stand for liquid separation. The aqueous phase is extracted with n-pentane. Combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain 23.9 g of colorless liquid, with a GC purity of 98.5% and a yield of 90%.

[0043] Preparation of Compound 3

[0044]

[0045] Into a 500 mL three-necked flask, add Compound 2 (20.0 g, 175.22 mmol) and 200 mL of dichloromethane in sequence. Place the reaction in an ice-water bath. When the system temperature drops to 0 - 5 °C, add solid m-CPBA (60.47 g, 262.83 mmol) with a mass fraction of 75% in batches, and control the temperature during the addition process at 0 - 10 °C. After dropping, hold the reaction for 5 h, then gently pour the reaction solution into 100 mL of a solution containing 10% Na 2 S 2 O 3 and 10% NaHCO 3In the mixed solution, stir until no bubbles emerge. Let it stand for layering. The aqueous phase is extracted once with 50 mL of dichloromethane. The organic phases are combined, washed once with 50 mL of water, once with 50 mL of saturated NaCl solution, and dried over anhydrous Na 2 SO 4 Dry. Filter and concentrate to obtain 21.89 g of a colorless oil. The GC purity is 98.5% and the yield is 96%.

[0046] Preparation of Compound 4

[0047]

[0048] Add epoxide 3 (20.0 g, 153.68 mmol), 150 mL of methanol, and thiourea (29.25 g, 384.19 mmol) to a 500 mL three-necked flask in sequence. Stir at 15 - 20 °C overnight. Under reduced pressure, concentrate the reaction solution to dryness. The resulting residue is redissolved in 120 mL of ethyl acetate. Then the ethyl acetate solution is washed once with 40 mL of drinking water and once with 40 mL of saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 21.12 g of a colorless oil. The GC purity is 95.9% and the yield is 94%.

[0049] Preparation of Compound 5

[0050]

[0051] Add compound 4 (20.0 g, 136.80 mmol) and 150 mL of tetrahydrofuran to a 500 mL three-necked flask in sequence, and add a thermometer and mechanical stirrer. Cool the reaction in an ice-water bath. When the system temperature drops to 0 - 5 °C, under nitrogen protection, cool to 0 - 5 °C. Dissolve cuprous bromide (3.92 g, 27.36 mmol) in 20 mL of tetrahydrofuran and add it to the reaction system. Continue stirring for 5 min, then slowly dropwise add a 1.0 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (137 mL, 137 mmol). After the addition is complete, keep the reaction at a constant temperature for 5 - 6 h. Slowly add 50 mL of saturated NH 4 Cl solution, extract twice with 50 mL of ethyl acetate each time. Combine the organic phases, wash once with 50 mL of saturated NaCl solution, and dry over anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain 15.5 g of a colorless oil. The GC purity is 96.0% and the yield is 65%.

[0052] Preparation of 1-(Mercaptomethyl)cyclopropylacetic Acid 6

[0053]

[0054] Take a 250 mL three-necked flask, and successively add compound 5 (15.0 g, 86.08 mmol) and 75 mL of EtOH. Stir and cool down in an ice-water bath. When the temperature of the system drops to 0 - 5 °C, slowly add dropwise a 2 M aqueous KOH solution (64.6 mL, 129.12 mmol). After the addition is complete, keep the reaction at 15 - 20 °C for 3 h, and then remove EtOH under reduced pressure. Slowly adjust the pH value of the aqueous phase to about 2 with a 2 M HCl solution, and extract with EtOAc (40 mL × 3). Combine the organic phases, wash once with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain an off-white solid. Recrystallize with n-heptane to obtain 11.7 g of a white solid, with a GC purity of 99.6% and a yield of 93%.

[0055] Example 2: 1-Mercaptomethylcyclopropylacetic acid

[0056] Preparation of Compound 2

[0057]

[0058] Add crotonic acid 1 (20.0 g, 232.32 mmol) to a 500 mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer. Connect a dropping funnel containing thionyl chloride (16.85 mL, 232.32 mmol) to the reaction flask. Under nitrogen protection, add thionyl chloride dropwise at a rate of about 3 - 5 drops per second, and finish adding in about 0.5 h. Slowly heat the reaction system to 75 °C and react until no more gas escapes (the reaction solution is light yellow). Then distill out the product under atmospheric pressure to obtain 21.98 g of colorless liquid crotonyl chloride.

[0059] Take another 1000 mL four-necked flask, successively add ethanol (18.32 mL, 313.97 mmol), 400 mL of n-pentane and triethylamine (20.70 mL, 209.31 mmol), add a thermometer and mechanical stirring, and cool the reaction to -5 °C in a cold trap. At -5 °C, slowly add dropwise the crotonyl chloride prepared above to the system, and white precipitates can be observed in the system during the addition. After about 0.5 h, the addition is complete. Place the reaction in a 25 °C water bath and stir to warm up, and the solid gradually dissolves at this time. After keeping the reaction at 25 °C for 3 h, add saturated sodium bicarbonate solution to the reaction mixture and continue stirring for 10 min. Then pour the reaction mixture into a separating funnel and let it stand for liquid separation. Extract the aqueous phase with n-pentane. Combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain 24.4 g of a colorless liquid, with a GC purity of 98.3% and a yield of 92%.

[0060] Preparation of Compound 3

[0061]

[0062] Compound 2 (20.0 g, 175.22 mmol) and 200 mL of dichloromethane were added to a 500 mL three-necked flask in sequence. The reaction was placed in an ice-water bath. When the system temperature dropped to -5-0°C, 75% m-CPBA (60.47 g, 262.83 mmol) solid was added in batches. The temperature during the addition process was controlled at -5-5°C. After the addition was completed, the reaction was kept warm for 5 h, and the reaction solution was gently poured into 100 mL of 10% Na 2 S 2 O 3 and 10 % NaHCO 3 The mixed solution was stirred until no bubbles appeared. After standing for stratification, the aqueous phase was extracted once with 50 mL of dichloromethane, the organic phases were combined, washed once with 50 mL of water, once with 50 mL of saturated NaCl solution, and then washed with anhydrous Na 2 SO 4 The product was dried, filtered and concentrated to obtain 21.66 g of a colorless oil with a GC purity of 98.8% and a yield of 95%.

[0063] Preparation of compound 4

[0064]

[0065] Epoxide 3 (20.0 g, 153.68 mmol), methanol 150 mL and thiourea (17.55 g, 230.56 mmol) were added to a 500 mL three-necked flask in sequence and stirred at 20-25°C overnight. The reaction solution was concentrated to dryness under reduced pressure, and the residue was redissolved with 120 mL of ethyl acetate. The ethyl acetate solution was then washed once with 40 mL of drinking water and 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 20.90 g of a colorless oil with a GC purity of 95.5% and a yield of 93%.

[0066] Preparation of compound 5

[0067]

[0068] Add 500 mL three-necked flask with compound 4 (20.0 g, 136.80 mmol), 150 mL of tetrahydrofuran, a thermometer and mechanical stirring in sequence. Cool the reaction in an ice-water bath. When the system temperature drops to 0 - 5 °C, under nitrogen protection, dissolve copper(I) iodide (7.82 g, 41.04 mmol) in 20 mL of tetrahydrofuran and then add it to the reaction system. Continue stirring for 5 min, and then slowly dropwise add a 1.0 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (137 mL, 137 mmol). After the addition is complete, keep the reaction at a constant temperature for 5 - 6 h. Slowly add 50 mL of saturated NH 4 Cl solution, extract with 50 mL of ethyl acetate twice, combine the organic phases, wash once with 50 mL of saturated NaCl solution, dry over anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain 16.0 g of a colorless oil, with a GC purity of 95.5% and a yield of 67%.

[0069] Preparation of 1-(mercaptomethyl)cyclopropylacetic acid 6

[0070]

[0071] Take a 250 mL three-necked flask, add compound 5 (15.0 g, 86.08 mmol) and 75 mL of EtOH in sequence, stir and cool in an ice-water bath. When the system temperature drops to 0 - 5 °C, slowly dropwise add 2 M aqueous NaOH solution (62.5 mL, 125 mmol). After the addition is complete, keep the reaction at a constant temperature of 20 - 25 °C for 3 h, and then remove EtOH under reduced pressure. Slowly adjust the pH value of the aqueous phase to about 2 with 2 M HCl solution, and extract with EtOAc (40 mL × 3). Combine the organic phases, wash once with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain an off-white solid, and recrystallize with n-heptane to obtain 11.3 g of a white solid, with a GC purity of 99.5% and a yield of 90%.

[0072] Example 3: 1-(mercaptomethyl)cyclopropylacetic acid

[0073] Preparation of compound 2

[0074]

[0075] Add crotonic acid 1 (20.0 g, 232.32 mmol) to a 500 mL four-necked flask equipped with a thermometer, a reflux condenser and a mechanical stirrer. Connect a dropping funnel containing thionyl chloride (16.85 mL, 232.32 mmol) to the reaction flask. Under nitrogen protection, slowly add thionyl chloride at a rate of about 3-5 drops per second, and finish adding in about 0.5 h. Slowly heat the reaction system to 70 °C and react until no more gas escapes (the reaction solution is light yellow). Then distill the product under atmospheric pressure to obtain 21.78 g of colorless liquid crotonyl chloride.

[0076] Take another 1000 mL four-necked flask, and successively add ethanol (18.32 mL, 313.97 mmol), 400 mL of n-pentane and triethylamine (20.70 mL, 209.31 mmol). Add a thermometer and a mechanical stirrer, and cool the reaction in a cold trap to 5 °C. At 5 °C, slowly add the crotonyl chloride prepared above to the system. During the addition process, white precipitates can be observed in the system. After about 0.5 h, finish adding. Place the reaction in a 40 °C water bath, stir and heat up, and at this time the solid gradually dissolves. After maintaining the reaction at 40 °C for 2 h, add saturated sodium bicarbonate solution to the reaction mixture and continue to stir for 10 min. Then pour the reaction mixture into a separatory funnel and let it stand for liquid separation. The aqueous phase is extracted with 50 mL of n-pentane. Combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain 23.1 g of colorless liquid, with a GC purity of 98.7% and a yield of 87%.

[0077] Preparation of Compound 3

[0078]

[0079] Add Compound 2 (20.0 g, 175.22 mmol) and 200 mL of dichloromethane to a 500 mL three-necked flask in sequence. Place the reaction in an ice-water bath. After the system temperature drops to 5-10 °C, add solid 75% m-CPBA (60.47 g, 262.83 mmol) in batches, and control the temperature during the addition process at 5-15 °C. After finishing adding, maintain the reaction for 5 h, and then gently pour the reaction solution into 100 mL of a mixed solution containing 10% Na 2 S 2 O 3 and 10% NaHCO 3 until no more bubbles emerge. Let it stand for liquid separation. The aqueous phase is extracted once with 50 mL of dichloromethane. Combine the organic phases, wash once with 50 mL of water, wash once with 50 mL of saturated NaCl solution, and use anhydrous Na 2 SO 4The product was dried, filtered and concentrated to obtain 22.12 g of a colorless oil with a GC purity of 98.9% and a yield of 97%.

[0080] Preparation of compound 4

[0081]

[0082] Epoxide 3 (20.0 g, 153.68 mmol), methanol 150 mL and thiourea (14.04 g, 184.44 mmol) were added to a 500 mL three-necked flask in sequence and stirred overnight at 25-30°C. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was redissolved with 120 mL of ethyl acetate. The ethyl acetate solution was then washed once with 40 mL of drinking water and 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 20.67 g of a colorless oil with a GC purity of 95.8% and a yield of 92%.

[0083] Preparation of compound 5

[0084]

[0085] Take a 500 mL three-necked flask and add compound 4 (20.0 g, 136.80 mmol) and 150 mL of tetrahydrofuran in turn. Add a thermometer and mechanical stirring. Place the reaction in an ice-water bath to cool down. When the system temperature drops to 0-5 °C, under nitrogen protection, dissolve cuprous bromide (1.96 g, 13.68 mmol) in 20 mL of tetrahydrofuran and add it to the reaction system. After stirring for 5 min, slowly drip 1.0 M cyclopropylmagnesium bromide in tetrahydrofuran solution (137 mL, 137 mmol). After the addition is complete, keep the reaction warm for 5-6 h. Slowly add saturated NH 4 Cl solution 50 mL, ethyl acetate 50 mL × 2 extraction, the organic phases were combined, washed once with 50 mL saturated NaCl solution, anhydrous Na 2 SO 4 The product was dried, filtered and concentrated under reduced pressure to give 16.7 g of a colorless oil with a GC purity of 95.2% and a yield of 70%.

[0086] Preparation of 1-mercaptomethylcyclopropylacetic acid 6

[0087]

[0088] Take a 250 mL three-necked flask, and successively add compound 5 (15.0 g, 86.08 mmol) and 75 mL of EtOH. Stir and cool down in an ice-water bath. When the temperature of the system drops to 0 - 5 °C, slowly add dropwise a 2 M aqueous KOH solution (64.6 mL, 129.12 mmol). After the addition is complete, keep the reaction at 25 - 30 °C for 3 h, and then remove EtOH under reduced pressure. Slowly adjust the pH value of the aqueous phase to about 2 with a 2 M HCl solution, and extract with EtOAc (40 mL × 3). Combine the organic phases, wash once with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain an off-white solid, and then recrystallize with n-heptane to obtain 10.9 g of a white solid, with a GC purity of 99.4% and a yield of 87%.

Claims

1. A method for preparing a key intermediate of montelukast sodium, characterized in that The following steps are involved: In the first step, crotonic acid 1 is used as the starting material to generate 3-butenoic acid ethyl ester 2 through esterification rearrangement reaction; In the second step, the olefin bond of 3-butenoic acid ethyl ester 2 undergoes epoxidation reaction with m-chloroperoxybenzoic acid to obtain epoxy compound 3; In the third step, compound 3 reacts with thiourea to obtain episulfide compound 4; Step 4: Compound 4 reacts with cuprous salt and cyclopropylmagnesium bromide successively to obtain compound 5, wherein the cuprous salt is cuprous bromide or cuprous iodide; Step 5 Compound 5 is further hydrolyzed under alkaline conditions to obtain the target compound 1-mercaptomethylcyclopropylacetic acid 。 2. The preparation method according to claim 1, characterized in that The esterification rearrangement described in the first step is to drop the crotonic acid chloride solution into a mixed solution containing ethanol, n-pentane and triethylamine at a temperature below 5°C, and then raise the temperature to react.

3. The preparation method according to claim 2, characterized in that The elevated temperature is raised to 25-40°C.

4. The preparation method according to claim 2, characterized in that The crotonic acid chloride is prepared by slowly dropping thionyl chloride into the crotonic acid 1 solution, and then heating the solution to 70-80° C. to react until no more gas is generated.

5. The preparation method according to claim 1, characterized in that The reaction temperature in the third step is controlled at 15-30°C.

6. The preparation method according to claim 1, characterized in that In the third step, the feed ratio of compound 3 to thiourea is 1:1-2.

7. The preparation method according to claim 1, characterized in that In the fourth step, the molar ratio of compound 4 to cyclopropylmagnesium bromide is 1:1, and the molar amount of cuprous salt added is not higher than 30% of compound 4.

8. The preparation method according to claim 7, characterized in that In the fourth step, the molar amount of cuprous salt added is 20% of compound 4.

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