Preparation method of tigorazan

Abstract

The invention belongs to the technical field of organic synthesis and medicine, and particularly relates to a preparation method of tigorazan, which comprises the following steps: S1, adding an organic solvent A, a compound I and a compound II, stirring and mixing, cooling, sequentially adding tributylphosphine and a mixed solution of diisopropyl azodicarboxylate and the organic solvent A, stirring for reaction, and post-processing to obtain a compound III; s2, mixing an organic solvent B and a compound III, adding a catalyst and a substance A in a stirring state, carrying out hydrogen replacement and reaction to obtain a crude product, and carrying out post-treatment to obtain a product tigorazan; the preparation method provided by the invention is mild in reaction condition and has a full industrial prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and medicine, and in particular relates to a preparation method of ticlopidine. Background Art

[0002] Tegoprazan, also known as tegorazan, has the chemical name 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]oxy]-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide, and its English name is Tegoprazan. Originally developed by Pfizer, it was licensed to raqualiapharma (which separated from Pfizer) for joint development in 2008. In 2014, raqualiapharma licensed it to CJ Healthcare Chemicalbookre, and ultimately successfully developed by CJ Healthcare in South Korea. It was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis. Tegoprazan reversibly inhibits H in a potassium ion competitive manner. + , K + -ATPase activity can stay in the gastric wall cells to inhibit the production of gastric acid, and can effectively inhibit the formation of upper gastrointestinal mucosal damage.

[0003] The excellent clinical effects of ticaglasan have promoted its widespread use, and improvements in its preparation methods have become a research hotspot. Pfizer's Chinese patent CN 101341149A discloses a preparation method for ticaglasan, which uses a multi-step reaction process to produce ticaglasan, resulting in a cumbersome process and unsatisfactory yield.

[0004] Based on patent CN101341149A, researchers have conducted extensive research in the hope of finding an ideal preparation process. In patent CN117024417A, compound VI and compound V undergo a Mitsunobu reaction to produce compound IV, which is then hydrolyzed, condensed, and deprotected to produce the product. In this route, step S4 utilizes high-pressure catalytic hydrogenation to remove the protecting group, while the hydrogenation reaction for compound III is carried out at a pressure of 9 MPa, which is high and potentially dangerous, making it unsuitable for industrial production.

[0005] Among the various preparation processes for ticlopidine, an important and widely used preparation process is to first obtain an intermediate through the Mitsunobu reaction and then catalytically hydrogenate the target product. However, the high-pressure conditions of the hydrogenation reaction hinder the industrial production of ticlopidine. The present invention achieves a low-pressure hydrogenation deprotection reaction of ticlopidine by adjusting the reactants and reaction process, providing an industrial process route with safer operation and considerable yield. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a preparation method of tigolaxant.

[0007] In order to solve the above problems, the technical solution adopted by the present invention is: The present invention provides a method for preparing tegrassen, comprising the following steps: S1: adding organic solvent A, compound I and compound II, stirring and mixing, controlling the temperature, sequentially adding tributylphosphine and a mixed solution of diisopropyl azodicarboxylate and organic solvent A, stirring for reaction, and post-treating to obtain compound III; S2: Mixing organic solvent B and compound III, adding catalyst and substance A under stirring, replacing with hydrogen, reacting to obtain a crude product, and post-processing to obtain the product ticagrelor; The substance A is selected from one or more of 1,1,1-trichloroethane, tetrachloroethylene and trichloroethylene; The molar ratio of compound III to substance A is 1:1-4; .

[0008] As a further improvement of the embodiment of the present invention, the molar ratio of compound I to compound II in S1 is 1:1~1.5.

[0009] As a further improvement of the embodiment of the present invention, the molar ratio of compound I to compound II in S1 is 1:1.2~1.4.

[0010] As a further improvement of the embodiment of the present invention, the controlled temperature in S1 is controlled to be between -10 and 5°C.

[0011] As a further improvement of the embodiment of the present invention, the mass ratio of diisopropyl azodicarboxylate to organic solvent A in the mixed solution of diisopropyl azodicarboxylate and organic solvent A in S1 is 1:2~8.

[0012] As a further improvement of the embodiment of the present invention, the reaction temperature in S1 is -10~20°C; and the reaction time is 3~8h.

[0013] As a further improvement of the embodiment of the present invention, the post-treatment in S1 is: extraction with water, collecting the organic phase, adding n-hexane and ethyl acetate after concentration, gradient cooling and stirring, filtering and drying; the mass ratio of ethyl acetate and n-hexane is 1:1~3; the operation of gradient cooling and stirring is: stirring at 50~65℃ for 2~5h, cooling to 10~30℃ and stirring for 12~15h.

[0014] As a further improvement of the embodiment of the present invention, the mass ratio of ethyl acetate to n-hexane is 1:1~1.5.

[0015] As a further improvement of the embodiment of the present invention, the mass ratio of ethyl acetate to n-hexane is 1:1.4.

[0016] As a further improvement of the embodiment of the present invention, the organic solvent A in S1 includes one or more of dichloromethane, chloroform or 1,2-dichloroethane; the organic solution B in S2 includes one or more of methanol, ethanol, isopropanol, butanol or tetrahydrofuran.

[0017] As a further improvement of the embodiment of the present invention, the catalyst described in S2 is selected from one or more of 10% palladium carbon, 10% palladium hydroxide carbon or rhodium carbon; the mass ratio of compound III described in S2 to the catalyst is 1:0.05~1.0.

[0018] As a further improvement of the embodiment of the present invention, the pressure of the hydrogen in S2 is 0.2~0.5MPa.

[0019] As a further improvement of the embodiment of the present invention, the reaction temperature in S2 is 35-50° C. and the reaction time is 2-8 h.

[0020] As a further improvement of the present invention, the post-treatment of S2 is: filtering, concentrating the filtrate, adding water to the concentrated filtrate, adjusting the pH, filtering, and drying the filter residue.

[0021] The beneficial effects of adopting the above technical solution are: 1,1,1-Trichloroethane, tetrachloroethylene and trichloroethylene are cheap, bulk chemicals and easy to purchase. Introducing them into the hydrogenation reaction not only reduces the pressure of the hydrogenation reaction while ensuring product quality, but also greatly shortens the reaction time, thereby reducing production costs and facilitating industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a hydrogen nuclear magnetic resonance spectrum of the ticagrelor product obtained in Example 1 of the present invention; Figure 2 1 is a mass spectrum of the ticagrelor product obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solutions and advantages of the present invention clearer, the invention is described clearly and completely below in conjunction with specific embodiments. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the technical field of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The experimental methods or test methods involved in the embodiments of the present invention, unless otherwise specified, are conventional methods in the prior art, and their names and / or abbreviations are conventional names in this area, and are very clear and definite in the relevant application fields. Those skilled in the art can understand conventional process steps and apply corresponding equipment according to the names, and implement them according to conventional conditions or conditions recommended by the manufacturer. The various instruments, equipment, raw materials or reagents used in the embodiments of the present invention have no special restrictions on source, are conventional products that can be purchased through regular commercial channels, and can also be prepared according to conventional methods well known to those skilled in the art.

[0024] 4-Hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I) was purchased from Shanghai Haoyuan Pharmaceutical Co., Ltd. with batch number 20240527.

[0025] Example 1 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, cooled to 25°C, and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0026] S2: Add 240g of methanol and 30g of compound III (62.8mmol) to a 1L three-necked flask, start stirring, add 6g of 10% palladium carbon and 16.75g of 1,1,1-trichloroethane (127.5mmol), and after hydrogen replacement, control the hydrogen pressure to 0.3MPa and react at 45℃ for 5h. After the reaction is complete, filter and concentrate. Add 300g of purified water to the residue, adjust the pH to 8-9 with sodium carbonate aqueous solution, continue stirring for 0.5h, filter, and dry the filter cake at 55℃ with air drying for 8h. The product of Tegolacrila was obtained, and the nuclear magnetic resonance hydrogen spectrum is as follows: Figure 1 As shown; the mass spectrum is as Figure 2 As shown, the yield was 95.0% and the purity was 99.5%.

[0027] Example 2 S1: At room temperature, 1900 g of 1,2-dichloroethane and 107.2 g of R-5,7-difluorochroman-4-ol (Compound II, 0.58 mol) were added to a 3 L three-necked flask, stirred for 10 min, 150 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.48 mol) was added, stirred for 30 min, cooled and controlled at -10~5°C, 147.0 g of tributylphosphine (0.72 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 400 g of 1,2-dichloroethane was added. After the addition, the mixture was stirred at -10°C for 8 h. After the reaction was complete, 700 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 540 g of n-hexane and 270 g of ethyl acetate were added to the residue. The mixture was stirred at 65°C for 2 h, then cooled to 25°C and stirred for 15 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0028] S2: Add 240 g of isopropanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. Then, 1.5 g of 10% palladium hydroxide on carbon and 16.75 g of 1,1,1-trichloroethane (127.5 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.2 MPa and the reaction was carried out at 40°C for 6 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 55°C for 8 h. The yield was 93.5% and the purity was 99.6%.

[0029] Example 3 S1: At room temperature, 600 g of chloroform and 19.5 g of R-5,7-difluorochroman-4-ol (Compound II, 0.11 mol) were added to a 2 L three-necked flask, stirred for 2 min, and 25 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.08 mol) was added, stirred for 30 min, cooled and controlled at -10~5°C, and 24.5 g of tributylphosphine (0.12 mol) was added, stirred for 30 min, and a mixed solution of 24.5 g of DIAD (0.12 mol) and 100 g of chloroform was added, and the mixture was stirred at 20°C for 3 h after the addition was completed. After the reaction was complete, 300 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 135 g of n-hexane and 45 g of ethyl acetate were added to the residue. The mixture was stirred at 50°C for 5 h, then cooled to 10°C and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0030] S2: Add 240 g of tetrahydrofuran and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated, followed by the addition of 30 g of 10% palladium on carbon and 16.75 g of 1,1,1-trichloroethane (127.5 mmol). After hydrogen substitution, the hydrogen pressure was maintained at 0.5 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, filtered, and the filter cake was air-dried at 55°C for 8 h. The yield was 94.0% and the purity was 99.0%.

[0031] Example 4 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, then cooled to 25°C and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0032] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. 6 g of 10% palladium on carbon and 16.75 g of tetrachloroethylene (127.5 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, filtered, and the filter cake was air-dried at 55°C for 8 h. The yield was 88.7% and the purity was 98.3%.

[0033] Example 5 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, then cooled to 25°C and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0034] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. 6 g of 10% palladium on carbon and 16.75 g of trichloroethylene (127.5 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 50-55°C for 8 h. The yield was 85.8% and the purity was 98.7%.

[0035] Example 6 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, then cooled to 25°C and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0036] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated, followed by the addition of 6 g of 10% palladium on carbon and 8.50 g of 1,1,1-trichloroethane (64.7 mmol). After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 55°C for 8 h. The yield was 86.0% and the purity was 99.0%.

[0037] Example 7 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, then cooled to 25°C and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0038] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated, followed by the addition of 6 g of 10% palladium on carbon and 33.00 g of 1,1,1-trichloroethane (251.2 mmol). After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, filtered, and the filter cake was air-dried at 55°C for 8 h. The yield was 88.0% and the purity was 99.5%.

[0039] Comparative Example 1 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, cooled to 25°C, and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0040] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. 6 g of 10% palladium on carbon and 4.20 g of 1,1,1-trichloroethane (32.0 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 55°C for 8 h. The yield was 45.2% and the purity was 95.7%.

[0041] Comparative Example 2 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, cooled to 25°C, and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0042] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. 6 g of 10% palladium on carbon and 49.60 g of 1,1,1-trichloroethane (377.5 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, filtered, and the filter cake was air-dried at 55°C for 8 h. The yield was 70.5% and the purity was 96.7%.

[0043] Comparative Example 3 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, cooled to 25°C, and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0044] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated, and 6 g of 10% palladium on carbon was added. After hydrogen displacement, the hydrogen pressure was controlled at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 55°C for 8 h. The yield was 30.5% and the purity was 70.1%.

[0045] Comparative Example 4 S1: At room temperature, add 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) to a 2 L three-necked flask. Stir for 10 min. Then add 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol). Stir for 30 min. Then add 49.0 g of tributylphosphine (0.24 mol). Stir for 30 min. Then add a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane. After addition, stir at 5°C for 4 h. After completion of the reaction, add 250 g of purified water, stir, separate the layers, collect the organic phase, and concentrate. Add 126 g of n-hexane and 90 g of ethyl acetate to the residue. Stir at 60°C for 3 h, then cool to 25°C and stir for 13 h. The mixture was filtered and the filter cake was dried under forced air at 55°C for 6 h to obtain compound III.

[0046] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated. 6 g of 10% palladium on carbon and 16.75 g of 1,1,1-trichloroethane (127.5 mmol) were added. After hydrogen substitution, the hydrogen pressure was maintained at 0.3 MPa and the reaction was carried out at 45°C for 5 h. After completion of the reaction, the mixture was filtered and concentrated. 300 g of purified water was added to the residue, and the pH was adjusted to 8-9 with aqueous sodium carbonate solution. Stirring was continued for 0.5 h, and the filter cake was air-dried at 55°C for 8 h. The yield was 66.8% and the purity was 94.3%.

[0047] Comparative Example 5 S1: At room temperature, 650 g of dichloromethane and 39.1 g of R-5,7-difluorochroman-4-ol (Compound II, 0.21 mol) were added to a 2 L three-necked flask, stirred for 10 min, 50 g of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (Compound I, 0.16 mol) were added, stirred for 30 min, cooled and controlled at -10~5°C, 49.0 g of tributylphosphine (0.24 mol) was added, stirred for 30 min, and a mixed solution of 49.0 g (0.72 mol) of diisopropyl azodicarboxylate (DIAD) and 150 g of dichloromethane was added. After addition, the mixture was stirred at 5°C for 4 h. After the reaction was complete, 250 g of purified water was added, stirred, and the mixture was separated. The organic phase was collected and concentrated. 126 g of n-hexane and 90 g of ethyl acetate were added to the residue, stirred at 60°C for 3 h, cooled to 25°C, and stirred for 13 h. Filtered, the filter cake was air-dried at 55°C for 6 h to obtain Compound III.

[0048] S2: Add 240 g of methanol and 30 g of Compound III (62.8 mmol) to a 1 L three-necked flask. Stirring was initiated, followed by the addition of 4.5 g of 10% palladium on carbon. After hydrogen displacement, the hydrogen pressure was maintained at 8.0 MPa and the temperature was maintained at 45°C. The reaction was allowed to proceed for 48 h. After completion of the reaction, the mixture was filtered, concentrated, and slurried with acetonitrile. The mixture was filtered and the filter cake was air-dried at 55°C for 8 h. The yield was 94.0% and the purity was 98.5%.

[0049] Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents; and such modifications or replacements do not deviate from the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing ticlopidine, characterized in that the steps include: S1: adding organic solvent A, compound I and compound II, stirring and mixing, controlling the temperature, sequentially adding tributylphosphine and a mixed solution of diisopropyl azodicarboxylate and organic solvent A, stirring for reaction, and post-treating to obtain compound III; S2: Mixing organic solvent B and compound III, adding catalyst and substance A under stirring, replacing with hydrogen, reacting to obtain a crude product, and post-processing to obtain the product ticagrelor; The substance A is selected from one or more of 1,1,1-trichloroethane, tetrachloroethylene and trichloroethylene; The molar ratio of compound III to substance A is 1:1-4; 。 2. The method for preparing ticlopidine according to claim 1, wherein: The molar ratio of compound I to compound II in S1 is 1:1~1.

5.

3. The method for preparing ticlopidine according to claim 1, wherein: The control temperature in S1 is controlled between -10 and 5°C.

4. The method for preparing ticlopidine according to claim 1, wherein: In the mixed solution of diisopropyl azodicarboxylate and organic solvent A described in S1, the mass ratio of diisopropyl azodicarboxylate to organic solvent A is 1:2~8.

5. The method for preparing ticlopidine according to claim 1, wherein: The reaction temperature in S1 is -10~20°C; and the reaction time is 3~8h.

6. The method for preparing ticlopidine according to claim 1, wherein: The post-treatment of S1 is as follows: extraction with water, collection of the organic phase, concentration, addition of n-hexane and ethyl acetate, gradient cooling and stirring, filtration and drying; the mass ratio of ethyl acetate to n-hexane is 1:1-3; the operation of gradient cooling and stirring is as follows: stirring at 50-65°C for 2-5h, cooling to 10-30°C and stirring for 12-15h.

7. The method for preparing ticlopidine according to claim 1, wherein: The organic solvent A in S1 includes one or more of dichloromethane, chloroform or 1,2-dichloroethane; the organic solution B in S2 includes one or more of methanol, ethanol, isopropanol, butanol or tetrahydrofuran.

8. The method for preparing ticlopidine according to claim 1, wherein: The catalyst described in S2 is selected from one or more of 10% palladium carbon, 10% palladium hydroxide carbon or rhodium carbon; the mass ratio of compound III described in S2 to the catalyst is 1:0.05~1.

0.

9. The method for preparing ticlopidine according to claim 1, wherein: The pressure of the hydrogen in S2 is 0.2~0.5MPa.

10. The method for preparing ticlopidine according to claim 1, wherein: The reaction temperature in S2 is 35-50° C., and the reaction time is 2-8 h.

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