Preparation method of tigorazan

Abstract

The invention relates to the technical field of compound synthesis, in particular to a preparation method of tigorazan, which comprises the following steps: (1) in an organic solvent, carrying out bromination reaction on 4-hydroxy-N, N, 2-trimethyl-1-(benzyl)-1H-benzimidazole-6-formamide and a bromination reagent to obtain a compound I; (2) in an organic solvent, carrying out Mitsunobu reaction on the compound I and (R)-5, 7-difluorochroman-4-ol under the catalysis of a phosphine reagent and an azo compound to prepare a compound II; and (3) carrying out hydrogenation reaction on the compound II in an organic solvent in a hydrogen atmosphere to obtain the tigorazan. A brand new process route is developed, the whole reaction route is short, raw materials are easy to obtain, operation is easy and convenient, reaction conditions are mild and safe, the yield of the obtained tigoran is high, the total yield is 83% or above, and industrial production can be achieved easily.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, and in particular to a method for preparing ticlopidine. Background Art

[0002] Tegoprazan, also known as Tegrazan, 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 is a potassium-competitive acid blocker (P-CAB) that reversibly inhibits H in a potassium-competitive manner without the need for acid activation. + / K + -ATPase activity, can stay in the gastric wall cells and inhibit the production of gastric acid, thereby effectively inhibiting the formation of upper gastrointestinal mucosal damage. The drug was first launched in South Korea and is a new drug for the treatment of gastroesophageal reflux disease and erosive esophagitis. It obtained the acceptance notice for the launch of a Class 1 new drug in my country in January 2021. Currently, a number of studies have been conducted on the clinical application of tigolasen, and the results showed that the drug is significantly better than placebo in the treatment of non-erosive reflux disease, is not inferior to esomeprazole in the treatment of erosive esophagitis, and is not inferior to lansoprazole in the treatment of gastric ulcers.

[0003] Currently, the representative routes for the synthesis of ticagrelor are as follows:

[0004] Route 1: Pfizer reported the following synthetic route in patent CN101341149:

[0005]

[0006] The main problem with this route is that the intermediate (-)-4-[((4S)-5,7-difluoro-3,4-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzo[d]imidazole-6-carboxamide needs to be purified by column chromatography. In addition, when the p-toluenesulfonyl group is hydrolyzed, the structure of dimethylformamide will be hydrolyzed, which affects the quality of the finished product, makes purification difficult, and cannot be scaled up industrially.

[0007] Route 2: Jiangsu Weiqida Pharmaceutical Co., Ltd. reported the following synthetic route in patent CN114805317:

[0008]

[0009] This route uses 4-amino-3-nitrobenzoic acid and bromine as starting materials and produces ticagrelor through a six-step reaction process: bromination, amidation, reduction, cyclization, hydroxylation, and condensation. However, the starting material, 4-amino-3-nitrobenzoic acid, is expensive and difficult to obtain, and the reaction involves multiple selectivity steps, resulting in low yields, low product purity, and difficult purification, making this route unsuitable for industrial production.

[0010] Route 3: Jae-Hong Kweon et al. from the original research company CJ Healthcare Co., Ltd. published an industrial preparation route for ticlopidine in Org. Process Res. Dev. 2024, 28: 1159-1169.

[0011]

[0012] In the report of this synthetic route, the intermediate 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide ( 1 ) and (R)-5,7-difluorochroman-4-ol ( 2 ) benzyl-protected tigolasen ( 3 ), and then catalytic hydrogenation is performed to remove the benzyl group to obtain ticagrelor. However, during the study, it was found that when performing the Mitsunobu reaction, alkylation-related by-products are inevitably produced. 3-a , and accounts for more than 15%, which leads to a significant reduction in the yield of this step of reaction, thereby making the production cost of the entire process relatively high.

[0013] To address prominent issues such as significant side reactions and low conversion of the target product during the Mitsunobu reaction, Chinese invention CN116789654A discloses a method for preparing tergolanzan, optimizing the existing technology. This invention utilizes an organic phosphine reagent, 2-di-tert-tert-butylphospho-3-methoxy-6-methyl-2'-4'-6'-triisopropylbiphenyl, in place of tri-n-butylphosphine, resulting in a yield of 95.58% and an HPLC purity of 99.95%. While this method offers advantages over industrialized methods in terms of high yield and purity, the phosphine reagent used, 2-di-tert-tert-butylphospho-3-methoxy-6-methyl-2'-4'-6'-triisopropylbiphenyl, is expensive and requires a large amount of 3 molar equivalents of substrate, resulting in extremely high production costs, hindering drug price control and adversely affecting patient safety. Furthermore, the overall yield of tergolanzan in this patent is low.

[0014] In summary, based on the above problems, the present invention provides a new method for preparing ticlopidine, which avoids problems such as alkylation byproducts produced during the Mitsunobu reaction in the current industrial route, and has low production costs and is more suitable for industrial production. Summary of the Invention

[0015] Purpose of the Invention: The technical problem to be solved by the present invention is to address the shortcomings of the existing technology, such as the problem of excessive production of alkylated by-products during the Mitsunobu reaction, resulting in low yield. The present invention provides a method for preparing ticlopidine, which has the advantages of no production of alkylated by-products, low production cost, simple operation, and good reaction safety, and is suitable for industrial scale-up production.

[0016] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0017] A preparation method of ticagrelor, comprising the following steps: Figure 1-3 Said method comprises the following steps:

[0018] (1) In an organic solvent, 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide is subjected to a bromination reaction with a bromination reagent to obtain 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide (Compound I);

[0019] (2) In an organic solvent, 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide and (R)-5,7-difluorochroman-4-ol undergo a Mistunobu reaction catalyzed by a phosphine reagent and an azo compound to prepare 5-bromobenzyl-protected ticlopidine (Compound II);

[0020] (3) In an organic solvent, under a certain hydrogen pressure, the 5-bromobenzyl-protected ticagrelene is hydrogenated with palladium-carbon catalysis to remove the bromo and benzyl protecting groups in compound II to obtain crude ticagrelene.

[0021]

[0022] In step (1), the organic solvent for the bromination reaction is any one of N,N-dimethylformamide, tetrahydrofuran and acetonitrile, preferably N,N-dimethylformamide; the volume mass ratio of the organic solvent to 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide is 3 to 10 mL:1 g, such as 4 mL:1 g, 8 mL:1 g.

[0023] In step (1), the bromination reagent for the bromination reaction is any one of N-bromosuccinimide, tetrabutylammonium tribromide and 1,3-dibromo-5,5-dimethylhydantoin, preferably N-bromosuccinimide and / or 1,3-dibromo-5,5-dimethylhydantoin.

[0024] In step (1), the molar ratio of the raw materials of 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide and the bromination reagent is 1:(0.5-2).

[0025] In step (1), the temperature of the bromination reaction is -10 to 10° C., such as -10° C., 0° C., and 10° C. In some embodiments, if the reaction temperature is relatively low, such as -10 to 0° C., it is necessary to first lower the reaction temperature, add the bromination reagent, and carry out the reaction at a low temperature; if the reaction temperature is high, such as 0 to 10° C., the bromination reagent can be directly added to carry out the reaction.

[0026] In step (1), the bromination reaction time is 1 to 12 hours, such as 2 hours, 3 hours, 4 hours, 6 hours, or 7 hours.

[0027] In step (1), after the bromination reaction is completed, water and / or alcohol is added, stirred, and filtered to obtain a filter cake as purified 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide. The alcohol includes ethanol; the volume mass ratio of the water and / or alcohol to 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide is 2-7 mL:1 g, such as 3-6 mL:1 g; the stirring is performed at room temperature; and the stirring time is 0.5-1.5 h, such as 1 h.

[0028] In step (2), the organic solvent of the Mitsunobu reaction is any one or a combination of dichloromethane, chloroform, tetrahydrofuran, toluene and acetonitrile, preferably dichloromethane; the volume mass ratio of the organic solvent to the mass of 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide is 5-15 mL: 1 g, such as 6-10 mL: 1 g; wherein the organic solvent is added twice, specifically, 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, (R)-5,7-difluorochroman-4-ol, phosphine reagent and part of the organic solvent are first stirred at the reaction temperature for 5-15 minutes, and then a mixed solution of the azo compound and the remaining organic solvent is added and stirred for reaction; the part of the organic solvent is 70% to 80% of the total volume of the organic solvent, such as 75%.

[0029] In step (2), the phosphine reagent of the Mitsunobu reaction is any one or a combination of triphenylphosphine and tri-n-butylphosphine, preferably tri-n-butylphosphine; the azo compound is any one or a combination of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and dipiperidine azodicarbonyl, preferably diisopropyl azodicarboxylate.

[0030] In step (2), the molar ratio of the raw materials of 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide and (R)-5,7-difluorochroman-4-ol, phosphine reagent and azo compound is 1:(1-2):(1-1.5):(1-3), preferably 1:(1-1.4):(1.1-1.4):(1.1-1.4), preferably 1:(1.1-1.3):(1.15-1.35):(1.15-1.35), preferably 1:1.2:1.25:1.25; as shown, the molar ratio of 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide and phosphine reagent is 1:1.15, 1:1.2, 1:1.25 and 1:1.3.

[0031] In step (2), the temperature of the Mitsunobu reaction is -10 to 60°C, such as -10 to 0°C, 0 to 5°C, 15 to 25°C, or 30 to 40°C.

[0032] In step (2), the Mitsunobu reaction time is 1 to 24 hours, such as 5 hours, 8 hours, 11 hours, or 13 hours.

[0033] In step (2), after the Mitsunobu reaction is completed, the resulting reaction solution is concentrated, ethyl acetate is added to the concentrate, the temperature is raised and stirred, n-heptane is added, the temperature is maintained and stirred for 20 to 40 minutes, the temperature is cooled to -5 to 5°C with continuous stirring, the temperature is maintained and stirred for another 40 to 80 minutes, and the filter cake is filtered to obtain the purified 5-bromobenzyl-protected ticlopidine. The volume mass ratio of the ethyl acetate to 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide is 4-8 mL: 1 g; the heating and stirring is stirring and heating at 55 to 65°C; and the volume mass ratio of the n-heptane to 5-bromo-4-hydroxy-N, N, 2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide is 3-5 mL: 1 g.

[0034] In step (3), the organic solvent is any one of methanol, ethanol, and acetonitrile, preferably methanol; the volume mass ratio of the organic solvent to the 5-bromobenzyl-protected ticlopidine is 5-15 mL:1 g.

[0035] In step (3), the palladium content of the palladium carbon is 5wt% to 10wt%, preferably 10wt%; the mass of the palladium carbon is 1 to 30% of the mass of the 5-bromobenzyl-protected ticlopidine.

[0036] In step (3), the hydrogen pressure is 0.2-2.0 MPa, the reaction temperature is 10-60° C., and the reaction time is 1-48 h. The reaction is continued until no more hydrogen is absorbed.

[0037] In step (3), after the reaction is completed, the product is further purified in acetonitrile to obtain ticaglan. Specifically, the reaction solution is concentrated, acetonitrile is added to the concentrate, stirred, cooled, and filtered to obtain a filter cake as the purified ticaglan. The volume mass ratio of the acetonitrile to the 5-bromobenzyl-protected ticaglan is 7-9 mL:1 g; the stirring is performed at 35-55° C. for 0.5-1.5 h, such as at 40-50° C. for 1 h; and the cooling is performed to room temperature.

[0038] The present application provides a new method for preparing ticagrelor. This route uses 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide as a starting material, first obtaining 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide through a bromination reaction, then preparing 5-bromobenzyl-protected ticagrelor through a Mitsunobu reaction with (R)-5,7-difluorochroman-4-ol, and finally obtaining ticagrelor through simultaneous removal of bromine and benzyl groups through a catalytic hydrogenation reaction. This route first uses bromine to occupy the 5-position of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, fundamentally avoiding the generation of alkylated byproducts during the Mitsunobu reaction. Simultaneously, by utilizing the characteristic that the halogen on the aromatic ring can be removed through a catalytic hydrogenation reaction, the target product is removed together with the benzyl protecting group. Compared with the current mainstream industrial route, the route of the present invention significantly reduces raw material consumption in the Mitsunobu reaction, does not generate alkylated byproducts, and increases the molar yield of this step by more than 15%, significantly reducing production costs. The palladium-on-carbon catalytic hydrogenation reaction can directly and simultaneously remove the bromine and benzyl protecting groups on the aromatic ring. The process is simple to operate, and the resulting finished product has high quality purity and high yield, making it suitable for industrial production.

[0039] Compared with the prior art, the advantages of the present invention are:

[0040] The present invention develops a completely new process route that avoids the production of alkylation byproducts during the Mitsunobu reaction, a process used in the mainstream route, significantly improving yield. The overall reaction route is short, raw materials are readily available, and the operation is simple. The reaction conditions are mild and safe. Using 1 to 1.5 molar equivalents of triphenylphosphine and tri-n-butylphosphine as the substrate phosphine reagent, the cost is low and the resulting product, ticagrelor, has a high yield. Calculated based on 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, the total yield is over 83%, facilitating industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0042] Figure 1 The following is a reaction scheme of step (1) of each embodiment of the present invention.

[0043] Figure 2 The following is a reaction scheme of step (2) of each embodiment of the present invention.

[0044] Figure 3 The following is a reaction scheme of step (3) of each embodiment of the present invention.

[0045] Figure 4 5-Bromo-4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide obtained in Example 1 of the present invention 1 H-NMR spectrum.

[0046] Figure 5 This is the HRMS spectrum of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide obtained in Example 1 of the present invention.

[0047] Figure 6 This is the HRMS spectrum of 5-bromobenzyl-protected ticoplasmin obtained in Example 1 of the present invention.

[0048] Figure 7 This is the HRMS spectrum of ticlopidine obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0049] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0050] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0051] Example 1: The preparation method of tigolaxant in this example is:

[0052] (1) Preparation of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide

[0053] At room temperature, 50.0 g (161.62 mmol) of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide and 200 mL of N,N-dimethylformamide were added to a reaction vessel. The mixture was cooled to -10-0°C with stirring. 34.5 g (193.94 mmol) of N-bromosuccinimide was added, and the reaction was stirred at -10-0°C for 2 h. 300 mL of purified water was added to the reaction solution, which was stirred at room temperature for 1 h. The mixture was filtered and the filter cake was dried under reduced pressure to yield 59.6 g of a pale yellow solid, 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, in a yield of 95%.

[0054] like Figure 4 As shown, 1 H NMR (400MHz, DMSO-d6): δ = 9.963 (s, 1H), 7.344–7.244 (m, 3H), 7.115 (d, J = 7.6Hz, 2H), 6.957 (s, 1H), 5.439 (s, 2H), 2.900 (s, 6H), 2.508 (s, 3H).

[0055] like Figure 5 As shown, HRMS (ESI) found 388.0651 [M + H] + .

[0056] (2) Preparation of 5-bromobenzyl-protected tigolaxant

[0057] At room temperature, add 50.0 g (128.78 mmol) of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, 28.8 g (154.53 mmol) of (R)-5,7-difluorochroman-4-ol, 32.6 g (160.97 mmol) of tri-n-butylphosphine, and 300 mL of dichloromethane to a reaction vessel. Stir at -10-0°C for 10 minutes. Add 32.6 g (160.97 mmol) of diisopropyl azodicarboxylate diluted with 100 mL of dichloromethane dropwise while maintaining the temperature. Continue stirring for 10 hours. Evaporate the solvent under reduced pressure, add 300 mL of ethyl acetate to the concentrate, and heat with stirring. 200 mL of n-heptane was added dropwise at 55-65° C. with continuous stirring. After the addition was completed, the mixture was kept warm and stirred for 30 min, then cooled to -5-5° C. over 2 h, and continued to be kept warm and stirred for 1 h. The mixture was filtered with suction, and the filter cake was dried under reduced pressure to obtain 68.8 g of an off-white solid, i.e., 5-bromobenzyl-protected ticlopidine, with a yield of 96%.

[0058] like Figure 6 As shown, HRMS (ESI) found 556.1016 [M + H] + .

[0059] (3) Preparation of Tegolasen

[0060] 50.0 g (89.86 mmol) of 5-bromobenzyl-protected ticagrelor and 2.5 g of 10% Pd / C were added to 400 mL of methanol and stirred at 45-50°C under a 0.8 MPa hydrogen atmosphere. The pressure was replenished to 0.8 MPa each time, and the reaction was terminated when the pressure dropped no more than 0.1 MPa after a 20-min interval. The palladium-on-carbon was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. 200 mL of acetonitrile was added to the concentrate, and the mixture was stirred at 40-50°C for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to yield 33.1 g of ticagrelor (95% yield).

[0061] like Figure 7 As shown, HRMS (ESI) found 388.1446 [M + H] + .

[0062] Example 2: The preparation method of tegrasin in this example is:

[0063] (1) Preparation of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide

[0064] At room temperature, 50.0 g (161.62 mmol) of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide and 200 mL of acetonitrile were added to a reaction vessel. The mixture was cooled to -10-0°C with stirring. 34.5 g (193.94 mmol) of N-bromosuccinimide was added, and the reaction was stirred at -10-0°C for 2 h. 300 mL of purified water was added to the reaction solution, which was stirred at room temperature for 1 h. The mixture was filtered and the filter cake was dried under reduced pressure to yield 58.4 g of a pale yellow solid, 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, in a yield of 93%.

[0065] (2) Preparation of 5-bromobenzyl-protected tigolaxant

[0066] At room temperature, add 50.0 g (128.78 mmol) of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, 36.0 g (193.17 mmol) of (R)-5,7-difluorochroman-4-ol, 41.7 g (206.04 mmol) of tri-n-butylphosphine, and 300 mL of dichloromethane to a reaction vessel. Stir at 0-5°C for 10 minutes. Add 41.7 g (206.04 mmol) of diisopropyl azodicarboxylate diluted with 100 mL of dichloromethane dropwise while maintaining the temperature. Continue stirring for 6 hours. Evaporate the solvent under reduced pressure, add 300 mL of ethyl acetate to the concentrate, and heat with stirring. 200 mL of n-heptane was added dropwise at 55-65° C. with continuous stirring. After the addition was completed, the mixture was kept warm and stirred for 30 min, then cooled to -5-5° C. over 2 h, and continued to be kept warm and stirred for 1 h. The mixture was filtered with suction, and the filter cake was dried under reduced pressure to obtain 66.0 g of an off-white solid, i.e., 5-bromobenzyl-protected ticlopidine, with a yield of 92%.

[0067] (3) Preparation of Tegolasen

[0068] 50.0 g (89.86 mmol) of 5-bromobenzyl-protected ticagrelor and 5.0 g of 10% Pd / C were added to 400 mL of methanol and stirred at 55-60°C under a 1.0 MPa hydrogen atmosphere. The pressure was replenished to 1.0 MPa each time, and the reaction was terminated when the pressure dropped no more than 0.1 MPa after a 20-min interval. The palladium-on-carbon was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. 200 mL of acetonitrile was added to the concentrate, and the mixture was stirred at 40-50°C for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to yield 33.5 g of ticagrelor (96% yield).

[0069] Example 3: The preparation method of tigolaxant in this example is:

[0070] (1) Preparation of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide

[0071] At room temperature, 50.0 g (161.62 mmol) of 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide and 400 mL of tetrahydrofuran were added to a reaction vessel. 116.9 g (242.43 mmol) of tetrabutylammonium tribromide was added with stirring, and the mixture was stirred at 0-10°C for 5 h. The solvent was evaporated under reduced pressure, and 150 mL of anhydrous ethanol was added to the concentrate, followed by stirring at room temperature for 1 h. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain 56.5 g of a yellow solid, 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, in a yield of 90%.

[0072] (2) Preparation of 5-bromobenzyl-protected tigolaxant

[0073] At room temperature, add 50.0 g (128.78 mmol) of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, 36.0 g (193.17 mmol) of (R)-5,7-difluorochroman-4-ol, 54.0 g (206.04 mmol) of triphenylphosphine, and 300 mL of dichloromethane to a reaction vessel. Stir at 15-20°C for 10 minutes. Add 41.7 g (206.04 mmol) of diisopropyl azodicarboxylate diluted with 100 mL of dichloromethane dropwise while maintaining the temperature. Continue stirring for 10 hours. Evaporate the solvent under reduced pressure, add 300 mL of ethyl acetate to the concentrate, and heat with stirring. 200 mL of n-heptane was added dropwise at 55-65° C. with continuous stirring. After the addition was completed, the mixture was kept warm and stirred for 30 min, then cooled to -5-5° C. over 2 h, and continued to be kept warm and stirred for 1 h. The mixture was filtered with suction, and the filter cake was dried under reduced pressure to obtain 66.7 g of an off-white solid, i.e., 5-bromobenzyl-protected ticlopidine, with a yield of 93%.

[0074] (3) Preparation of Tegolasen

[0075] 50.0 g (89.86 mmol) of 5-bromobenzyl-protected ticagrelor and 5.0 g of 5% Pd / C were added to 400 mL of methanol and stirred at 55-60°C under a 1.5 MPa hydrogen atmosphere. The pressure was replenished to 1.5 MPa each time, and the reaction was terminated when the pressure dropped no more than 0.1 MPa after a 20-min interval. The palladium-on-carbon solution was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. 200 mL of acetonitrile was added to the concentrate, and the mixture was stirred at 40-50°C for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to yield 32.7 g of ticagrelor (94% yield).

[0076] Example 4: The preparation method of tigolaxant in this example is:

[0077] (1) Preparation of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide

[0078] At room temperature, 50.0 g (161.62 mmol) of 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide and 200 mL of N,N-dimethylformamide were added to a reaction vessel. The mixture was cooled to -10-0°C with stirring. 27.7 g (96.97 mmol) of 1,3-dibromo-5,5-dimethylhydantoin was added, and the reaction was stirred at -10-0°C for 2 h. 300 mL of purified water was added to the reaction solution, which was stirred at room temperature for 1 h. The mixture was filtered and the filter cake was dried under reduced pressure to yield 60.2 g of a pale yellow solid, 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, in a yield of 96%.

[0079] (2) Preparation of 5-bromobenzyl-protected tigolaxant

[0080] At room temperature, add 50.0 g (128.78 mmol) of 5-bromo-4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide, 28.8 g (154.53 mmol) of (R)-5,7-difluorochroman-4-ol, 32.6 g (160.97 mmol) of tri-n-butylphosphine, and 300 mL of dichloromethane to a reaction vessel. Stir at 30-40°C for 10 minutes. Add 32.6 g (160.97 mmol) of diisopropyl azodicarboxylate diluted with 100 mL of dichloromethane dropwise while maintaining the temperature. Continue stirring for 4 hours. Evaporate the solvent under reduced pressure, add 300 mL of ethyl acetate to the concentrate, and heat with stirring. 200 mL of n-heptane was added dropwise at 55-65° C. with continuous stirring. After the addition was completed, the mixture was kept warm and stirred for 30 min, then cooled to -5-5° C. over 2 h, and continued to be kept warm and stirred for 1 h. The mixture was filtered with suction, and the filter cake was dried under reduced pressure to obtain 68.0 g of an off-white solid, i.e., 5-bromobenzyl-protected ticlopidine, with a yield of 95%.

[0081] (3) Preparation of Tegolasen

[0082] 50.0 g (89.86 mmol) of 5-bromobenzyl-protected ticagrelor and 10 g of 5% Pd / C were added to 400 mL of methanol and stirred at 55-60°C under a 0.8 MPa hydrogen atmosphere. The pressure was replenished to 0.8 MPa each time, and the reaction was terminated when the pressure dropped no more than 0.1 MPa after a 20-min interval. The palladium-on-carbon was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. 200 mL of acetonitrile was added to the concentrate, and the mixture was stirred at 40-50°C for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to yield 32.4 g of ticagrelor (93% yield).

[0083] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for preparing ticlopidine, characterized in that: The following steps are involved: (1) In an organic solvent, 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide is subjected to a bromination reaction with a bromination reagent to obtain compound I; (2) Compound I and (R)-5,7-difluorochroman-4-ol undergo a Mitsunobu reaction in an organic solvent under the catalysis of a phosphine reagent and an azo compound to prepare Compound II; (3) Compound II is subjected to hydrogenation reaction in an organic solvent under a hydrogen atmosphere to obtain ticagrelor; 2. The method for preparing ticlopidine according to claim 1, wherein: In step (1), the organic solvent is any one or a combination of N,N-dimethylformamide, tetrahydrofuran and acetonitrile; preferably, the volume mass ratio of the organic solvent to 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide is 3-10 mL:1 g.

3. The method for preparing ticlopidine according to claim 1, wherein: In step (1), the bromination reagent is any one or a combination of N-bromosuccinimide, tetrabutylammonium tribromide and 1,3-dibromo-5,5-dimethylhydantoin; preferably, the molar ratio of the 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide to the bromination reagent is 1:(0.5-2).

4. The method for preparing ticlopidine according to claim 1, wherein: In step (1), the temperature of the bromination reaction is -10 to 10° C., and the reaction time is 1 to 12 h.

5. The method for preparing ticlopidine according to claim 1, wherein: In step (2), the organic solvent is any one or a combination of dichloromethane, chloroform, tetrahydrofuran, toluene and acetonitrile; preferably, the volume mass ratio of the organic solvent to compound I is 5-15 mL: 1 g.

6. The method for preparing tigolaxant according to claim 1, wherein: In step (2), the phosphine reagent is any one or a combination of triphenylphosphine and tri-n-butylphosphine; the azo compound is any one or a combination of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and dipiperidine azodicarbonyl; preferably, the molar ratio of the raw materials of the compound I and (R)-5,7-difluorochroman-4-ol, the phosphine reagent and the azo compound is 1:(1-2):(1-1.5):(1-3).

7. The method for preparing tigolaxant according to claim 1, wherein: In step (2), the temperature of the Mitsunobu reaction is -10 to 60° C., and the reaction time is 1 to 24 hours.

8. The method for preparing ticlopidine according to claim 1, wherein: In step (3), the organic solvent is any one or a combination of methanol, ethanol and acetonitrile; the volume mass ratio of the organic solvent to compound II is 5-15 mL: 1 g.

9. The method for preparing tigolaxant according to claim 1, wherein: In step (3), the catalyst for the hydrogenation reaction is palladium carbon; the palladium content in the palladium carbon is 5wt% to 10wt%; and the mass of the palladium carbon is 1 to 30% of the mass of compound II.

10. The method for preparing ticlopidine according to claim 1, wherein: In step (3), the pressure of the hydrogen is 0.2 to 2.0 MPa, the reaction temperature is 10 to 60° C., and the reaction time is 1 to 48 h.

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