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Preparation method of ilaprazole key intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole

A technology of mercaptobenzimidazole and ilaprazole, applied in directions such as organic chemistry, can solve problems such as troublesome processing of reducing agents, expensive metal catalysts, unfavorable industrial production, etc., and achieves low price, stable yield, and easy control of the reaction process. Effect

Pending Publication Date: 2021-09-07
SHANGHAI GAOZHUN PHARMA CO LTD
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0018] The technical problem to be solved in the present invention is that in the existing preparation method, dichloromethane and water are used as solvents, two-phase reaction is unfavorable for the reaction, the reducing agent used is troublesome to handle, and the metal catalyst is expensive, which is unfavorable for industrial production. The invention provides a preparation method of 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole, which not only has a simple process route, but also has many advantages such as simpler operation, higher yield, and environmental friendliness from the perspective of industrialization. The intermediate produced by this method is easy to obtain the ilaprazole that meets the requirements of the Pharmacopoeia, so as to solve the defects caused by the prior art

Method used

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  • Preparation method of ilaprazole key intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole
  • Preparation method of ilaprazole key intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole
  • Preparation method of ilaprazole key intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The reaction formula of embodiment 1 is as follows:

[0060]

[0061] 2-Nitro-1,4-phenylenediamine, intermediate VII (100g, 1.0eq) was added to tetrahydrofuran THF (500ml), and sodium acetate trihydrate (88.9g, 1.0eq), acetic acid (196g, 5.0eq), add water (500ml), finally add 2,5-dimethoxytetrahydrofuran (129.5g, 1.5eq), replace with nitrogen, heat up to reflux, react at 60°C for 18 hours, cool to 40°C, add water ( 1.6L, 16.0v / w), the aqueous phase was extracted 4 times with ethyl acetate (500ml), the organic phase was washed once with water (1.0L), methanol (500ml) was added to the crude product and refluxed for 1.5 hours, and water (160ml, 1.6v / w) and reflux for 1.0 hour, then lower the temperature (0-10°C) and stir for 1 hour, and dry the solid in vacuum at 50°C for 18 hours to obtain 120g of red solid 2-nitro-4-(1H-pyrrol-1-yl) Aniline is intermediate Ⅵ with a yield of 90.2%;

[0062] Add ethanol (1.0L), 2-nitro-4-(1H-pyrrol-1-yl) aniline, intermediate VI (100g...

Embodiment 2

[0066] The reaction formula of embodiment 2 is as follows:

[0067]

[0068] 2-Nitro-1,4-phenylenediamine, intermediate VII (100g, 1.0eq) was added to tetrahydrofuran THF (500ml), and sodium acetate trihydrate (88.9g, 1.0eq), acetic acid (196g, 5.0eq), add water (500ml), finally add 2,5-dimethoxytetrahydrofuran (172.6g, 2.0eq), replace with nitrogen, heat up to reflux, react at 62.5°C for 18 hours, cool down to 40°C, add water (1.6L, 16.0v / w), extract the aqueous phase with ethyl acetate (500ml) for 4 times, wash the organic phase with water (1.0L) once, add methanol (500ml) to the crude product and reflux for 1.5 hours, then add water (160ml , 1.6v / w) and reflux for 1.0 hour, then lower the temperature (0-10°C) and stir for 1 hour, and dry the solid in vacuum at 50°C for 18 hours to obtain 121g of red solid 2-nitro-4-(1H-pyrrole-1- Base) aniline is intermediate VI, yield 90.7%;

[0069] Add ethanol (1.0L), 2-nitro-4-(1H-pyrrol-1-yl) aniline, intermediate VI (100g, 1.0eq)...

Embodiment 3

[0073] The reaction formula of embodiment 3 is as follows:

[0074]

[0075] 2-Nitro-1,4-phenylenediamine, intermediate VII (100g, 1.0eq) was added to tetrahydrofuran THF (500ml), and sodium acetate trihydrate (88.9g, 1.0eq), acetic acid (117.6g ,3.0eq), add water (500ml), finally add 2,5-dimethoxytetrahydrofuran (129.5g, 1.5eq), replace with nitrogen, heat up to reflux, react at 65°C for 18 hours, cool to 40°C, add Water (1.6L, 16.0v / w), extracted the aqueous phase with ethyl acetate (500ml) 4 times, the organic phase was washed once with water (1.0L), added methanol (500ml) to the crude product and refluxed for 1.5 hours, then added water ( 160ml, 1.6v / w) and reflux for 1.0 hour, then lower the temperature (0-10°C) and stir for 1 hour, and dry the solid under vacuum at 50°C for 18 hours to obtain 110g of red solid 2-nitro-4-(1H-pyrrole-1- Base) aniline is intermediate VI, and the yield is 83%;

[0076] Add ethanol (1.0L), 2-nitro-4-(1H-pyrrol-1-yl) aniline (100g, 1.0eq)...

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Abstract

The invention discloses a preparation method of an ilaprazole key intermediate 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole, which comprises the following steps of: 1, adding acid and alkali into 2-nitro-1, 4-phenylenediamine, namely an intermediate VII, in a solvent to prepare 2-nitro-4-(1H-pyrrole-1-yl) aniline, namely an intermediate VI; 2, adding the intermediate VI into a reaction solvent, mixing, adding a reducing agent thiourea dioxide and a catalyst sodium hydroxide, and reacting to obtain 4-(1H-pyrrole-1-yl) benzene-1, 2-diamine, namely an intermediate V; and 3, adding the intermediate V into a reaction solvent and mixing, and adding alkali and CS2 for a reaction to obtain 5-(1H-pyrrole-1-yl)-2-mercaptobenzimidazole. The method not only has a simple process route, but also can reduce the cost and is beneficial to industrial production, and ilaprazole meeting the requirements of pharmacopeia can be easily obtained from the compound produced by the method.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole, a key intermediate of ilaprazole. Background technique [0002] Ilaprazole is an irreversible proton pump inhibitor. After oral absorption, it is metabolized and transformed into its active product, estrogenamide, which is covalently bound to H+ / K+ATPase, thereby inhibiting central or peripheral gastric acid secretion; [0003] The chemical structure of Ilaprazole (laprazole) (I) is a benzimidazole structure, which includes omeprazole, lansoprazole, pantoprazole, rabeprazole, etc. Researched and developed by Pharmaceutical Co., Ltd., China Livzon Group took the lead in listing; [0004] [0005] However, in the existing synthesis process of this drug, 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole (Ⅲ) is an important intermediate for the synthesis of ilaprazole, and then a substitution reaction and an oxidatio...

Claims

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Application Information

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IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 丁永真李维华刘真豪王江淮胡家豪
Owner SHANGHAI GAOZHUN PHARMA CO LTD
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