Esomeprazole preparation method

A technology for esomeprazole and benzimidazole, applied in the field of chemical drug preparation, can solve the problems of complicated preparation process, unsatisfactory esomeprazole yield and purity, etc., and achieves the effects of high purity and improved yield

Inactive Publication Date: 2017-10-10
武汉励合生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The yield of esomeprazole in the prior art and its purity are not ideal enough, and the preparation of esomeprazole mainly utilizes sodium source to react with esomeprazole to generate sodium salt, and the preparation process is loaded down with trivial details

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] The present invention proposes a kind of preparation method of esomeprazole, comprises the steps:

[0020] S1: Select 3,5-lutidine and 5-methoxy-2-mercapto-1H-benzimidazole as raw materials, and keep them sealed to prevent reaction with air;

[0021] S2: Move 3,5-lutidine into the reactor, stir slowly at 40 degrees Celsius, and add oxides to it, after complete mixing, add nitrates to it again, react for 3 minutes, place again Into methoxy substitution to obtain 3,5-dimethyl-4-methoxypyridine-N-oxide;

[0022] S3: Add cyano group to the 3,5-dimethyl-4-methoxypyridine-N-oxide generated above at 50 degrees Celsius, replace with cyano group, acidify and hydrolyze to obtain 3,5-dimethyl Base-4-methoxypyridine-2-carboxylic acid;

[0023] S4: 3,5-dimethyl-4-methoxypyridine-2-carboxylic acid in S3 is reduced and chlorinated by lithium aluminum hydride to obtain 3,5-dimethyl-4-methoxy- 2-Chloromethylpyridine hydrochloride;

[0024] S5: Put the above-mentioned 3,5-dimethyl-4-...

Embodiment 2

[0031] The present invention proposes a kind of preparation method of esomeprazole, comprises the steps:

[0032] S1: Select 3,5-lutidine and 5-methoxy-2-mercapto-1H-benzimidazole as raw materials, and keep them sealed to prevent reaction with air;

[0033] S2: Move 3,5-lutidine into the reactor, stir slowly at 41 degrees Celsius, and add oxides to it, after complete mixing, add nitrates to it again, after 3.5 minutes of reaction, again Inserting a methoxy group to obtain 3,5-dimethyl-4-methoxypyridine-N-oxide;

[0034] S3: Add cyano group to the 3,5-dimethyl-4-methoxypyridine-N-oxide generated above at 53 degrees Celsius, replace with cyano group, acidify and hydrolyze to obtain 3,5-dimethyl Base-4-methoxypyridine-2-carboxylic acid;

[0035] S4: 3,5-dimethyl-4-methoxypyridine-2-carboxylic acid in S3 is reduced and chlorinated by lithium aluminum hydride to obtain 3,5-dimethyl-4-methoxy- 2-Chloromethylpyridine hydrochloride;

[0036] S5: Put the above-mentioned 3,5-dimethy...

Embodiment 3

[0043] The present invention proposes a kind of preparation method of esomeprazole, comprises the steps:

[0044] S1: Select 3,5-lutidine and 5-methoxy-2-mercapto-1H-benzimidazole as raw materials, and keep them sealed to prevent reaction with air;

[0045] S2: Move 3,5-lutidine into the reactor, stir slowly under the environment of 43 degrees Celsius, and add oxide to it. Into methoxy substitution to obtain 3,5-dimethyl-4-methoxypyridine-N-oxide;

[0046] S3: Add cyano group to the 3,5-dimethyl-4-methoxypyridine-N-oxide generated above at 56 degrees Celsius, replace with cyano group, acidify and hydrolyze to obtain 3,5-dimethyl Base-4-methoxypyridine-2-carboxylic acid;

[0047] S4: 3,5-dimethyl-4-methoxypyridine-2-carboxylic acid in S3 is reduced and chlorinated by lithium aluminum hydride to obtain 3,5-dimethyl-4-methoxy- 2-Chloromethylpyridine hydrochloride;

[0048]S5: Put the above-mentioned 3,5-dimethyl-4-methoxy-2-chloromethylpyridine hydrochloride at 55 degrees Cel...

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Abstract

The invention discloses an esomeprazole preparation method which includes the steps: transferring 3, 5-dimethyl pyridine into a reactor; adding oxide into the reactor; adding nitride into the reactor; placing methoxyl into the reactor and performing substitution to obtain 3, 5-dimethyl-4-methoxypyridine-N-oxide; adding cyano and performing cyano substitution and acidifying hydrolysis to obtain 3, 5-dimethyl-4-methoxypyridine-2-carboxylic acid; reducing and chloro-substituting the 3, 5-dimethyl-4-methoxypyridine-2-carboxylic acid by lithium aluminum hydride to obtain 3, 5-dimethyl-4-methoxyl-2-chloromethylpyridine hydrochloride; adding 5-methoxyl-2-sulfydryl-1H-benzimidazole into the 3,5-dimethyl-4-methoxyl-2-chloromethylpyridine hydrochloride; mixing and stirring materials for 5-10 minutes; asymmetrically oxidizing 5-methoxyl-2-[(4-methoxyl-3, 5-dimethyl-2-pyridyl) methylthio]-1H-benzimidazole by titanium isopropoxide, D-tartaric acid propanamide and isopropyl benzene hydroperoxide to obtain esomeprazole. The finished product ratio of the esomeprazole is remarkably increased, the obtained esomeprazole is high in purity, and no impurities remain in the esomeprazole.

Description

technical field [0001] The invention relates to the technical field of chemical medicine preparation, in particular to a preparation method of esomeprazole. Background technique [0002] Omeprazole is the first proton pump inhibitor (PPI) on the market, and it is mainly metabolized by the cytochrome P450 isoenzyme system CYF2C19 and CYP3A4, while (R)-omeprazole is mainly metabolized by the former into inactive substances, Metabolism is faster, and (S)-omeprazole is mainly metabolized by the latter, and the metabolism is slower. (S)-omeprazole is esomeprazole, and its drug effect is far stronger than omeprazole in the general population. [0003] The esomeprazole yield and its purity in the prior art are not ideal enough, and the preparation of esomeprazole mainly utilizes sodium source to react with esomeprazole to generate sodium salt, and the preparation process is loaded down with trivial details. For this reason, we have proposed a kind of preparation method of esomepr...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 彭凡李娜田军叶杨欢陈金利
Owner 武汉励合生物医药科技有限公司
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