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Preparation method of rebamipide bulk drug

A technology of rebamipide and raw material medicine, which is applied in the field of preparation of rebamipide raw material medicine, can solve problems such as unfavorable industrial production, unsatisfactory improvement of purity, and increased production cost, so as to facilitate industrial production, avoid crystallization and purification, The effect of reducing the content of impurities

Pending Publication Date: 2021-08-13
千辉药业(安徽)有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] There are the following disadvantages in adopting the above synthesis process: there are obvious impurities in the obtained product, including various intermediates and reaction by-products remaining therein; although the rebamipide crude product can be refined by methods such as repeated recrystallization in the follow-up, there are refining times Many, large solvent consumption, unsatisfactory improvement in purity, resulting in low overall yield, increased production costs, and unfavorable for industrialized production

Method used

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  • Preparation method of rebamipide bulk drug
  • Preparation method of rebamipide bulk drug
  • Preparation method of rebamipide bulk drug

Examples

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Effect test

Embodiment 1

[0030] Step 1: Preparation of crude product of rebamipide bulk drug: Add sodium hydroxide solution to a three-necked flask with thermometer, reflux tube, and stirrer, and at 0°C, 150r / min, add compound three and Dimethylacetamide, after stirring at constant temperature and speed for 10 minutes, slowly add the toluene solution of 4-chlorobenzoyl chloride dropwise, and control the temperature of the reaction system during the dropwise addition process to be less than 5°C. React at 3°C ​​for 5 hours, then add methanol, heat up to 75°C, add dropwise glacial acetic acid under stirring, cool to 22°C after the glacial acetic acid is added completely, then filter, wash the filter cake with deionized water and then with methanol to obtain The crude product of rebamipide bulk drug, wherein the mass ratio of sodium hydroxide solution, compound three, dimethylacetamide, 4-chlorobenzoyl chloride toluene solution, methanol, and glacial acetic acid is 450:28:95 :380:17, and the mass concentr...

Embodiment 2

[0039] Step 1: Preparation of crude product of rebamipide bulk drug: Add sodium hydroxide solution to a three-necked flask with thermometer, reflux tube, and stirrer, and at 0°C, 150r / min, add compound three and Dimethylacetamide, after stirring at constant temperature and speed for 10 minutes, slowly add the toluene solution of 4-chlorobenzoyl chloride dropwise, and control the temperature of the reaction system during the dropwise addition process to be less than 5°C. React at 3°C ​​for 5 hours, then add methanol, heat up to 75°C, add dropwise glacial acetic acid under stirring, cool to 22°C after the glacial acetic acid is added completely, then filter, wash the filter cake with deionized water and then with methanol to obtain The crude product of rebamipide raw material drug, wherein, the mass ratio of sodium hydroxide solution, compound three, dimethylacetamide, 4-chlorobenzoyl chloride toluene solution, methanol, and glacial acetic acid is 480:29:100 :390:18, and the mas...

Embodiment 3

[0048] Step 1: Preparation of crude product of rebamipide bulk drug: Add sodium hydroxide solution to a three-necked flask with thermometer, reflux tube, and stirrer, and at 0°C, 150r / min, add compound three and Dimethylacetamide, after stirring at constant temperature and speed for 10 minutes, slowly add the toluene solution of 4-chlorobenzoyl chloride dropwise, and control the temperature of the reaction system during the dropwise addition process to be less than 5°C. React at 3°C ​​for 5 hours, then add methanol, heat up to 75°C, add dropwise glacial acetic acid under stirring, cool to 22°C after the glacial acetic acid is added completely, then filter, wash the filter cake with deionized water and then with methanol to obtain The crude product of rebamipide bulk drug, wherein, the mass ratio of sodium hydroxide solution, compound three, dimethylacetamide, 4-chlorobenzoyl chloride toluene solution, methanol, and glacial acetic acid is 600:30:110 :400:20, and the mass concen...

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Abstract

The invention discloses a preparation method of a rebamipide bulk drug. The preparation method comprises the following steps: 1, preparing a crude product of the rebamipide bulk drug: preparing the crude product of the rebamipide bulk drug by utilizing a compound III and 4-chlorobenzoyl chloride; and 2, purifying the rebamipide bulk drug. The compound III is prepared from a compound II, deionized water and concentrated hydrochloric acid, the compound II is prepared from a compound I, glacial acetic acid and concentrated hydrochloric acid, and the compound I is prepared from diethyl acetamidomalonate and 4-bromomethylquinolone. A process control method is utilized, impurities in the synthesized compound I, impurities in the synthesized compound II and impurities in the synthesized compound III are respectively subjected to impurity removal and purification by a common purification method, and the purity of the rebamipide bulk drug is improved in combination with a method for crystallizing and purifying the crude product of the rebamipide bulk drug.

Description

technical field [0001] The invention belongs to the technical field of preparation of raw materials, and in particular relates to a preparation method of rebamipide raw materials. Background technique [0002] Rebamipide (Rebamipide), is a kind of quinolone compound as shown in (1), chemical name is: 2-(4-chlorobenzamido)-3-[2(1 hydrogen)-quinolone- 4-base] propionic acid, its molecular formula is as follows: [0003] [0004] Rebamipide is an active new-generation gastric mucosal protective agent, which can improve the histological healing quality of gastric ulcer, reduce ulcer recurrence, and treat gastric mucosal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs), alcohol and other factors. It has a good effect on injury, and it still has a good curative effect on gastric mucosal lesions that cannot be eradicated by Helicobacter pylori infection. It is the only gastric mucosal protective agent that can increase PG synthesis and scavenge and inhibit free r...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 毛杰张志伟袁勇
Owner 千辉药业(安徽)有限责任公司
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