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Preparation method of high-purity rebamipide

A rebamipide, high-purity technology, applied in the field of preparation of high-purity rebamipide, can solve problems such as difficult filtration, lower production efficiency, lower product yield, etc.

Active Publication Date: 2014-12-24
CHONGQING SHENGHUAXI PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

When the inventor repeated the above-mentioned patent method, he found that due to the viscous reaction solution, and the crude product of rebamipide precipitated very fine slurry-like solids, it was very difficult to filter, which increased the production intensity and reduced the production efficiency. Crystallization also increases the operating steps and the consumption of solvents and additives, which increases the cost and reduces the product yield

Method used

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  • Preparation method of high-purity rebamipide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 50g (0.215mol) of 2-amino-3-[2(1H)-quinolinone-4-methylpropionic acid], compound (5), into 250ml of acetone, and dropwise add the Chlorobenzoyl chloride 40g (0.228mol) and 12% NaOH solution 250ml, dropwise, keep the temperature for 1.5 hours. Cool to 0-5 ° C and stir for crystallization for 2 hours. After filtering, the filter cake was dried under normal pressure at 50-60°C for 8 hours, and the crude product of Rebamipide sodium salt was 78.8g (HPLC purity 99.63%).

Embodiment 2

[0019] Add 60g KOH (1.07mol) into 250ml water and 250ml tetrahydrofuran mixed solvent, add 50g (0.215mol) of compound (5) under stirring, add 40g (0.228mol) p-chlorobenzoyl chloride dropwise at 0-15°C, and drop , continue the reaction for 2.5 hours, cool the reaction solution to 0-5°C for crystallization for 2 hours, filter, and dry the filter cake at 50-60°C under normal pressure for 8 hours, yielding 72.2 g of crude product of Rebamipide salt (HPLC 99.55 %).

Embodiment 3

[0021] Mg(OH) 2 Add 50g (0.86mol) into 250ml of water and 500ml of acetonitrile mixed solvent, add 50g (0.215mol) of compound (5) under stirring, add 100g (0.571mol) of p-chlorobenzoyl chloride dropwise at 20-30°C, dropwise, keep React for 3 hours, cool the reaction solution to 0-5°C and crystallize for 2 hours, filter, and dry the filter cake under normal pressure at 50-60°C for 8 hours to obtain 70.5 g of crude product of rebamipide salt (HPLC purity 99.58%).

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Abstract

The invention discloses a preparation method of high-purity rebamipide. During synthesis process of a rebamipide crude product, the rebamipide crude product is precipitated out, in the form of a rebamipide salt solid, directly from a reaction solution. Thus, effective separation of impurities from a product is realized. A rebamipide salt crude product has good quality and high purity. Without further refining, dissociating is carried out directly by an acid-alkali method so as to obtain a high-purity rebamipide finished product. By the above method to obtain rebamipide, operational steps and refining frequency are minimized, and production efficiency is raised remarkably. In addition, a solvent used is cheap and easily available, and it is beneficial to realize industrial production.

Description

technical field [0001] The invention relates to a preparation method of high-purity rebamipide, which belongs to the field of medicine and chemical industry. Background technique [0002] Rebamipide is a quinolone compound with the chemical formula (1), and its chemical name is: 2-(4-chlorobenzamido)-3-[2(1hydrogen)-quinolone- 4-yl] propionic acid, the original manufacturer is Japan Otsuka Pharmaceutical Co., Ltd. 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. The damage has a good effect, and it still has a good curative effect on gastric mucosal lesions that failed to eradicate H.pylori infection, and it is the only gastric mucosal protective agent that can increase PG synthesis and scavenge and inhibit free radicals, and has high clinica...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 苏家宏何亮姜维平
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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