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Preparation method of right-handed rabeprazole sodium monohydrate crystal

A technology for dex-rabeprazole sodium and dex-rabeprazole is applied in the field of preparation of dex-rabeprazole sodium monohydrate crystal, can solve the problems of low yield, low purity and the like, and achieves a simple process , Significant economic value, easy to operate effect

Active Publication Date: 2015-02-04
HUNAN WUZHOUTONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The main problem in Chinese patent CN102924434A and Chinese patent CN104031030A is that the purity is low. According to the inventor’s test according to the same conditions, the purity is generally lower than 99.0%, and the yield is lower in addition, generally less than 55%.

Method used

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  • Preparation method of right-handed rabeprazole sodium monohydrate crystal
  • Preparation method of right-handed rabeprazole sodium monohydrate crystal
  • Preparation method of right-handed rabeprazole sodium monohydrate crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 20 g of rabeprazole sulfide (molecular weight 266.1642) into a 1000 ml four-neck flask, add 400 g of toluene, heat up to 60°C and stir until it dissolves, add 16.8 g of L-(+)-diethyl tartrate (molecular weight 206.19), Tetraisopropyl titanate (molecular weight: 284.22) 11.6g, stir for 1 hour, add water 1g, keep stirring for 1 hour, add N,N-diisopropylethylamine (molecular weight: 129.25) 5.26g, react for 30 minutes, then cool down To 0°C, add 11 g of toluene solution of cumene hydroperoxide (molecular weight 152.19) dropwise, and keep the reaction for 12 hours after dropping, and monitor the progress of the reaction by TLC until the reaction is almost complete (developing agent: methanol-dichloromethane=1:10, ).

[0023] After the reaction, 200 ml of 10% NaOH aqueous solution was added, stirred for 30 minutes, and separated. The aqueous phase obtained after liquid separation, i.e. NaOH aqueous solution, was extracted (washed) once with 40 g of toluene, separated, a...

Embodiment 2

[0029]Add 20g of rabeprazole sulfide into a 1000ml four-necked flask, add 400g of toluene, raise the temperature to 60°C and stir until it dissolves, add 16.8g of L-(+)-diethyl tartrate, 11.6g of tetraisopropyl titanate After stirring for 1 hour, add 1 g of water, keep stirring for 1 hour, add 5.26 g of diisopropylethylamine, react for 30 minutes and cool down to 0 ° C, add dropwise a toluene solution of cumene hydroperoxide 11 g, and keep warm after dropping The reaction was carried out for 12 hours, and the progress of the reaction was monitored by TLC until the reaction was almost complete (developing solvent: methanol-dichloromethane=1:10).

[0030] After the reaction, 200 ml of 10% NaOH aqueous solution was added, stirred for 30 minutes, and separated. The aqueous phase obtained after liquid separation, i.e. NaOH aqueous solution, was extracted once with 40 g of toluene, and the liquid was separated, and then 80 g of toluene was added to the obtained water phase, the temp...

Embodiment 3

[0032] Add 20g of rabeprazole sulfide into a 1000ml four-necked flask, add 400g of toluene, raise the temperature to 60°C and stir until it dissolves, add 16.8g of L-(+)-diethyl tartrate, 11.6g of tetraisopropyl titanate , keep stirring for 2 hours, add 5.26g of diisopropylethylamine, react for 30 minutes and cool down to 0°C, add dropwise a toluene solution of 11g of cumene hydroperoxide, after dropping the heat preservation reaction for 72 hours, TLC monitors the reaction It shows progress until the reaction is not complete (developing solvent: methanol-dichloromethane=1:10).

[0033] Add 200 ml of 10% NaOH aqueous solution to the above reaction product, stir for 30 minutes, and separate the layers. The water phase obtained after liquid separation, that is, the NaOH aqueous solution was extracted once with 40 g of toluene, and the liquid was separated, and then 80 g of toluene was added to the obtained water phase, the temperature was lowered to about 5 ° C, and the pH was a...

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Abstract

The invention discloses a preparation method of a right-handed rabeprazole sodium monohydrate crystal. In the method, through control of addition amount of a key material, water, in an intermediate product during a reaction for generating the right-handed rabeprazole from rabeprazole thioether, pH value during a process of adjusting the pH value by an acid during one-time salification of the right-handed rabeprazole is controlled and usage amounts of a polar solvent, such as ethanol, and a non-polar solvent, such as normal hexane, normal heptanes or diethyl ether, during a re-crystallization process are controlled, thereby greatly increasing purity and yield of the right-handed rabeprazole sodium monohydrate crystal.

Description

technical field [0001] The invention relates to a preparation method of dex-rabeprazole sodium monohydrate crystal. Background technique [0002] Rabeprazole sodium is a drug used to treat duodenal ulcer and gastric ulcer to inhibit the secretion of gastric acid. It can attach to the surface of gastric parietal cells and inhibit the secretion of gastric acid by inhibiting H+ / K+-ATPase. At present, there are not many documents about the salification of dex-rabeprazole sodium, most of which are the salification of racemic rabeprazole. For example, Liu Shenggao et al. The salt-forming and crystallization method of rabeprazole sodium comprises the steps of salt-forming rabeprazole and alkoxide in alcohol, and after the salt-formed solution is concentrated, a sufficient amount of anti-solvent is added for crystallization. In this method, ethanol is used as a salt-forming solvent to form a salt, and then the ethanol is distilled out by rotary steaming, and the salt is directly fo...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07B2200/13C07D401/12
Inventor 谭淑珍李浦江刘小艳
Owner HUNAN WUZHOUTONG PHARMA
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