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Production method of high-optical-purity esomeprazole

A technology of esomeprazole and benzimidazole, applied in the production field of high optical purity esomeprazole salt

Inactive Publication Date: 2013-03-13
NANJING XUNAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method adopts the basic sodium salt of m-chloroperoxybenzoic acid, which is a commonly used oxidizing agent, to oxidize sulfide to sulfoxide, and uses a water-miscible organic solvent as the reaction solvent, and adds the reaction solution in the form of an aqueous solution of sodium m-chloroperbenzoate In this way, the problem that the acidity of m-chloroperoxybenzoic acid cannot be applied to the preparation of esomeprazole has been solved

Method used

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Examples

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Embodiment 1

[0018]

[0019] Weigh 9 kg of sulfide shown in formula I, add 35 L of tetrahydrofuran, add 3 L of D-diethyl tartrate, 2.5 L of tetraisopropyl titanate under stirring, slowly raise the temperature to 35 ° C, stir for 90 minutes, and dropwise add triethylamine 1.4 L, lower the temperature to -10°C, add dropwise a solution of 5.2kg of sodium m-chloroperoxybenzoate dissolved in 8L of water, continue stirring for 60 minutes after the dropwise addition, add 25L of 10% ammonia water to the reaction solution, stir, and wash the water with 10L of toluene Phase once, separate the water phase, slowly add acetic acid dropwise to adjust pH = 7.5 ~ 8.0, extract twice with 20 L of dichloromethane, combine the dichloromethane, and remove the solvent under reduced pressure at 40 ° C to obtain a brown oily substance, which is dissolved in 10 L Add dropwise 20 L of 0.5% sodium bicarbonate aqueous solution to acetone, stir to obtain a white solid, and air-dry at 40° C. to obtain 5.1 kg of esome...

Embodiment 2

[0022] Weigh 9kg of sulfide shown in formula I, add 35L of tetrahydrofuran, add 3L of D-diethyl tartrate and 2.5L of tetraisopropyl titanate under stirring, slowly raise the temperature to reflux at 65°C, stir for 30min, add diisopropyl 1.8 L of ethyl ethylamine, cooled to 0 ° C, dropwise added a solution of 5.2 kg of sodium m-chloroperoxybenzoate dissolved in 8 L of water, continued to stir for 60 min after the dropwise addition, added 15 L of 25% ammonia water to the reaction solution, stirred, and Wash the water phase once with 10L of toluene, separate the water phase, slowly add acetic acid dropwise to adjust the pH=8.0-8.5, extract twice with 20L of ethyl acetate, combine the organic phases, and remove the solvent under reduced pressure at 40°C to obtain a brown oil. Dissolve in 10L of acetone, add 20L of 0.25% sodium bicarbonate solution dropwise, stir to obtain a white solid, and air-dry at 40°C to obtain 4.9kg of esomeprazole, which can be used to prepare esomeprazole s...

Embodiment 3

[0025] Weigh 18 kg of the sulfide shown in formula I, add 65 L of tetrahydrofuran, add 6.2 L of D-diethyl tartrate and 5.0 L of tetraisopropyl titanate under stirring, slowly raise the temperature to 65°C and reflux, stir for 60 minutes, and dropwise add diisopropyl titanate Propylethylamine 3.1L, cooled to 5°C, dropwise added a solution of 10.0kg sodium m-chloroperoxybenzoate dissolved in 13L water, continued to stir for 60min after the dropwise addition, added 45L of 12.5% ​​ammonia water to the reaction solution, stirred, Wash the water phase once with 20L of toluene, separate the water phase, slowly add acetic acid dropwise to adjust the pH=8.0~8.5, extract twice with 40L of dichloromethane, combine the organic phase, and remove the solvent under reduced pressure at 40°C to obtain a brown oily substance , dissolved in 20L of acetone, added dropwise to 35L of 0.2% sodium bicarbonate aqueous solution, stirred to obtain a white solid, and air-dried at 40°C to obtain 10.7kg of ...

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Abstract

The invention belongs to the field of pharmacy and relates to a production method of high-optical-purity esomeprazole salt. The method takes m-chloro peroxy-sodium benzoate as an oxidizing agent and takes an organic solvent which is dissolved into water as a reaction solvent, so that the problem that the acidity of the m-chloro peroxy-sodium benzoate cannot be applied to preparing the esomeprazole is solved. The method is simple to operate and has a low cost; and the optical purify of the prepared product is high and the impurity content is low.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a production method of esomeprazole salt with high optical purity. Background technique [0002] The launch of proton pump inhibitors (PPI) is a milestone breakthrough in the treatment of acid-related diseases. The first marketed proton pump inhibitor, omeprazole, was developed and launched by AstraZeneca in 1988, followed by a series of drugs such as pantoprazole, lansoprazole, and rabeprazole. Due to the presence of a chiral sulfur in the chemical structure of prazoles, foreign pharmaceutical companies have successively developed esomeprazole and dexlansoprazole and launched them on the market. [0003] Esomeprazole (esomeprazole) is a single optically pure S-isomer of omeprazole (omeprazole), developed by AstraZeneca Pharmaceuticals Co., Ltd., and the injection was listed in the United States in 2005. The trade name is Nexium ). It is clinically used as an alternative th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 刘晓雯
Owner NANJING XUNAN PHARMA TECH
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