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Preparation method of esomeprazole potassium

A technology of esomeprazole potassium and omeprazole sulfide is applied in the field of preparation of esomeprazole potassium, can solve problems such as low yield and purity, achieve high product yield and high purity, and is beneficial to The effect of commercial production

Inactive Publication Date: 2017-08-18
上海华源医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to the method described in the patent US6369085B1 to prepare Esso esomeprazole potassium, the yield and purity are low, and the sulfide is easily over-oxidized into sulfone, and the R-enantiomer is relatively high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] A kind of preparation method of esomeprazole potassium, its step is as follows:

[0037] (1) drop into 1200L toluene in the dry reactor, pass into nitrogen in the toluene to centrifugation and finish;

[0038] (2) Throw in 300Kg of omeprazole sulfide, heat up to 30-32°C, and put in 26Kg of D-(-)diethyl tartrate;

[0039] (3) be warming up to 44~46 ℃, drop into 16Kg titanium isopropoxide (IV) after stirring for 30 minutes;

[0040] (4) Cool to 31~35 ℃, drop into 12Kg diisopropylethylamine;

[0041] (5) Keep the temperature at 31-33°C, and add 180Kg of cumene hydroperoxide dropwise within 30 minutes to 2 hours;

[0042] (6) Insulate and react at 31-33°C for 15 minutes;

[0043] QC checks the sulfide content (limit: no more than 5.0%) to monitor whether the reaction is over

[0044] (7) After the reaction finishes, stir the methanol solution of potassium hydroxide (66kg potassium hydroxide+300L methanol);

[0045] (8) Cool to 25-30°C and keep for 1 hour;

[0046] (9)...

Embodiment 2

[0061] A kind of preparation method of esomeprazole potassium, its step is as follows:

[0062] (1) drop into 1200L toluene in the dry reactor, pass into nitrogen in the toluene to centrifugation and finish;

[0063] (2) Throw in 300Kg of omeprazole sulfide, heat up to 30-32°C, and put in 26Kg of D-(-)diethyl tartrate;

[0064] (3) be warming up to 44~46 ℃, drop into 16Kg titanium isopropoxide (IV) after stirring for 30 minutes;

[0065] (4) Cool to 31~35 ℃, drop into 12Kg diisopropylethylamine;

[0066] (5) Keep the temperature at 31-33°C, and add 180Kg of cumene hydroperoxide dropwise within 30 minutes to 2 hours;

[0067] (6) Insulate and react at 31-33°C for 15 minutes;

[0068] QC checks the sulfide content (limit: no more than 5.0%) to monitor whether the reaction is over

[0069] (7) After the reaction finishes, stir the methanol solution of potassium hydroxide (66kg potassium hydroxide+300L methanol);

[0070] (8) Cool to 25-30°C and keep for 1 hour;

[0071] (9)...

Embodiment 3

[0086] A kind of preparation method of esomeprazole potassium, its step is as follows:

[0087] (1) drop into 1200L toluene in the dry reactor, pass into nitrogen in the toluene to centrifugation and finish;

[0088] (2) Throw in 300Kg of omeprazole sulfide, heat up to 30-32°C, and put in 26Kg of D-(-)diethyl tartrate;

[0089] (3) be warming up to 44~46 ℃, drop into 16Kg titanium isopropoxide (IV) after stirring for 30 minutes;

[0090] (4) Cool to 31~35 ℃, drop into 12Kg diisopropylethylamine;

[0091] (5) Keep the temperature at 31-33°C, and add 180Kg of cumene hydroperoxide dropwise within 30 minutes to 2 hours;

[0092] (6) Insulate and react at 31-33°C for 15 minutes;

[0093] QC checks the sulfide content (limit: no more than 5.0%) to monitor whether the reaction is over

[0094] (7) After the reaction finishes, stir the methanol solution of potassium hydroxide (66kg potassium hydroxide+300L methanol);

[0095] (8) Cool to 25-30°C and keep for 1 hour;

[0096] (9)...

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PUM

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Abstract

The invention discloses a preparation method of esomeprazole potassium. The preparation method comprises the following steps: (1) putting methylbenzene into a dry reaction kettle, and introducing nitrogen into the methylbenzene until the end of centrifugation; (2) putting omeprazole sulfide, rising the temperature to 30 to 32 DG C, and putting 26 KG of D-(-)diethyl tartrate; (3) rising the temperature to 44 to 46 DEG C, and putting isopropyl titanate (IV) after stirring for 30 minutes; (4) cooling to 31 to 35 DEG C, and putting diisopropylethylamine; (5) keeping the temperature be 31 to 33 DEG C, and dropwise adding cumyl hydroperoxide within 30 minutes to 2 hours; (6) keeping the temperature be 31 to 33 DEG C for 15 minutes for reacting; checking the content of sulfide through QC (Quality Control), and monitoring whether the reaction ends or not; (7) after the end of the reaction, stirring a methanol solution of potassium hydroxide; (8) cooling to 25 to 30 DEG C and keeping for 1 hour; (9) centrifuging, thus obtaining a coarse product, and refining further.

Description

technical field [0001] The invention relates to a preparation method of esomeprazole potassium, which belongs to the field of pharmacy. Background technique [0002] Esomeprazole magnesium is also known as levo-omeprazole, esomeprazole, chemical name (S)-(-)-5-methoxy-2-{[(4-methoxy-3,5 -Dimethyl-2-pyridyl)methyl]sulfinyl}-1H-benzimidazole magnesium salt, which is the magnesium salt of (S)-(-)-type single enantiomer of the marketed drug omeprazole Salt preparation, developed by Astra Zeneca Company in Sweden, was launched in my country in 2004; it is a new type of proton pump inhibitor, which can inhibit the activity of H+ / K+-ATPase, and is mainly used clinically to treat gastric ulcer caused by excessive gastric acid secretion. Duodenal ulcer and reflux esophagitis and other digestive system diseases. [0003] The preparation method of the esomeprazole magnesium intermediate esomeprazole potassium published by the patent US6369085B1 (the same family patent WO9854171A) is as ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘朝霞刘敏钊彭志红郑云丽徐艳梅朱晓娟王进陈良强
Owner 上海华源医药科技发展有限公司
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