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Method for preparing pinaverium bromide and application thereof

A kind of pinaverium bromide, reaction technology, applied in the field of preparation technology of pinaverium bromide, can solve the problem of low content of pinaverium bromide cis isomer etc.

Active Publication Date: 2009-09-16
SHANGHAI CHENPON PHARM TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But the cis-isomer content of the obtained intermediate is 95%, and the trans-isomer content is 5%, the cis-isomer content of the pinaverium bromide (formula I) synthesized by this intermediate is not high, and exists above defects

Method used

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  • Method for preparing pinaverium bromide and application thereof
  • Method for preparing pinaverium bromide and application thereof
  • Method for preparing pinaverium bromide and application thereof

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preparation example Construction

[0056] The preparation method of the intermediate compound shown in formula II provided by the present invention includes the steps:

[0057] (a) Mixing reaction of nopol with a chemical structure of formula IV, palladium on carbon and methanol to obtain a compound of chemical structure with formula V;

[0058]

[0059] (b) Mixing the compound of formula V obtained in step (a), toluene and sodium hydroxide, and heating to react;

[0060] (c) Add a mixture of a compound with a chemical structure of formula VI and toluene, reflux, and cool to room temperature;

[0061] (d) Extract with water, take the organic layer, and distill under reduced pressure to obtain the compound intermediate of formula II.

[0062] A preferred solution is:

[0063] (a) Mixing nopol with a chemical structure of formula IV, palladium carbon and methanol to react for 2-8 hours, filtering, and removing methanol to obtain a compound with a chemical structure of formula V;

[0064] (b) Mixing the compound of fo...

Embodiment 1

[0098] Preparation of 2-[2-(2-morpholinyl-2-ethoxy-ethyl)]-6,6-dimethylnorphan (Formula II)

[0099] 1. At room temperature, put 600L of methanol, 100Kg of nopol (Formula IV), 10Kg of palladium on carbon in the autoclave, react for 4-6 hours under 6-7 kg of hydrogen pressure, filter the catalyst, wash with methanol, and evaporate under reduced pressure Methanol to obtain 90Kg of the compound of formula V with a yield of 88.7%;

[0100] 2. Then add 300L of toluene, 50Kg of compound of formula V into a 1000L reaction kettle, add 13kg of sodium hydroxide at room temperature, heat to reflux, and react for 2 hours;

[0101] 3. Then add 45kg of 2-chloroethylmorpholine (formula VI) and 100L of toluene mixture, reflux for 1 hour after addition, cool, add 300L of water for extraction, and separate the organic layer;

[0102] 4. The water layer was extracted twice with toluene, 200L each time, the organic layers were combined, washed with 200L water, and the toluene was evaporated under red...

Embodiment 2

[0106] Preparation of 2-[2-(2-morpholinyl-2-ethoxy-ethyl)]-6,6-dimethylnorphan (Formula II)

[0107] 1. At room temperature, put 600L of methanol, 100Kg of nopol (Formula IV), 10Kg of palladium on carbon in the autoclave, react for 2 hours under 9-10 kg of hydrogen pressure, filter the catalyst, wash with methanol, and evaporate the methanol under reduced pressure. 91.3Kg of compound of formula V was obtained, with a yield of 90.4%;

[0108] 2. Then add 300L of toluene, 50Kg of compound of formula V into a 1000L reaction kettle, add 13kg of sodium hydroxide at room temperature, heat to reflux, and react for 2 hours;

[0109] 3. Then add 45kg of 2-chloroethylmorpholine (formula VI) and 100L of toluene mixture, reflux for 1 hour after addition, cool, add 300L of water for extraction, and separate the organic layer;

[0110] 4. The water layer was extracted twice with toluene, 200L each time, the organic layers were combined, washed with 200L water, and the toluene was evaporated und...

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Abstract

The invention provides a method for preparing pinaverium bromide and an intermediate thereof, which relate to the pharmaceutical process. The cis isomer content of the intermediate 2-[2-(2-morpholino-2-ethoxy-ethyl)]-6, 6-dimethyl nopyl alkyl is high and the cis-isomer content of the obtained pinaverium bromide is more than or equal to 99 percent. The intermediate 2-[2-(2-morpholino-2-ethoxy-ethyl)]-6, 6-dimethyl nopyl alkyl is prepared by collecting cut fraction of 133-134 DEG C under 270 Pa.

Description

Technical field [0001] The invention relates to a pharmaceutical process, in particular to a preparation process of pinaverium bromide. Background technique [0002] Pinaverium bromide is a calcium antagonist that is clinically used to treat pain related to intestinal dysfunction, abnormal bowel movements and gastrointestinal discomfort, and pain related to biliary dysfunction. The synthetic route reported abroad is 2-[2-(2-morpholinyl-2-ethoxy-ethyl)]-6,6-dimethylnorphan (formula II) and 2-bromo-4, 5-Dimethoxybenzyl bromide (formula III) is reacted to obtain pinaverium bromide (formula I). [0003] [0004] Pinaverium bromide is optically active, and it is its cis isomer that has clinical therapeutic effects. In the pinaverium bromide obtained in the prior art, it is often required that the content of its trans isomer does not exceed 9%, and it is difficult to achieve even lower levels. As a result, the content of the cis-isomer of pinaverium bromide with a therapeutic effect ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/088C07D295/096A61K31/5375A61P1/06A61P1/16
Inventor 杜狄峥吴瑜亮胡克斌吴波峰卢鑫
Owner SHANGHAI CHENPON PHARM TECH CO LTD
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