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Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof

A technology of hydroxyethyl and pyrrolidine, applied in the field of drug synthesis, can solve problems affecting the optical purity of the final product, racemization of raw materials, and easy racemization, etc., to improve the optical purity of the product, not easy to racemize, Ease of industrialization

Active Publication Date: 2014-09-10
山东川成医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, this is likely to cause racemization of the raw material in the subsequent reaction steps. In the process from compound 1 to compound 2, the raw material compound 1 is refluxed in the presence of acid and water, and racemization easily occurs.
Thereby affecting the optical purity of the final product, reducing the drug efficacy, in order to improve the product quality, it needs to be refined several times in the end

Method used

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  • Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof
  • Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof
  • Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Put 37.6 grams of L-(-)-dibenzoyl tartaric acid monohydrate into 14.84 grams of ethanol, heat to dissolve, and obtain solution Ⅰ

[0048] (2) Put 12.9 grams of N-methyl-2-(2-hydroxyethyl)pyrrolidine racemate into 90.3 grams of ether, stir and mix evenly to obtain solution II

[0049] (3) Slowly pour solution II into slowly stirred solution I to obtain cloudy solution III.

[0050] (4) Place the cloudy solution III at room temperature for crystallization for 1 hour; then put the cloudy solution in an ice-water bath at 0~-5°C and let it stand for crystallization for 4 hours.

[0051] (5) Filter, wash the filter cake with a mixture of ethanol and ether, and drain.

[0052] (6) Put the filter cake into 200ml of water, cool down in an ice bath, adjust the pH value to 13 with sodium hydroxide at 0~5°C, extract with chloroform three times, each time with 80ml of chloroform.

[0053] (7) The chloroform layers were combined and dried by adding 50 g of anhydrous sodium sulf...

Embodiment 2

[0061] (1) Put 45.2 grams of L-(-)-dibenzoyl tartaric acid monohydrate into 15.82 grams of methanol, heat and dissolve to obtain solution Ⅰ

[0062] (2) Put 12.9 grams of N-methyl-2-(2-hydroxyethyl)pyrrolidine racemate into 90.3 grams of ether, stir and mix evenly to obtain solution II

[0063] (3) Slowly pour solution II into slowly stirred solution I to obtain a cloudy solution.

[0064] (4) The turbid solution was crystallized at room temperature for 3 hours. Then put the turbid solution into an ice-water bath at 0~-5°C, and let it crystallize for 8 hours.

[0065] (5) Filter, wash the filter cake with a mixture of methanol and ether, and drain.

[0066] (6) Put the filter cake into 200ml of water, cool down in an ice bath, adjust the pH value to 13 with potassium hydroxide solution at 0~5°C, and extract with dichloromethane 3 times, each time with 80ml of dichloromethane.

[0067] (7) The dichloromethane layers were combined and dried by adding 50 g of anhydrous magnesi...

Embodiment 3

[0071] (1) Put 41.4 grams of L-(-)-dibenzoyl tartaric acid monohydrate into 22.8 grams of ethanol, heat and dissolve to obtain solution Ⅰ

[0072] (2) Put 12.9 grams of N-methyl-2-(2-hydroxyethyl)pyrrolidine racemate into 129 grams of methyl tert-butyl ether, stir and mix evenly to obtain solution II

[0073] (3) Slowly pour solution II into slowly stirred solution I to obtain a cloudy solution.

[0074] (4) The turbid solution was crystallized at room temperature for 3 hours. Then put the turbid solution into an ice-water bath at 0~-5°C, and let it crystallize for 8 hours.

[0075] (5) Filter, wash the filter cake with a mixture of ethanol and methyl tert-butyl ether, and drain it.

[0076] (6) Put the filter cake into 200ml of water, cool down in an ice bath, adjust the pH value to greater than 13 with sodium hydroxide solution at 0-5°C, and extract with dichloroethane 3 times, each time with 80ml of dichloroethane.

[0077] (7) The dichloroethane layers were combined and...

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Abstract

The invention provides a resolution method of N-methyl-2-(2-hydroxyethyl)pyrrolidine and its application. N-methyl-2-(2-hydroxyethyl)pyrrolidine is prepared by chiral The resolution reagent is used for resolution to obtain R-(+)-N-methyl-2-(2-hydroxyethyl)pyrrolidine. The yield of R-(+)-N-methyl-2-(2-hydroxyethyl)pyrrolidine obtained by the resolution method of the present invention can reach 40%, the yield is stable, the optical purity is high, the operation is simple and practical Strong, easy to industrial production, split products used in the synthesis of clemastine fumarate, can directly obtain the final desired chiral drug with high optical purity, low production cost, high yield.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a resolution method and application of N-methyl-2-(2-hydroxyethyl)pyrrolidine. Background technique [0002] N-methyl-2-(2-hydroxyethyl)pyrrolidine is an important intermediate in the synthesis of clemastine fumarate. Its structural formula is: . N-methyl-2-(2-hydroxyethyl)pyrrolidine, as an intermediate in the synthesis of clemastine fumarate, usually exists in the form of a racemate. In the prior art, there is no one with high efficiency and low cost , The resolution method of N-methyl-2-(2-hydroxyethyl)pyrrolidine with high optical purity and good stability. [0003] Clemastine Fumarate is a typical and representative second-generation H1 receptor antagonist, which is clinically used to treat various allergic diseases caused by histamine. It has a strong H1 receptor antagonistic effect, can block the combination of histamine and H1 receptors, reduce the permeabilit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/08
Inventor 郭明刘怀振
Owner 山东川成医药有限公司
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