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Synthesis and refining method of chlorpheniramine maleate intermediate

A kind of technology of chlorpheniramine acid intermediate and refining method is applied in the field of synthesis and purification of the production of chlorpheniramine maleate intermediate, which can solve the problem of low yield, dark color of chlorpheniramine maleate and impurity High content and other problems, to achieve high yield, mild reaction conditions, simple post-treatment effect

Inactive Publication Date: 2021-09-14
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But because in the common route, the intermediate 2-(4-chlorophenyl)-2-(pyridin-2-yl) acetonitrile is directly used in the next step of production after being processed, resulting in dark color of the chlorpheniramine maleate obtained , high impurity content, low yield

Method used

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  • Synthesis and refining method of chlorpheniramine maleate intermediate
  • Synthesis and refining method of chlorpheniramine maleate intermediate
  • Synthesis and refining method of chlorpheniramine maleate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Put 60% NaH (7.2g, 0.18mol) into THF (100ml), lower the temperature to 2°C, and add p-chlorophenylacetonitrile (22.7g, 0.15mol) in THF (20ml) dropwise under temperature control, During the dropwise addition, the temperature was raised slowly. After the dropwise addition, stir at room temperature for 1 hour. After the timing, the temperature was raised to 40°C. The heating was removed, and 2-bromopyridine (15.8g, 0.1mol) was slowly added dropwise. The temperature rose violently during the dropwise addition. After the dropwise addition, the temperature dropped to At about 40°C, start heating to reflux, time the reaction for about 10 hours (TLC detects that the raw material disappears), cool down to room temperature, quench the reaction with water, extract with toluene, and concentrate the organic phase under reduced pressure until no liquid drops out to obtain the crude product. After the temperature is below 30°C, add 126.4g of n-hexane / ethyl acetate (7:1) mixed solvent ...

Embodiment 2

[0025] Put 95% CaH (8.84g, 0.2mol) into THF (100ml), lower the temperature to 2°C, and add p-chlorophenylacetonitrile (22.7g, 0.15mol) in THF (20ml) dropwise, During the dropwise addition, the temperature was raised slowly. After the dropwise addition, stir at room temperature for 1 hour. After the timing, the temperature was raised to 40°C. The heating was removed, and 2-bromopyridine (15.8g, 0.1mol) was slowly added dropwise. The temperature rose violently during the dropwise addition. After the dropwise addition, the temperature dropped to At about 40°C, start heating to reflux, time the reaction for about 10 hours (TLC detects that the raw material disappears), cool down to room temperature, quench the reaction with water, extract with toluene, and concentrate the organic phase under reduced pressure until no liquid drops out to obtain the crude product. After the temperature is below 30°C, add 126.4g of n-hexane / ethyl acetate (7:1) mixed solvent to the crude product for s...

Embodiment 3

[0027] Put 60% NaH (7.2g, 0.18mol) into THF (100ml), lower the temperature to 2°C, and add p-chlorophenylacetonitrile (22.7g, 0.15mol) in THF (20ml) dropwise under temperature control, During the dropwise addition, the temperature was raised slowly. After the dropwise addition, stir at room temperature for 1 hour. After the timing, the temperature was raised to 40°C. The heating was removed, and 2-bromopyridine (15.8g, 0.1mol) was slowly added dropwise. The temperature rose violently during the dropwise addition. After the dropwise addition, the temperature dropped to At about 40°C, start heating to reflux, time the reaction for about 10 hours (TLC detects that the raw material disappears), cool down to room temperature, quench the reaction with water, extract with toluene, and concentrate the organic phase under reduced pressure until no liquid drops out to obtain the crude product. After the temperature is below 30°C, add 126.4g of petroleum ether / ethyl acetate (7:1) mixed s...

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Abstract

The invention discloses a synthesis and refining method of a chlorpheniramine maleate intermediate. The method comprises the steps: in tetrahydrofuran, carrying out a reaction on chlorobenzyl cyanide and 2-bromopyridine by using a strong base to generate a 2-(4-chlorphenyl)-2-(pyridin-2-yl) acetonitrile crude product, stirring and washing with a 2-10 times mixed solvent, and filtering to obtain a 2-(4-chlorphenyl)-2-(pyridin-2-yl) acetonitrile refined product. The synthesis method is low in raw material cost, simple and easy to operate and high in yield, the product purity can be greatly improved through simple refining of the product, steps are simplified for obtaining high-purity chlorpheniramine, the yield is improved, and powerful support is provided for large-scale industrial production of chlorpheniramine maleate.

Description

technical field [0001] The invention relates to the technical field of organic synthesis of medicines, in particular to a synthesis and purification method for producing an intermediate of chlorpheniramine maleate. Background technique [0002] The chemical name of chlorpheniramine maleate (CPM) is N, N-dimethyl-γ-(4-chlorophenyl)-2-pyridine propylamine maleate, which is the first generation of propylamine H 1 receptor antagonists, mainly used for the treatment of asthma and other respiratory allergies and other diseases, chlorpheniramine maleate is also a common component of compound preparations for the treatment of cough and cold symptoms, and its unilateral preparations mainly include chloropheniramine maleate Namin Tablets and Chlorpheniramine Maleate Injection are mainly used for the treatment of allergic rhinitis, skin and mucous membrane allergy, urticaria, vasodilation rhinitis, hay fever, contact dermatitis, and allergic diseases caused by drugs and food . The ne...

Claims

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Application Information

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IPC IPC(8): C07D213/57
CPCC07D213/57
Inventor 张杰霍志甲姜根华石亮亮姚媛璐张瑜
Owner TIANJIN LISHENG PHARM CO LTD
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