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Preparation method of itopride hydrochloride

A technology of itopride hydrochloride and hydrochloride, which is applied in the field of preparation of itopride hydrochloride, can solve the problems of environmental pollution, high price, high cost, etc., and achieve the effect of short and convenient reaction route, low cost and cheap materials

Inactive Publication Date: 2018-10-02
迪嘉药业集团股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses expensive copper trifluoromethanesulfonate, the cost is too high, and copper-containing waste causes environmental pollution

Method used

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  • Preparation method of itopride hydrochloride
  • Preparation method of itopride hydrochloride
  • Preparation method of itopride hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Compound Preparation of:

[0032] Take 18.1 g (0.10 mol) of 3,4-dimethoxybenzamide, 8.1 g (containing 0.10 mol of formaldehyde) in 37% formaldehyde solution, 10.0 g of N,N-dimethylacetamide, and 18.8 g (0.20 mol) of phenol ), added 9.0 g of Hβ zeolite into a 100 mL three-neck flask, raised the temperature to 80 °C, reacted for 12 h, filtered, concentrated the filtrate to dryness, added 100.0 g of water to the obtained solid, beat at 55-65 °C for 2 h, suction filtered, and dried the solid to obtain the compound 23.0 g, yield 88.1%, HPLC purity 97.9%.

Embodiment 2

[0033] Example 2: Compounds Preparation of:

[0034] Take 90.6 g (0.50 mol) of 3,4-dimethoxybenzamide, 60.8 g of 37% formaldehyde solution (containing 0.75 mol of formaldehyde), 94.1 g (1.0 mol) of phenol, 30.0 g of silicon dioxide, and 98% concentrated sulfuric acid 15.0 g, 80.0 g of N,N-dimethylacetamide, heated to 100 °C, reacted for 10 h, filtered, concentrated the filtrate to dryness, added 500.0 g of water to the obtained solid, beat at 55-65 °C for 2 h, suction filtered, and dried the solid to obtain compound 132.2 g, yield 92.8%, HPLC purity 98.3%.

Embodiment 3

[0035] Embodiment 3: the preparation of compound II:

[0036] take compound 80.0 g (0.28 mol), 400 mL of methanol, and 31.4 g (0.56 mol) of potassium hydroxide were added to a 1000 mL three-neck flask, stirred and heated to reflux, and 40.3 g (0.28 mol), dissolved in 80.0 g of water, slowly added to the system, and monitored by thin-layer chromatography (developing agent ratio dichloromethane:methanol=10:1) until the reaction was completed. Concentrate to recover methanol, add 400.0 g of water, stir and crystallize at 10-30 °C for 3 h, filter with suction, and dry the solid to obtain 82.6 g of compound II, with a yield of 90.8% and a purity of 98.9% by HPLC.

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Abstract

The invention relates to a preparation method of itopride hydrochloride and belongs to the technical field of raw material preparation. The technical scheme is as follows: the preparation method of itopride hydrochloride comprises the steps as follows: an intermediate I is prepared from initial materials including 3,4-dimethoxybenzamide, formaldehyde and phenol with a one-pot method; the intermediate I and N,N-dimethyl chloroethane hydrochloride are subjected to a substitution reaction to produce an intermediate II; finally, itopride hydrochloride is prepared through salification. The itopridepreparation process comprises a short and convenient route and is economical and environmentally friendly.

Description

technical field [0001] The invention relates to a preparation method of itopride hydrochloride, which belongs to the technical field of raw material medicine preparation. Background technique [0002] Itopride hydrochloride was developed by Japan Hokuriku Pharmaceutical (acquired by Abbott in 2002, and Abbott was acquired by Mylan in 2014), and it was first launched in Japan in September 1995. It is used to treat various gastrointestinal symptoms of chronic gastritis (abdominal distension, heartburn, nausea and vomiting). [0003] In 1991, Japan's Hokuriku Pharmaceutical disclosed the synthesis method of itopride hydrochloride for the first time. The method uses p-hydroxybenzaldehyde as the starting material, undergoes nucleophilic substitution, condensation into oxime, and hydrogenation reduction to obtain the key intermediate 4-(N ,N-dimethylaminoethoxy)benzylamine; veratraldehyde is oxidized and chlorinated to obtain veratrolyl chloride, and then condensed with 4-(N,N-di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/48
CPCC07C231/08C07C231/12C07C235/48
Inventor 潘昭喜高永臣苗华明霍玉文蔡亚辉
Owner 迪嘉药业集团股份有限公司
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