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Method for preparing acotiamide hydrochloride

The technology of a compound and an organic base is applied in the field of preparing the gastric motility drug acotiamide hydrochloride, which can solve the problems of high price, troublesome operation, unfavorable industrial production and the like, and achieve the effects of simple operation and low cost.

Active Publication Date: 2013-11-13
CHANGZHOU NO 4 PHARMA FACTORY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is cumbersome to operate, and triphenyl borate needs to be added as a reaction aid, which is expensive and unfavorable for industrial production

Method used

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  • Method for preparing acotiamide hydrochloride
  • Method for preparing acotiamide hydrochloride
  • Method for preparing acotiamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester

[0030] Dissolve 19.0 g of triphosgene in 90 ml of CH 2 Cl 2 Placed in a four-necked bottle, N 2 Under air flow, 2-hydroxy-4,5-dimethoxybenzoic acid (22.2 g) was dissolved in 150 ml CH 2 Cl 2 and 45ml of pyridine, drop it into a four-neck flask under an ice-salt bath and control the temperature at 0-5°C. The dropwise addition was completed within 45 minutes, and kept stirring at low temperature for 10 minutes. Then rise to room temperature (20°C) and stir for 50 minutes to stop the reaction. Suction filtration under normal pressure, and the filtrate was rotary evaporated at room temperature to constant weight, 35g of methyl 2-aminothiazole-4-carboxylate and 240ml of 1,2-dichloroethane were added, heated to reflux, and reacted for 6h. After stopping, cool down and filter with suction. The resulting solid was washed with 40 ml of methanol under reflux, and filtered wh...

Embodiment 2

[0032] Synthesis of 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester

[0033] Dissolve 3.0 g of triphosgene in 15 ml of CH 2 Cl 2 Placed in a four-necked bottle, N 2 Under air flow, 2-hydroxy-4,5-dimethoxybenzoic acid (3.0 g) was dissolved in 30 ml CH 2 Cl 2 and 6ml of pyridine, drop it into a four-neck flask under an ice-salt bath and control the temperature at 0-5°C. After 20 minutes of dropwise addition, keep stirring at low temperature for 1 hour. Then it was raised to room temperature (20°C) and stirred overnight, and the reaction was stopped after 24 hours. Rotary steam at room temperature to constant weight, add 3.5g methyl 2-aminothiazole-4-carboxylate and 30ml 1,2-dichloroethane, heat to reflux, react for 6h. After stopping, evaporate the solvent to dryness, add 30ml of methanol to reflux and filter to obtain 4.1g of white solid, evaporate the mother liquor to dryness, add 20ml of methanol to wash and filter to obtain 0.85g o...

Embodiment 3

[0035] Synthesis of 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester

[0036] Dissolve 3.0 g of diphosgene in 15 ml of CH 2 Cl 2 Placed in a four-necked bottle, N 2 Under air flow, 2-hydroxy-4,5-dimethoxybenzoic acid (3.0 g) was dissolved in 30 ml CH 2 Cl 2 and 6ml of pyridine, drop it into a four-neck flask under an ice-salt bath and control the temperature at 0-5°C. After 20 minutes of dropwise addition, keep stirring at low temperature for 1 hour. Then it was raised to room temperature (20°C) and stirred overnight, and the reaction was stopped after 24 hours. Rotary steam at room temperature to constant weight, add 3.5g methyl 2-aminothiazole-4-carboxylate and 30ml 1,2-dichloroethane, heat to reflux, react for 6h. After stopping, the solvent was evaporated to dryness, 30ml of methanol was added to reflux and suction filtered to obtain 4.57g of white solid, with a yield of 89.6%.

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Abstract

The invention discloses a method for preparing a compound of formula (5). The method comprises the following steps: 1, reacting a compound of formula (2) with triphosgene, diphosgene or phosgene in a non-polar solvent in the presence of an organic alkali to obtain a product, reacting the obtained product with a compound of formula (3) to obtain a compound of formula (1); and 2, reacting the compound of formula (1) with a compound of formula (6) in 1,4-dioxane to obtain a substance, reacting the substance with HCl to form a salt which is the compound of formula (5), wherein R in the compound of formula (3) and the compound of formula (5) is a methyl group or an ethyl group.

Description

technical field [0001] The invention relates to a new method for preparing gastric motility drug acotiamide hydrochloride (Acotiamide hydrochloride, Z-338). Background technique [0002] Acotiamide hydrochloride (Z-338) is a new type of M1 and M2 receptor antagonist originally developed by Zeria Company in Japan, which is clinically used to treat functional dyspepsia. [0003] Chinese patent application CN200580028537 describes the preparation method of acotiamide hydrochloride (Z-338), and the reaction process is as follows. [0004] [0005] Acotiamide hydrochloride (Z-338) compound patent application (CN96194002.6) chose to use 2,4,5-trimethoxybenzoic acid as raw material to react with ethyl 2-aminothiazole-4-carboxylate to generate 2-[ (2-Hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester, and then remove the 2-position methyl group of the benzene ring, the yield of this method is low, The demethylation selectivity is not good. Therefore...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 谢智乾王哲烽益兵刘启皓钟静芬时惠麟
Owner CHANGZHOU NO 4 PHARMA FACTORY
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