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Preparation method of acotiamide hydrochloride

A technology of acotiamide hydrochloride and alkyl formate, which is applied in the field of preparing acotiamide hydrochloride, and can solve the problems of non-utilization of industrialized production, danger, high toxicity and the like

Inactive Publication Date: 2015-12-30
山东富创医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The phosgene and diphosgene used in step 1 of the method are highly toxic, and have greater danger in industrial use, and the low temperature control is stricter during the reaction, so it does not utilize industrial production

Method used

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  • Preparation method of acotiamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0021] Synthesis of 2-hydroxy-4,5-dimethoxybenzoyl chloride (compound of formula I)

[0022] Take 19.8g (0.1mol) of 2-hydroxy-4,5-dimethoxybenzoic acid in a three-necked flask (with thermometer, drying tube and tail gas absorption device), then add 50ml of thionyl chloride to it, and heat to reflux After 3 hours, TLC tracking showed that the reaction was complete, and the excess thionyl chloride was distilled off. After post-treatment, 18.8 g of the product 2-hydroxy-4,5-dimethoxybenzoyl chloride was obtained, and the yield was about 86.8%.

Embodiment 1b

[0024] Synthesis of 2-hydroxy-4,5-dimethoxybenzoyl chloride (compound of formula I)

[0025] Take 19.8g (about 0.1mol) of 2-hydroxy-4,5-dimethoxybenzoic acid in a three-necked flask (with thermometer, drying tube and tail gas absorption device), and then add 50ml of thionyl chloride and tetrahydrofuran to it (THF) 1ml, DMF0.05ml was added dropwise and heated to reflux for 2.5h, followed by TLC, the reaction was complete, the excess thionyl chloride was distilled off, and the product 2-hydroxy-4,5-dimethoxybenzoyl chloride was obtained after post-treatment. 20.1 g, about 92.8% yield.

Embodiment 2a

[0027] Synthesis of ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylate

[0028] Take 21.7g (about 0.1mol) of 2-hydroxy-4,5-dimethoxybenzoyl chloride prepared according to the method of Example 1a in a three-necked flask, add 17.2g (about 0.1mol) of 2-aminothiazole-4 -Ethyl formate and 100ml of dichloromethane, heated to reflux, reacted for 4h. After the reaction, the solvent was evaporated to dryness, and 70ml of methanol was added to reflux and suction filtered to obtain about 32.6g of solid, with a yield of 92.6%.

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Abstract

The invention discloses a preparation method of acotiamide hydrochloride. The preparation method is characterized by comprising the following steps: 1, making 2-hydroxy-4, 5-dimethoxybenzoic acid react with SOCl<2>, and obtaining a midbody, namely 2-hydroxy-4, 5-dimethoxy benzoyl chloride; 2, making the product obtained in step 1 react with 2-aminothiazole-4-formic acid alkyl ester, and obtaining 2-[(2-hydroxy-4,5-dimethoxy benzoyl chloride) amidogen]-1,3-thiazole-4-formic acid alkyl ester; 3, making the product obtained in step 2 react with N, N-diisopropyl ethanediamine, and obtaining acotiamide; 4, introducing hydrogen chloride directly for reaction without conducting separation, and obtaining the acotiamide hydrochloride after post-treatment is conducted on the product. The preparation method has the advantages of being high in purity and yield, low in cost, simple to operate and the like.

Description

technical field [0001] The invention relates to a new method for preparing Acotiamide hydrochloride. Background technique [0002] Acotiamide hydrochloride (Z-338) is a new type of M1 and M2 receptor antagonist originally developed by Zeria New Drug Co., Ltd. in Japan. It was approved in Japan in February 2013 for the treatment of functional dyspepsia (FD), mainly used to improve gastric motility disorder and delayed gastric emptying, thereby improving FD symptoms, including postprandial fullness, upper abdominal distension, early satiety, etc. [0003] The structure of acotiamide hydrochloride is as follows: [0004] [0005] In the prior art, there are few studies on the preparation method of the drug, and the main methods include: [0006] In the preparation method of the patent application (CN96194002.6), 2,4,5-trimethoxybenzoic acid is used as raw material to react with ethyl 2-aminothiazole-4-carboxylate to generate 2-[(2-hydroxy-4,5 -dimethoxybenzoyl)amino]-1,3-...

Claims

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Application Information

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IPC IPC(8): C07D277/56
Inventor 宫庆创翟兆彬李国丽司志现符义刚李丽娥
Owner 山东富创医药科技有限公司
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