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Industrial production method of acotiamide hydrochloride

The technology of acotiamide hydrochloride and production method, which is applied in the field of medicine and chemical industry, can solve the problems of low purity of acotiamide hydrochloride, unfavorable industrial production and high equipment requirements, and achieves simplified equipment requirements, low production cost and high response. Yield effect

Active Publication Date: 2019-05-21
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The disadvantages of this method include: (1) the ammonolysis reaction not only requires the use of the second-class solvent chloroform with a low limit, but also has a low yield of less than 70%; (2) the salt-forming reaction uses hydrogen chloride gas, which requires more equipment. High, unfavorable for industrialized production, and the salt-forming reaction is carried out in the single solvent isopropanol, test shows, gained acotiamide hydrochloride purity is not high

Method used

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  • Industrial production method of acotiamide hydrochloride
  • Industrial production method of acotiamide hydrochloride
  • Industrial production method of acotiamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0036] This embodiment is the preparation method of intermediate II, specifically as follows:

[0037] Add 100L of dichloromethane into a 300L reaction kettle, add 20.95kg of 2,4,5-trimethoxybenzoic acid under stirring, control the temperature at 20-25°C, add 16.22kg of oxalyl chloride dropwise, about 1.5 drops, The gas generated during the dropping process (mainly hydrogen chloride, carbon dioxide and a small amount of carbon monoxide) is absorbed by the tail gas absorption device, and the reaction solution changes from a white turbid solution to a yellow-green solution. Slowly add 0.85kg of DMF after dropping for about 0.5h. A large amount of gas (mainly hydrogen chloride, carbon dioxide and a small amount of carbon monoxide) generated during the dropping process is absorbed by the tail gas absorption device, and the reaction solution turns into a dark green solution. After dropping, keep it warm at 20-25°C for 1 hour.

[0038] The reaction solution was distilled under redu...

Embodiment 2）

[0042] This embodiment is the preparation method of intermediate III, specifically as follows:

[0043]Add 125L of DMF to a 300L reactor, then add 12.5kg of intermediate II prepared in Example 1, 11.83kg of pyridine hydrochloride and 5.4kg of pyridine under stirring, then heat up to reflux (about 145-150 ℃), insulated and stirred for 9 hours, and the reaction solution was a brown solution. After the reaction is over, stop heating and cool to 20-25°C for about 2 hours.

[0044] Add 210L of water into another 500L reaction kettle, stir and cool down to 0-5°C, then slowly add the above reaction solution into the reaction kettle, stir and crystallize at 15-25°C for 2h, and centrifuge.

[0045] Add 125L of glacial acetic acid and the filter cake obtained after centrifugation to another 300L reactor, stir and heat to reflux (about 115-120°C), dissolve and keep stirring for 2 hours. After the reaction, stop heating, cool to 20-25°C for about 2 hours, stir for another 30 minutes, ce...

Embodiment 3）

[0047] The present embodiment is the preparation method of acotiamide, specifically as follows:

[0048] First, prepare 10wt% sodium carbonate aqueous solution: add 125L of water in a 500L reactor, then add 12.5kg of Na 2 CO 3 Solid, stir to dissolve, store at 15-25°C until use.

[0049] Then, add 100L of toluene into the 300L reaction kettle, add 10.00kg of the intermediate III prepared in Example 2 under stirring, stir and heat to 70-80°C, and then dropwise add 34.98kg of N,N-diisopropylethylene di Amine, after dropping, heat to reflux (about 105-110°C), keep stirring and react for 4h. After the reaction is over, stop heating, cool down naturally to 20-25°C (about 2 hours), then slowly add 50L of glacial acetic acid dropwise, the temperature is controlled at no higher than 30°C, after the drop, the pH is 6.0-6.5, and quickly drops to 20 ~25°C.

[0050] Next, 75 L of water was added to the reactor for extraction and liquid separation. The water layer was transferred to an...

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Abstract

The invention discloses an industrial production method of acotiamide hydrochloride. The industrial production method comprises the following steps that firstly, 2,4,5-trimethoxy benzoic acid serves as an initial raw material, acylating chlorination is carried out to prepare 2,4,5-trimethoxy benzoyl chloride, and then 2,4,5-trimethoxy benzoyl chloride and 2-aminothiazole-4-ethyl formate are subjected to amidation to prepare an intermediate II; secondly, the intermediate II is subjected to selective demethylation and re-crystallized with acetic acid to obtain an intermediate III; thirdly, the intermediate III and N,N-diisopropylamino are subjected to an ammonolysis reaction to prepare acotiamide; fourthly, acotiamide is subjected to salification and refining to prepare acotiamide hydrochloride. The intermediate in each step of the method is high in purity and high in yield, a final product is high in purity and environmentally friendly, the production is low, and the industrial production can be carried out.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to an industrial production method of acotiamide hydrochloride. Background technique [0002] Acotiamide hydrochloride [also known as acotiamide hydrochloride trihydrate] was jointly developed by Japan's Zeli Shinyaku Co., Ltd. and Anstelles Pharmaceutical Co., Ltd., and was first listed in Japan on June 6, 2013. The trade name is for Acofide®. Chemical name: N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-4-thiazolecarboxamide hydrochloride Salt trihydrate, molecular formula: C 21 h 30 N 4 o 5 S·HCl·3H 2 O; molecular weight: 541.06, the structural formula is as follows: [0003] . [0004] Acotiamide hydrochloride is the world's first approved drug for the treatment of functional dyspepsia. Dyspepsia symptoms are prevalent and significantly reduce the quality of life of patients, most of whom have functional dysp...

Claims

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Application Information

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IPC IPC(8): C07D277/56
Inventor 胡国宜胡锦平王仁冬黄健李艳芬
Owner CHANGZHOU SUNLIGHT PHARMA
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