Acotiamide hydrochloride intermediate, and synthesis technique and application thereof

A technology of acotiamide hydrochloride and synthesis process, applied in the direction of organic chemistry and the like, can solve the problems of complicated post-processing, unsuitable for industrial scale-up production, long reaction time, etc., and achieves the advantages of short reaction time and reduction of rearrangement to generate by-products. The effect of less chance and side effects

Active Publication Date: 2017-06-06
SUZHOU SIXTH PHARMA PLANT OF JIANGSU WUZHONG PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the defects of long reaction time and complicated post-treatment in the existing synthesis process of acotiamide hydrochloride intermediate, which are not suitable for in

Method used

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  • Acotiamide hydrochloride intermediate, and synthesis technique and application thereof
  • Acotiamide hydrochloride intermediate, and synthesis technique and application thereof
  • Acotiamide hydrochloride intermediate, and synthesis technique and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation method of the acotiamide hydrochloride intermediate 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-ethoxycarbonyl-1,3-thiazole provided in this example includes the following steps step:

[0032]

[0033] 25.5g (0.12mol) 2,4,5-trimethoxybenzoic acid, 22.7g (0.132mol) ethyl 2-aminothiazole-4-carboxylate, 17.8g (0.132mol) 1-hydroxybenzotriazole , 20mL of triethylamine and 500mL of dichloromethane were put into a 1L reaction flask, cooled to 5°C, and 30mL of dichloromethane solution dissolved with 18.0g (0.143mol) of diisopropylcarbodiimide was added dropwise under stirring, and the dropwise , heated to 30°C for 4 hours, filtered, washed the filter cake with dichloromethane, and dried in vacuo to obtain 27.5g of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-ethane Oxycarbonyl-1,3-thiazole, the yield is 62.5%, and the purity of the product measured by HPLC normalization method is 98.8%.

Embodiment 2

[0035] The preparation method of the acotiamide hydrochloride intermediate 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-ethoxycarbonyl-1,3-thiazole provided in this example includes the following steps step:

[0036]

[0037] 51g (0.24mol) 2,4,5-trimethoxybenzoic acid, 44.7g (0.26mol) ethyl 2-aminothiazole-4-carboxylate, 35.6g (HOBt, 0.26mol) 1-hydroxybenzotriazepam Put oxazole, 50mL N,N-diisopropylethylamine and 600mL 1,2-dichloroethane into a 1L reaction flask, cool to 10°C, add dropwise 40.0g (0.32mol) diisopropyl 50 mL of carbodiimide in 1,2-dichloroethane solution was added, and the temperature was raised to 50° C. to react for 3 hours. Filtration, the filter cake was soaked with 1,2-dichloroethane, and vacuum-dried to obtain 58g 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-ethoxycarbonyl-1, 3-thiazole, the yield is 65.9%, and the purity of the product measured by HPLC normalization method is 97.6%.

Embodiment 3

[0039] The preparation method of the acotiamide hydrochloride intermediate 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-ethoxycarbonyl-1,3-thiazole provided in this example includes the following steps step:

[0040]

[0041]25.5g (0.12mol) 2,4,5-trimethoxybenzoic acid, 20.9g (0.1212mol) ethyl 2-aminothiazole-4-carboxylate, 24.27g (0.18mol) 1-hydroxybenzotriazole , 17.5mL of triethylamine and 500mL of dichloromethane were put into a 1L reaction flask, cooled to 0°C, and 50mL of dichloromethane solution in which 45.3g (0.35mol) of diisopropylcarbodiimide was dissolved was added dropwise under stirring. After completion, the temperature was raised to 35°C for 2.5 hours, filtered, the filter cake was soaked with dichloromethane, and vacuum-dried to obtain 29.9 g of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4 -Ethoxycarbonyl-1,3-thiazole, the yield is 68%, and the purity of the product measured by HPLC normalization method is 98.8%.

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Abstract

The invention provides an acotiamide hydrochloride intermediate, and a synthesis technique and application thereof, belonging to the technical field of drug synthesis. The synthesis technique comprises the following steps: (1) mixing 2,4,5-trimethoxy benzoic acid, ethyl 2-aminothiazolyl-4-formate, 1-hydroxybenzotriazole, an acid binder and an organic solvent; (2) adding diisopropyl carbodiimide into the mixture in the step (1); and (3) after the step (2) finishes, carrying out reaction while controlling the temperature of 25-50 DEG C, thereby obtaining the acotiamide hydrochloride intermediate. The synthesis technique avoids using sulfoxide chloride, improves the operating environment, has the advantages of short reaction time, fewer side reactions, simple purification treatment, high yield (the optimal yield can reach 68%) and high purity (98.8%), and is suitable for industrialized scale-up production.

Description

technical field [0001] The invention relates to an acotiamide hydrochloride intermediate and its synthesis process and application, belonging to the technical field of drug synthesis. [0002] technical background [0003] The chemical name of acotiamide hydrochloride is N-2-[(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4 -Formamide hydrochloride trihydrate, which is an antagonist of muscarinic M1, M2 receptors and adenosine A1 receptors, has the effects of promoting gastric motility, anti-acetylcholinesterase activity and improving digestive tract motility, acoral hydrochloride Thiamine was approved for marketing in Japan in 2013. It is the first drug for the treatment of functional dyspepsia. It is used to treat functional dyspepsia symptoms such as postprandial fullness, epigastric flatulence and premature satiety caused by functional dyspepsia. Its structural formula as follows: [0004] [0005] The synthetic route of traditional acotia...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 武卫邓银来陈言德臧建英袁卫东
Owner SUZHOU SIXTH PHARMA PLANT OF JIANGSU WUZHONG PHARMA GROUP
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