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Preparation method of acotiamide hydrochloride intermediate

A technology for acotiamide hydrochloride and intermediates, which is applied in the field of preparation of acotiamide hydrochloride intermediates, can solve the problems of low overall yield, cumbersome post-processing, difficult to scale up production and the like, and achieves good yield and high purity , the effect of simple operation

Inactive Publication Date: 2015-05-06
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The thionyl chloride used in this step of condensation reaction is a strong corrosive solvent, which will cause great damage to the equipment, and the post-treatment of this method is cumbersome, it is not easy to scale up production, the overall yield is low, and the cost is high

Method used

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  • Preparation method of acotiamide hydrochloride intermediate
  • Preparation method of acotiamide hydrochloride intermediate
  • Preparation method of acotiamide hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Preparation of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester

[0024] Put 2,4,5-trimethoxybenzoic acid 400g (1.887mol), TBTU664g (2.069mol), DIEA685ml, toluene 4L, 2-aminothiazole-4-ethyl carboxylate 340g (1.977mol) into a 10L reaction flask in sequence , heating and stirring the reaction solution to reflux state. TLC detected that the reaction of the raw materials was basically complete (about 8h), the heating was stopped, the reaction solution was stirred and cooled to room temperature (25°C) naturally. 4L of ethanol was added to the reaction solution, slurried for 2 hours, filtered, and the filter cake was washed with ethanol and dried at 45°C overnight (about 12 hours) to obtain 530 g of an off-white solid with a molar yield of 76%.

[0025] 1 H NMR (400MHz, CDCl 3 ):δ=1.29-1.32(t,J=7.2Hz,3H),3.77(s,3H),3.91(s,3H),4.01(s,3H),4.29(q,J=7.6Hz,2H) ,6.85(s,1H),7.40(s,1H),8.09(s,1H),11.66(s,1H);

[0026] 13 C NMR (100MHz)...

Embodiment 2

[0029] Example 2: Preparation of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester

[0030] 5.3 g (0.025 mol) of 2,4,5-trimethoxybenzoic acid, 5.0 g (0.03 mol) of CDI, 1.9 g of DBU, 53 mL of toluene, and 4.3 g of ethyl 2-aminothiazole-4-carboxylate were put into 250 mL of The reaction flask was stirred at 90°C. TLC detected that the reaction of the raw materials was basically complete (about 8h), the heating was stopped, the reaction solution was stirred and cooled to room temperature (25°C) naturally. 53 mL of ethanol was added to the reaction solution, slurried for 2 hours, filtered, and the filter cake was washed with ethanol, and dried at 45°C overnight (about 12 hours) to obtain an off-white solid with a molar yield of 62%.

[0031] The resulting product was determined to be the same as Example 1 through the analysis of the structure of the spectrum.

Embodiment 3

[0032] Example 3: Preparation of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester

[0033] 5.3 g (0.025 mol) of 2,4,5-trimethoxybenzoic acid, 5.0 g (0.03 mol) of CDI, 1.9 g of DBU, 53 mL of toluene, and 4.3 g of ethyl 2-aminothiazole-4-carboxylate were put into 250 mL of The reaction flask was heated and stirred to reflux. TLC detected that the reaction of the raw materials was basically complete (about 8h), the heating was stopped, the reaction solution was stirred and cooled to room temperature (25°C) naturally. 53 mL of ethanol was added to the reaction solution, slurried for 2 hours, filtered, the filter cake was washed with ethanol, and dried at 45°C overnight (about 12 hours) to obtain an off-white solid with a molar yield of 67%.

[0034] The resulting product was determined to be the same as Example 1 through the analysis of the structure of the spectrum.

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Abstract

The invention relates to a preparation method of an acotiamide hydrochloride intermediate. The preparation method comprises that 2,4,5-trimethoxybenzoic acid and ethyl 2-aminothiazol-4-formate as initial raw materials undergo a condensation reaction under the action of a condensing agent TBTU and an acid binding agent DIEA to produce a desired product. The preparation method is free of a highly corrosive solvent, can be operated simply, is suitable for industrial production and realizes a high yield and good purity.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of acotiamide hydrochloride intermediate. Background technique [0002] Acotiamide hydrochloride, chemical name: N-2-[(bisisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazole-4 - Formamide hydrochloride trihydrate, CAS: 773092-05-0, which has the following structure: [0003] [0004] Acotiamide hydrochloride is an antagonist of muscarinic M1, M2 receptors and adenosine A1 receptors, which has the activity of promoting gastric motility and anti-acetylcholinesterase, and has a good effect on improving digestive tract movement. It is useful for prevention and treatment of discomfort, nausea, vomiting, chest tightness, loss of appetite, abdominal distension, reflux esophagitis, etc. Originally developed by Zeria Pharmaceutical Co Ltd, it is now jointly developed and marketed by Zeria and Astellas. [0005] At present, the preparation me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 于海洲余俊杨宝海
Owner JIANGSU HANSOH PHARMA CO LTD
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