Preparation methods for acotiamide and hydrochloride thereof

A technology of hydrochloric acid and propylethylenediamine, which is applied in the direction of organic chemistry, can solve the problems of slow reaction and incomplete reaction of toluene, and achieve the effect of complete reaction, reduction of toluene residue and high reaction yield

Inactive Publication Date: 2016-03-30
REGENEX PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] No need to use toluene as a reaction solvent, it is economical and convenient, and the reaction proceeds relatively quickly. 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl The ester [Formula (4)] can also react completely, which overcomes the problem of violent boiling when the temperature is high when using toluene as a solvent, and there are hidden dangers in production safety. Completely remove defects, reduce toluene residues in the final product, and improve product quality

Method used

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  • Preparation methods for acotiamide and hydrochloride thereof
  • Preparation methods for acotiamide and hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of 2-hydroxy-4,5-dimethoxybenzoic acid [Formula (2)] - Reaction Condition 1

[0033] Put 2-iodo-4,5-dimethoxybenzoic acid [Formula (1)] (20.0g), anhydrous copper sulfate (1.0g), 10% sodium hydroxide aqueous solution (300ml), pyridine into a 250ml reaction bottle (4.0ml), under nitrogen protection, stir and heat up to 95-100°C, keep warm for 1.5-2h, take samples for testing, after the reaction is complete (if the reaction is not complete, continue to keep warm for 0.5h), cool down to 20-30°C, filter and collect For the filtrate, add 6N hydrochloric acid (120ml) dropwise to the filtrate under stirring, cool down to 15-25°C, keep warm and stir to crystallize for 0.5-1h, filter, wash the filter cake with 100ml of water, drain it, and dry it with air at 70-80°C 3 After ~4h, the weight was constant, and the material was collected to obtain 12.8g of 2-hydroxy-4,5-dimethoxybenzoic acid.

Embodiment 2

[0035] Preparation of 2-hydroxy-4,5-dimethoxybenzoic acid [Formula (2)] - Reaction Condition 2

[0036] Put 2-iodo-4,5-dimethoxybenzoic acid [Formula (1)] (45.0g), anhydrous copper sulfate (2.3g), 10% sodium hydroxide aqueous solution (675ml), pyridine into a 250ml reaction bottle (10.0ml), under nitrogen protection, stir and heat up to 90°C, keep warm for 2-2.5 hours, take samples for testing, after the reaction is complete (if the reaction is not complete, continue to keep warm for 0.5h), cool down to 20-30°C, filter, and collect the filtrate , add 6N hydrochloric acid (270ml) dropwise to the filtrate under stirring, cool down to 15-25°C, keep stirring and crystallize for 0.5-1h, filter, wash the filter cake with 100ml of water, drain, and dry the material with air at 75-85°C for 2.5~ After 3 hours, the weight was constant, and the material was collected to obtain 27.4 g of 2-hydroxy-4,5-dimethoxybenzoic acid.

Embodiment 3

[0038] Preparation of phenyl 2-hydroxy-4,5-dimethoxybenzoate [Formula (3)]

[0039]Add 2-hydroxy-4,5-dimethoxybenzoic acid [Formula (2)] (11.8g), triphenyl phosphite (20g,), toluene (23ml) into a 250ml reaction bottle, under nitrogen protection, stir Add sulfuric acid (0.6ml), raise the temperature to 110-115°C, keep it warm for 3.5-4.5h, take a sample and check it, after the reaction is complete (if the reaction is not complete, continue to keep warm for 0.5h), cool down to 20-30°C, add methanol (70ml ), continue to cool to 15-25°C, keep warm and crystallize for 0.5-1h, filter, rinse the filter cake with 20ml of methanol, drain it, dry it with air at 40°C to constant weight, and collect the material to obtain 2-hydroxy-4,5 - 11.4 g of phenyl dimethoxybenzoate.

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Abstract

The invention discloses preparation methods for acotiamide and hydrochloride thereof; 2[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester and N,N-diisoprylamino ethylamine are subjected to a reaction in a molten state to obtain N-[2-(diisopropylamino)ethyl]-2-(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide, and hydrochloric acid is dropwise added to N-[2-(diisopropylamino)ethyl]-2-(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide in methanol to prepare acotiamide hydrochloride trihydrate. The preparation methods reduce the use of toluene, and are economical and convenient, complete in reaction, and safe in process; at the same time, toluene residues in the final products and the amount of an impurity 2[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-4-carboxyl-1,3-thiazole are reduced, and the product quality is improved; and the crude products are easy to refine and purify, and the reaction yield is high.

Description

technical field [0001] The invention relates to a method for preparing acotiamide and its hydrochloride. Background technique [0002] Acotiamide, chemical name: N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1, 3-thiazole-4-carboxamide, the structure is as follows: [0003] [0004] Currently on the market is its hydrochloride, which was jointly developed by Zeria Pharmaceutical Company of Japan and Astellas. Acotiamide is an acetylcholinesterase inhibitor-like gastric motility drug, that is, a drug for the treatment of functional dyspepsia (FD), 2013 It was first launched in Japan in June 2010 under the product name Acofide. With the improvement of people's quality of life requirements and awareness of functional dyspepsia, the number of patients with FD is gradually increasing, becoming one of the most common syndromes in gastroenterology. The high prevalence provides a huge market for drugs for the treatment of functional dyspepsia. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 唐翊翔陈与华陈洪光裴大转汤丹袁永玲彭贵子左联卢智俊
Owner REGENEX PHARMA LTD
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