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Method for preparing Nintedanib ethylsulfonate

A technology of nintedanib ethanesulfonate and acetyl group, which is applied in the field of preparation of nintedanib ethanesulfonate, can solve problems such as shortage, and achieve the effects of low impurity level, simple preparation process and high purity

Active Publication Date: 2019-07-09
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Therefore, prior art lacks a kind of preparation method of nintedanib ethanesulfonate which is easy to operate, high in product yield, good in purity, impurity especially genotoxic impurity few, suitable for industrialized production

Method used

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  • Method for preparing Nintedanib ethylsulfonate
  • Method for preparing Nintedanib ethylsulfonate
  • Method for preparing Nintedanib ethylsulfonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add 900ml methanol, 90.0g 1-acetyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-formic acid methyl ester (compound A) and 2L glass reaction flask 80.6g compound N-(4-aminophenyl)-N,4-dimethyl-1-piperazineacetamide (compound B), heated to 45-50°C, reacted for 2h, then added 18.2g pyrrolidine, Stir the reaction at 45-50°C for 1h, cool down to 25-30°C, stir and crystallize for 3h, filter, stir wash with a mixed solvent of dichloromethane:methanol with a volume ratio of 10:1, and dry to obtain (3Z)-3-{[ (4-{Methyl-[(4-methylpiperazin-1-yl)acetyl]amino}phenyl}amino}-(phenyl)methylene}-2-oxo-2,3-di Methyl indoline-6-carboxylate (compound C) 126.3 g, yield 91.37%, purity 99.89%.

[0051] Add 1.2L of anhydrous methanol to a 2L glass bottle, add 100.0g of (3Z)-3-{[(4-{methyl-[(4-methylpiperazin-1-yl)acetyl] prepared in Example 1 Amino}phenyl}amino}-(phenyl)methylene}-2-oxo-2,3-dihydroindoline-6-carboxylic acid methyl ester (compound C), warming up to 50-55°C, drop 70% ethanes...

Embodiment 2

[0054] Using 900mL N,N-dimethylformamide instead of methanol as the reaction solvent in step 1, the other operations were the same as in Example 1, step 1 obtained compound C124.3g, yield 89.92%, purity 99.85%, step 2 obtained compound D finished product 107.3g, yield 89.11%, purity 99.93%. The total yield of the two-step reaction was 80.1%.

Embodiment 3

[0056] The cooling and crystallization temperature in Step 2 was controlled at 30-35°C, and other operations were the same as in Example 1. In Step 2, 106.2 g of the finished compound D was obtained, with a yield of 88.20% and a purity of 99.95%. The total yield of the two-step reaction was 80.6%.

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Abstract

The invention relates to a method for preparing Nintedanib ethylsulfonate. The method comprises the following steps: (1) adding 1-acetyl-3-[methoxy(phenyl)methylene]-2-oxo-indolinyl-6-methyl formate (compound A) into a reaction solvent to react with N-(4-amino phenyl)-N,4-dimethyl-1-piperazinyl acetamide (compound B), adding pyrrolidine for continuous reaction after the reaction ends up, carryingout crystallization, carrying out stirring washing with a mixed solvent, and carrying out drying, so as to produce (3Z)-3-{[(4-{methyl-[(4-methyl piperazin-1-yl)acetyl]amino}phenyl)amino]-(phenyl)methylene} -2-oxo-2,3-indolinyl-6-methyl formate (compound C); and (2) subjecting the compound C to a reaction with ethyl sulfonic acid, carrying out crystallization, carrying out filtering, and carryingout drying, thereby producing the Nintedanib ethylsulfonate. According to the method, the Nintedanib ethylsulfonate with high purity, good yield and low impurity level is obtained through reactions oftwo steps.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a preparation method of nintedanib ethanesulfonate. Background technique [0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease with lesions confined to the lungs, mostly in middle-aged and elderly people, whose lung histology and / or chest high-resolution CT (HRCT) is characterized by usual interstitial pneumonia (UIP) of unknown etiology. [0003] There is no large-scale epidemiological study on the incidence and prevalence of IPF. However, the overall incidence of IPF showed a significant increase trend. A study from the United Kingdom reported that the total incidence of IPF was only 4.6 / 100,000, but the incidence of IPF was estimated to have increased by 11% per year from 1991 to 2003. This increase does not seem to be related to the aging of the population or the increase in the diagnosis r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34C07C303/32C07C303/44C07C309/04
CPCC07C303/32C07C303/44C07D209/34C07C309/04
Inventor 吴立红梁敏钟文辉张素娟李冬梅王悦孙文涛池晓雷
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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