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A kind of preparation method of high-purity nintedanib ethanesulfonate

A high-purity technology for nintedanib ethanesulfonate, which is applied in the field of preparation of high-purity nintedanib ethanesulfonate, can solve problems such as difficult removal, and achieve the effects of improving purity, improving reaction efficiency, and shortening reaction time

Active Publication Date: 2021-09-24
JIANGXI GUOYAO PHARMA LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the salt-forming process experiment, it was found that there was a specific impurity at the position of 0.9 times the retention time of the main peak of nintedanib, which was difficult to remove by crystallization or washing with methyl tert-butyl ether. The ratio of sulfonic acid, temperature, time, and crystallization solvent can reduce a specific impurity before the main peak of nintedanib in the liquid phase spectrum: the N on the piperazine ring is methylated (chemical name: 1H-indole-6 -Carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-dimethyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene ]-2-oxo-, methyl ester; IMP01), but the impurity obtained by the existing method is above 0.1%

Method used

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  • A kind of preparation method of high-purity nintedanib ethanesulfonate
  • A kind of preparation method of high-purity nintedanib ethanesulfonate
  • A kind of preparation method of high-purity nintedanib ethanesulfonate

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Effect test

Embodiment 1

[0058] A preparation method for high-purity nintedanib ethanesulfonate, comprising the following steps:

[0059] S1: Preparation of intermediate INT02:

[0060] Add 1730g of toluene, 200g of SM01, 1170g of triethyl orthobenzoate, 1070g of acetic anhydride, 4g of DMAP into the reactor at room temperature, mechanically stir, heat up, and reflux reaction. During the reaction, part of the solvent is evaporated, the temperature is lowered, and the crystal is grown with heat preservation and stirring. Filter, wash the filter cake with toluene, pulverize the wet product, and dry in vacuum to obtain the earthy gray solid product INT02;

[0061] In described step S1, the mass ratio of SM01, triethyl orthobenzoate, acetic anhydride, toluene, DMAP is 1: 5.8: 5.4: 8.7: 0.02, the reflux temperature of reaction is 104-110 ℃, the stirring of reaction Time 7h.

[0062] In step S1, the volume of the distilled solvent is twice the weight of the starting material SM01;

[0063] In step S1, th...

Embodiment 2

[0076] A preparation method for high-purity nintedanib ethanesulfonate, comprising the following steps:

[0077] S1: Preparation of intermediate INT02:

[0078] Add 1000g of toluene, 100g of SM01, 620g of triethyl orthobenzoate, 610g of acetic anhydride, 3g of DMAP into the reactor at room temperature, mechanically stir, heat up, and reflux reaction. During the reaction, part of the solvent is evaporated, the temperature is lowered, and the crystal is grown with heat preservation and stirring. Filter, wash the filter cake with toluene, pulverize the wet product, and dry in vacuum to obtain the earthy gray solid product INT02;

[0079] In described step S1, the mass ratio of SM01, triethyl orthobenzoate, acetic anhydride, toluene, DMAP is 1: 6.2: 6.1: 10: 0.03, the reflux temperature of reaction is 106-114 ℃, the stirring of reaction Time 6h.

[0080] In step S1, the volume of the distilled solvent is 3 times the weight of the starting material SM01;

[0081] In step S1, the...

Embodiment 3

[0094] A preparation method for high-purity nintedanib ethanesulfonate, comprising the following steps:

[0095] S1: Preparation of intermediate INT02:

[0096] Add 1200g of toluene, 100g of SM01, 520g of triethyl orthobenzoate, 720g of acetic anhydride, 4g of DMAP into the reactor at room temperature, mechanically stir, heat up, and reflux reaction. During the reaction, part of the solvent is evaporated, the temperature is lowered, and the crystal is grown with heat preservation and stirring. Filter, wash the filter cake with toluene, pulverize the wet product, and dry in vacuum to obtain the earthy gray solid product INT02;

[0097] In described step S1, the mass ratio of SM01, triethyl orthobenzoate, acetic anhydride, toluene, DMAP is 1: 5.2: 7.2: 12: 0.04, the reflux temperature of reaction is 104-114 ℃, the stirring of reaction Time 8h.

[0098] In step S1, the volume of the distilled solvent is 4 times the weight of the starting material SM01;

[0099] In step S1, the...

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Abstract

The invention discloses a method for preparing high-purity nintedanib ethanesulfonate. The steps of the method are as follows: step 1, toluene, SM01, triethyl orthobenzoate, acetic anhydride, and DMAP "one-pot" reaction , the high-purity intermediate INT02 can be obtained by suction filtration; step 2, INT02, SM02 are reacted in a specific solvent system and separated to obtain the intermediate INT03; step 3, INT03, methanol, KOH are reacted to obtain INT04; step 4, INT04, methanol , Ethylsulfonic acid reaction, adding methyl tert-butyl ether, isopropyl ether, in nintedanib ethylsulfonate.

Description

technical field [0001] The invention relates to a preparation method of high-purity nintedanib ethanesulfonate, which belongs to the field of drug synthesis. Background technique [0002] Nintedanib ethanesulfonate (Nintedanib) is an oral small molecule kinase inhibitor developed by Boehringer Ingelheim, Germany, which can simultaneously block vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) And the signaling pathway of fibroblast growth factor receptor (FGFR). The US FDA and the EU EMA approved nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, and the EU EMA approved nintedanib combined with docetaxel after first-line chemotherapy in 2014 Adult patients with locally advanced or metastatic or locally recurrent NSCLC with a histological diagnosis of adenocarcinoma. In 2016, the European Commission (EC) and the U.S. Food and Drug Administration (FDA) granted nintedanib orphan drug designation f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34C07C309/04C07C303/32C07C303/44
CPCC07C303/32C07C303/44C07C309/04C07D209/34
Inventor 杨建国蔡南平郭海兵赵鹏王宝珠庄泽阳万义斌葛友群左飞鸿杨明孟周钧
Owner JIANGXI GUOYAO PHARMA LLC
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