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Nintedanib esilate impurity as well as preparation method and application thereof

A technology of nintedanib ethanesulfonate and ethanesulfonic acid is applied in the field of nintedanib ethanesulfonate impurity and its preparation, and can solve the problem of low yield, difficult purification of nintedanib ethanesulfonate impurity, and difficulty in obtaining Nintedanib ethanesulfonate and other problems, to achieve the effect of high yield, optimized solvent screening and good purity

Inactive Publication Date: 2020-02-07
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent CN105001143A has reported that nintedanib ethanesulfonate impurities are difficult to purify, and the yield after refining is low. nintedanib ethanesulfonate

Method used

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  • Nintedanib esilate impurity as well as preparation method and application thereof
  • Nintedanib esilate impurity as well as preparation method and application thereof
  • Nintedanib esilate impurity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] 1, preparation formula III compound

[0070]

[0071] Add 2-chloro-N-methyl-(4-nitrophenyl)acetamide (30g, 131.6mmol) and methyl tert-butyl ether (450mL) into the reaction flask, stir, add piperazine (5.4g, 62.7mmol) and cesium carbonate (204g, 627mmol), heated to reflux, reacted for 7 hours, cooled, filtered, washed with dichloromethane, concentrated and dried under reduced pressure at 40°C, added 100ml isopropanol for crystallization, filtered, and dried at 40°C After 5 hours, 27.5 g of the compound of formula III was obtained, the molar yield: 92.8% (based on piperazine), HPLC: 99.41%.

[0072] 2. Nintedanib ethanesulfonate impurity shown in the preparation formula II

[0073]

[0074] The compound of formula III (20g, 42.5mmol) was added to 1000mL ethyl formate, ferric chloride hexahydrate (0.9g, 3.4mmol) and activated carbon (1.6g, 127.5mmol) were added successively, heated to 40°C, batchwise Add 85% hydrazine hydrate (11.8 g, 199.8 mmol). After the reacti...

Embodiment 2

[0079] 1, preparation formula III compound

[0080] Add 2-chloro-N-methyl-(4-nitrophenyl)acetamide (28.7g, 125.8mmol) and acetonitrile (620mL) into the reaction flask, stir, add piperazine (5.4g, 62.7mmol) and Triethylamine (87g, 627mmol), heated to reflux, reacted for 6 hours, cooled, filtered, washed with dichloromethane, concentrated and dried under reduced pressure at 40°C, added 100ml of isopropanol for crystallization, and obtained 24.1g of the compound of formula III. Yield: 81.2% (based on piperazine), HPLC: 99.25%.

[0081] 2. Nintedanib ethanesulfonate impurity shown in the preparation formula II

[0082] The compound of formula III (20g, 42.5mmol) was added to 1000mL ethyl acetate, ferric chloride hexahydrate (0.57g, 2.13mmol), activated carbon (2.6g, 212.5mmol) were added successively, heated to 50°C, batchwise Add 85% hydrazine hydrate (12.5 g, 212.5 mmol). After the reaction is complete, filter, wash with dichloromethane-methanol (5:1), concentrate the filtrat...

Embodiment 3

[0087] 1, preparation formula III compound

[0088] Add 2-chloro-N-methyl-(4-nitrophenyl)acetamide (31.5g, 137.9mmol) and tetrahydrofuran (450mL) into the reaction flask, stir, add piperazine (5.4g, 62.7mmol) and Potassium carbonate (60.6g, 438.9mmol), heated to reflux, reacted for 7 hours, cooled, filtered, washed with dichloromethane, concentrated and dried under reduced pressure at 40°C, added 100ml of isopropanol for crystallization, filtered, and dried at 40°C for 5 hours , to obtain 24.5 g of compound of formula III, molar yield: 82.5% (based on piperazine), HPLC: 98.37%.

[0089] 2. Nintedanib ethanesulfonate impurity shown in the preparation formula II

[0090] The compound of formula III (20g, 42.5mmol) was added to 1000mL of isopropyl acetate, ferric chloride hexahydrate (2.3g, 8.5mmol), activated carbon (5.0g, 425mmol) were added successively, heated to 50°C, batchwise Add 85% hydrazine hydrate (25 g, 425 mmol). After the reaction is complete, filter, wash with d...

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PUM

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Abstract

The invention relates to a nintedanib esilate impurity as well as a preparation method and application thereof. By using the nintedanib esilate impurity, an analytic reference can be provided for detecting a nintedanib esilate product, the quality standard of nintedanib esilate can be improved, and the guarantee can be provided for the safe medication of nintedanib esilate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a nintedanib ethanesulfonate impurity and a preparation method and application thereof. Background technique [0002] Nintedanib ethanesulfonate, chemical name: (3Z)-3-{[(4-{N-methyl-2-(4-methylpiperazin-1-yl)acetamido}phenyl)amino] (Phenyl)methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester ethanesulfonate, English name: Nintedanib Ethanesulfonate, manufactured by Boehringer Ingelheim (Boeringer Ingelheim), a multiple tyrosine kinase inhibitor developed to inhibit growth factor receptors associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). On October 15, 2014, nintedanib ethanesulfonate was approved by the US Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary fibrosis (IPF) and non-small cell lung cancer. [0003] The structural formula of nintedanib ethanesulfonate is as follows: [0004] [000...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07D295/13
CPCC07D209/14C07D295/13
Inventor 曹金杨文彬游军辉余俊张小兵
Owner JIANGSU HANSOH PHARMA CO LTD
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