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Preparation method of nintedanib key intermediate

A nintedanib and intermediate technology, which is applied in the field of medicinal chemistry, can solve the problems of high death risk, environmental pollution, and hidden safety hazards, and achieves the effects of process safety and environmental protection, simple technical operation, and improved feasibility.

Inactive Publication Date: 2020-10-16
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] To sum up, there are still problems of environmental pollution and high potential safety hazards in the reported routes. In addition, given that there have been few drug options for the treatment of IPF for a long time, patients are facing the threat of rapid disease progression and high risk of death.

Method used

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  • Preparation method of nintedanib key intermediate
  • Preparation method of nintedanib key intermediate
  • Preparation method of nintedanib key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: Preparation of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (compound II)

[0056] 100ml of dichloromethane was added to the reaction flask, and 38.5g (131.7mmol) of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide was added ( Compound IV), 62g trichlorosilane (460mmol) and 90ml triethylamine (647mmol), reacted at room temperature until the reaction was detected by TLC, added 300ml methyl tert-butyl ether to the filtrate, stirred and crystallized, suction filtered, and vacuum-dried at 50°C. 28.4 g of off-white solid was obtained, yield 82.2%, HPLC purity: 99.66%.

Embodiment 2

[0057] Embodiment 2: Preparation of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (compound II)

[0058] 100ml of chloroform was added to the reaction flask, and 38.5g (131.7mmol) of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide was added ( Compound IV), 62g of trichlorosilane (460mmol) and 87ml of N,N-diisopropylethylamine (526.8mmol), reacted at room temperature until the reaction was detected by TLC, added 300ml of n-hexane, stirred and crystallized, suction filtered, 50°C After vacuum drying, 28.1 g of off-white solid was obtained, yield 81.3%, HPLC purity: 99.67%.

Embodiment 3

[0059] Embodiment 3: Preparation of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (compound II)

[0060] 100ml of chloroform was added to the reaction flask, and 38.5g (131.7mmol) of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide was added ( Compound IV), 53.5g trichlorosilane (395.1mmol) and 90ml triethylamine (647mmol), react at room temperature until TLC detects that the reaction is complete, add 300ml cyclohexane, stir and crystallize, filter with suction, and dry under vacuum at 50°C to obtain White solid 28.9g, yield 83.6%, HPLC purity: 99.62%.

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib key intermediate compound II. A compound IV is reduced by adopting a common reaction reagent under the conditions of normal temperature and normal pressure, so that a high-purity compound II can be conveniently obtained. The adopted reaction conditions are mild, high-pressure equipment is avoided, the technical operation is simple, the conditions are mild, the process is safer and more environmentally friendly, and the feasibility of large-scale productionof nintedanib is greatly improved.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to the key intermediate N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1) of the tyrosine kinase inhibitor drug nintedanib -base) the preparation method of acetamide. Background technique [0002] Nintedanib Ethanesulfonate (compound of formula I), English name Nintedanib Ethanesulfonate, chemical name: (3Z)-2,3-dihydro-3-[[[4-[methyl[2-(4-methyl Base-1-piperazinyl)acetyl]amino]phenyl]amino]benzylidene]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate, developed by Boehringer Ingelheim An oral tyrosine kinase inhibitor, approved by the FDA in 2014, under the trade name Launched for the treatment of idiopathic pulmonary fibrosis (IPF), becoming the first tyrosine kinase inhibitor (TKI) approved for the treatment of IPF. Launched in China in 2017, it is currently listed in the United States, the European Union and many other countries around the world. ...

Claims

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Application Information

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IPC IPC(8): C07D295/15
CPCC07D295/15
Inventor 初乐玲仉明张涛赵承彪
Owner QILU PHARMA
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