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Method for utilizing microchannel reactor for synthesizing Nintedanib intermediate

A technology of microchannel reactor and nintedanib, which is applied in chemical instruments and methods, chemical/physical/physical chemical reactors, chemical/physical/physical chemical processes, etc., can solve the problem of low frequency of catalyst recycling and easy occurrence Problems such as violent explosion and long reaction time, etc., to achieve the effect of easy realization of automatic control, economical production guarantee and short reaction time

Inactive Publication Date: 2018-02-09
HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In order to solve the problems of low yield, poor purity, danger of severe explosion, long reaction time at high temperature, low frequency of catalyst recovery and other problems in the traditional synthesis reaction, the technical problem to be solved by the present invention is to provide an intrinsically safe And the catalytic hydrogenation synthesis technology of N-(4-aminophenyl)-N-4-dimethyl-1-piperazineacetamide, which is green and environmentally friendly, especially an innovative microchannel or microreactor technology The catalytic hydrogenation reaction of N-(4-aminophenyl)-N-4-dimethyl-1-piperazine acetamide, the synthesis method has not been reported in the literature so far

Method used

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  • Method for utilizing microchannel reactor for synthesizing Nintedanib intermediate
  • Method for utilizing microchannel reactor for synthesizing Nintedanib intermediate
  • Method for utilizing microchannel reactor for synthesizing Nintedanib intermediate

Examples

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Embodiment 1

[0042] This embodiment provides a method for synthesizing nintedanib intermediate using a microchannel reactor, and the synthesis method is as follows:

[0043] 1) Weigh 150g of N-(4-nitrophenyl)-N,4-dimethyl-1-piperazineacetamide and add 3L of anhydrous methanol, stir evenly, add 5g of 10% Pd / C, stir well Mix to form material I, and transport material I to the preheating module of the microchannel reactor for preheating;

[0044] 2) Hydrogen is directly delivered to the reaction module group of the microchannel reactor, and the reduction hydrogenation reaction is carried out with the preheated material I in the reaction module group, wherein: the flow rate of the slurry pump is adjusted so that the flow rate of the material I is 30.0g / min, adjust H 2 The flow rate of the gas flow meter is 450ml / min, the reduction hydrogenation reaction temperature is 100°C, and the nitro compound of the nintedanib intermediate is mixed with H 2 The molar ratio is 1:3.5, the total residence ...

Embodiment 2

[0046] This embodiment provides a method for synthesizing nintedanib intermediate using a microchannel reactor, and the synthesis method is as follows:

[0047] 1) Weigh 200g of N-(4-nitrophenyl)-N,4-dimethyl-1-piperazineacetamide and add 4L of absolute ethanol, stir evenly, add 6g of 10% Pd / C, stir well Mix to form material I, and transport material I to the preheating module of the microchannel reactor for preheating;

[0048] 2) Hydrogen is directly delivered to the reaction module group of the microchannel reactor, and the reduction hydrogenation reaction is carried out with the preheated material I in the reaction module group, wherein: the flow rate of the slurry pump is adjusted so that the flow rate of the material I is 35.0g / min, adjust H 2 The flow rate of the gas flow meter is 500ml / min, the reduction hydrogenation reaction temperature is 90°C, and the nitro compound of the nintedanib intermediate is mixed with H 2 The molar ratio is 1:3.4, the total residence tim...

Embodiment 3

[0050] This embodiment provides a method for synthesizing nintedanib intermediate using a microchannel reactor, and the synthesis method is as follows:

[0051] 1) Weigh 180g of N-(4-nitrophenyl)-N,4-dimethyl-1-piperazineacetamide and add 3.6L of anhydrous methanol, stir evenly, add 5g of 10% Pd / C, fully Stir and mix to form material I, and transport material I to the preheating module of the microchannel reactor for preheating;

[0052] 2) Hydrogen is directly delivered to the reaction module group of the microchannel reactor, and the reduction hydrogenation reaction is carried out with the preheated material I in the reaction module group, wherein: the flow rate of the slurry pump is adjusted so that the flow rate of the material I is 35.0g / min, adjust H 2 The flow rate of the gas flow meter is 600ml / min, the reduction hydrogenation reaction temperature is 100°C, and the nitro compound of the nintedanib intermediate is mixed with H 2 The molar ratio is 1:3.5, the total res...

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Abstract

The invention discloses a method for synthesizing a nintedanib intermediate by using a microchannel reactor, and belongs to the technical field of synthesis of antitumor drugs. The inventive method is that N-(4-nitrophenyl)-N,4-dimethyl-1-piperazine acetamide is added in an organic solvent, and then the active carbon catalyst of loading 10% Pd is added as material I, and The material I is sent to the preheating module of the microchannel reactor for preheating; the preheated material I is sent to the reaction module group of the microchannel reactor, and the hydrogen is directly sent to the reaction module group of the microchannel reactor , make hydrogen and material I carry out reductive hydrogenation reaction, collect the reaction liquid that flows out from microchannel reactor outlet, aftertreatment obtains N-(4-aminophenyl)-N-4-dimethyl-1-piperazine B amides. The synthesis method of the invention can effectively shorten the reaction time, greatly reduce the potential safety hazard of hydrogen leakage, combustion and explosion, and is suitable for synthesizing the nintedanib intermediate.

Description

technical field [0001] The invention belongs to the field of synthesis of antitumor drugs in organic synthesis, and in particular relates to a method for synthesizing nintedanib intermediates using a microchannel reactor. Background technique [0002] The chemical name of nintedanib is (3Z)-2,3-dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl ]amino]benzylidene]-2-oxo-1H-indole-6-carboxylic acid methyl ester, its chemical structure is as follows: [0003] [0004] Nintedanib is a drug for the treatment of idiopathic pulmonary fibrosis (IPF). It is an orally administered triple tyrosine kinase inhibitor developed by Boehringer Ingelheim, Germany. It is now on the market in the United States and the European Union. For tumor therapy, such as colorectal cancer, ovarian cancer, multiple myeloma, etc. [0005] Wherein the compound N-(4-aminophenyl)-N-4-dimethyl-1-piperazine acetamide is a key intermediate for the synthesis of nintedanib, the structure is ...

Claims

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Application Information

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IPC IPC(8): C07D295/15B01J19/00
CPCC07D295/15B01J19/0093
Inventor 任吉秋杨昆李海涛
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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