Method for synthesizing osimertinib intermediate through micro-channel reactor

A micro-channel reactor and intermediate technology, applied in the direction of organic chemistry, etc., can solve the problems of low catalyst recovery times, long reaction time, violent explosion, etc., and achieve stable online production and post-processing, yield and purity improvement, Production cost reduction effect

Inactive Publication Date: 2018-09-04
HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In order to solve the problems of low yield, poor purity, risk of violent explosion, degradation caused by long reaction time at high temperature, and low number of times of catalyst recovery and mechanical application in the traditional high-pressure catalytic hydrogenation reactor synthesis process, the present invention provides a micro The method for synthesizing the Osimertinib intermediate in a channel reactor, the chemical reaction formula is as follows:

Method used

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  • Method for synthesizing osimertinib intermediate through micro-channel reactor
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  • Method for synthesizing osimertinib intermediate through micro-channel reactor

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Embodiment 1

[0038] Embodiment 1. The method for synthesizing the intermediate of Osimertinib in a microchannel reactor.

[0039] 1) Weigh 200 g of the raw material hydrogenation precursor nitro, and then add it to a mixture of 4 L of methanol and 100 g of concentrated hydrochloric acid, stir and dissolve, add 10 g of Pd / C catalyst with a mass content of 5% Pd, and fully stir and mix to form Material I, transport the material I to the preheating module 1 of the microchannel reactor for preheating, and then enter the reaction module group of the microchannel reactor after preheating.

[0040] 2) Hydrogen is delivered to the reaction module group of the microchannel reactor and step 1) reacts with the preheated material I in the reaction module group, wherein: adjust the flow rate of the slurry pump so that the flow rate of the material I is 40.0g / min , adjust H 2 The flow rate of the gas flowmeter is 500ml / min, the molar ratio of raw material hydrogenation precursor nitro and hydrogen is 1...

Embodiment 2

[0041] Embodiment 2. The method for synthesizing Osimertinib intermediates in a microchannel reactor.

[0042] 1) Weigh 200 g of the raw material hydrogenation precursor nitro, and then add it into a mixture of 4 L of ethanol and 100 g of concentrated hydrochloric acid, stir and dissolve, add 7 g of Pd / C catalyst with a Pd mass content of 8%, and fully stir and mix to form a material I, the material I is transported to the preheating module 1 of the microchannel reactor for preheating, and then enters the reaction module group of the microchannel reactor after preheating.

[0043] 2) Hydrogen is delivered to the reaction module group of the microchannel reactor and step 1) the material I after preheating is reacted in the reaction module group, wherein: adjust the flow rate of the slurry pump so that the flow rate of the material I is 35.0g / min , adjust H 2 The flow rate of the gas flowmeter is 400ml / min, the molar ratio of raw material hydrogenation precursor nitro and hydro...

Embodiment 3

[0044] Embodiment 3. The method for synthesizing Osimertinib intermediate in microchannel reactor.

[0045] 1) Weigh 300g of the raw material hydrogenation precursor nitro, and then add it to a mixed solution of 5L of ethanol and 150g of concentrated hydrochloric acid, stir and dissolve, add 10g of Pt / C catalyst with a mass content of 10% of Pt, fully stir and mix to form a material I, the material I is transported to the preheating module 1 of the microchannel reactor for preheating, and then enters the reaction module group of the microchannel reactor after preheating.

[0046] 2) Hydrogen is delivered to the reaction module group of the microchannel reactor and step 1) the material I after preheating is reacted in the reaction module group, wherein: adjust the flow rate of the slurry pump so that the flow rate of the material I is 25.0g / min , adjust H 2 The flow rate of the gas flowmeter is 300ml / min, the molar ratio of raw material hydrogenation precursor nitro and hydrog...

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Abstract

The invention discloses a method for synthesizing an osimertinib intermediate through a micro-channel reactor and belongs to the technical field of anticancer drug synthesis in organic synthesis. Aiming at the problems in the traditional high-pressure catalytic hydrogenation reactor synthesis process that the yield is low, the purity is low, violent explosion easily occurs to cause danger, and thecatalyst recycling and reusing frequency is low, the method for synthesizing the osimertinib intermediate through the micro-channel reactor is provided. The osimertinib intermediate is N-1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indole-3-yl)-2-pyrimidyl]-1,2,4-triaminobenzene. The method comprises the following synthesis steps: adding N-(2-(dimethylamino-ethyl)-2-methoxy-N-(4-(1-methyl-1-indole-3-yl)-pyrimidyl-2-yl)-5-nitro-phenyl-1,4-diamine into a mixture of an organic solvent and concentrated hydrochloric acid in a microchannel reactor, adding an activated carbon supported noble metal catalyst, and preheating to form a material I; performing reaction on hydrogen and the preheated material I, thereby obtaining the osimertinib intermediate. The method is applicable to synthesis of anticancer drugs.

Description

technical field [0001] The invention relates to a method for synthesizing an osimertinib intermediate in a microchannel reactor, and belongs to the technical field of anticancer drug synthesis in organic synthesis. Background technique [0002] The chemical name of osimertinib is N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(l-methyl-lH -Indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide, its monomethanesulfonate is the third generation oral epidermal growth factor receptor inhibitor developed by AstraZeneca, It can effectively overcome the drug resistance mutation caused by 60% of Asian patients receiving the previous two generations of drug treatment, and at the same time reduce the risk of hyperglycemia, gastrointestinal and skin adverse reactions. In 2015, the FDA accelerated the approval of osimertinib mesylate for the treatment of metastatic small cell lung cancer. It is the third targeted therapy drug. The trade name is Tagrisso, and its chemical s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 任吉秋杨昆李海涛
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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