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Method of synthesizing apixaban intermediate by microchannel reactor

A microchannel reactor, apixaban technology, applied in organic chemistry and other directions, 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. The effect of improving and reducing production costs

Inactive Publication Date: 2018-07-27
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

[0004] 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 channel reactor synthesis apixaban intermediate, chemical reaction formula is as follows:

Method used

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  • Method of synthesizing apixaban intermediate by microchannel reactor
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  • Method of synthesizing apixaban intermediate by microchannel reactor

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Embodiment 1

[0041] This embodiment provides a method for synthesizing an intermediate of apixaban in a microchannel reactor, and the specific steps are as follows:

[0042] 1) Weigh the raw material hydrogenation precursor nitro (4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo Substitute-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester) 300g, then join in the anhydrous methanol of 5L, then add the Pd mass content of 10g to be the Pd / C catalyst of 5% , fully stirred and mixed to form the material I, and the material I was transported to the preheating module 1 of the microchannel reactor for preheating, and then entered 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 , ...

Embodiment 2

[0045] This embodiment provides a method for synthesizing an intermediate of apixaban in a microchannel reactor, and the specific steps are as follows:

[0046] 1) Weigh the raw material hydrogenation precursor nitro (4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo Generation-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester) 250g, then join in the absolute ethanol of 4L, then add the Pd mass content of 5g to be the Pd / C catalyst of 10% , fully stirred and mixed to form the material I, and the material I was transported to the preheating module 1 of the microchannel reactor for preheating, and then entered the reaction module group of the microchannel reactor after preheating;

[0047] 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...

Embodiment 3

[0049] This embodiment provides a method for synthesizing an intermediate of apixaban in a microchannel reactor, and the specific steps are as follows:

[0050] 1) Weigh the raw material hydrogenation precursor nitro (4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo Generation-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester) 200g, then join in the isopropanol of 3L, add the Pt mass content of 8g subsequently and be the Pt / C catalyst of 6% , fully stirred and mixed to form the material I, and the material I was transported to the preheating module 1 of the microchannel reactor for preheating, and then entered the reaction module group of the microchannel reactor after preheating;

[0051] 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 ,...

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Abstract

The invention discloses a method of synthesizing apixaban intermediate by a microchannel reactor and belongs to the technical field of synthesis of antithrombotic drugs. The method comprises: adding ethyl 4,5,6,7-tetrahydro-1-(4-benzyloxyphenyl)-6-(4-nitrophenyl)-7-oxo-1-H-pyrazolo[3,4-c]pyridine-3-carboxylate into an organic solvent, adding an activated carbon-loaded noble metal catalyst to obtain a mixture as material I, delivering the material I to a preheating module of the microchannel reactor, preheating, and feeding into a reaction module unit; delivering hydrogen to the reaction moduleunit of the microchannel reactor and the material I to the reaction module unit for the purpose of reaction, collecting reacted liquid from a cooling module, and post-treating to obtain the apixabanintermediate. The method can effectively shorten the reaction time and greatly reduce the safety potential hazard that hydrogen leakage causes combustion and explosion, and is applicable to the synthesis of apixaban intermediates.

Description

technical field [0001] The invention relates to a method for synthesizing an apixaban intermediate in a microchannel reactor, and belongs to the technical field of synthesizing antithrombotic drugs in organic synthesis. Background technique [0002] Apixaban is an anticoagulant jointly developed by Bristol-Myers Squibb and Pfizer, which can directly act on coagulation factors and is used to treat venous thrombosis diseases including deep vein thrombosis and pulmonary thrombosis. A large number of clinical data at this stage show that oral anticoagulant inhibitors will be widely used to replace traditional intravenous anticoagulants. Because apixaban has good drug safety, low possibility of drug interaction and multiple elimination methods in clinical data, it is expected to be used in special groups of patients with liver disease or renal function impairment, so it has great market prospects . [0003] The main synthetic method of apixaban is as image 3 As shown, the inte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 任吉秋杨昆李海涛
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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