Preparation method of EGFR molecular targeting antitumor drug

A cyano and ethoxy technology, applied in antitumor drugs, drug combinations, organic chemistry, etc., can solve the problems of low conversion rate, difficult quality control, and high impurity content of compound IV

Active Publication Date: 2020-11-03
JIANGSU SUZHONG PHARM GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN105175331A reports a preparation method of compound (I): methanesulfonic acid is used as a catalyst in the reaction process, the conversion rate of the reaction process is low, and the obtained compound IV has a high impurity content, which is difficult to carry out quality control

Method used

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  • Preparation method of EGFR molecular targeting antitumor drug
  • Preparation method of EGFR molecular targeting antitumor drug
  • Preparation method of EGFR molecular targeting antitumor drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0065] Embodiment 1-1: Preparation of Compound IV

[0066] In a 50L reactor, add 1.155kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 18.48kg n-propanol, stir well; add 0.52kg m-aminophenylacetylene (the molar ratio of compound III to compound II is: 1.1:1); heat up to 90°C-95°C, react for 3 hours to reach the end, cool down to 0°C-5°C, centrifuge, wash the solid with n-propanol, dry to obtain the product 1.544kg, in the form of hydrochloride, the yield is 96%, and the HPLC test content is 99.58%.

Embodiment 1-2

[0067] Embodiment 1-2: the preparation of compound IV

[0068] In a 50L reactor, add 1.500kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 18.00kg n-propanol, stir well; add 0.789kg m-aminophenylacetylene (the molar ratio of compound III to compound II is 1.3:1); heat up to 85°C to 90°C, react for 3 hours to reach the end, cool to 10°C to 15°C, centrifuge, wash the solid with n-propanol, and dry to obtain the product 2.015kg, the content is 99.46%, and the yield is 96%.

Embodiment 1-3

[0069] The preparation of embodiment 1-3 compound IV:

[0070] In a 50L reactor, add 1.00kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 15.00kg n-propanol, stir well; add 0.325kg m-aminophenylacetylene (the molar ratio of compound III to compound II is: 0.8: 1); the temperature is raised to boiling reflux, and the reaction reaches the end point in 2.7 hours, the temperature is lowered to 0°C to 10°C, centrifuged, the solid is washed with n-propanol, and dried to obtain 1.336kg of product, The yield is 95%, and the content is 99.53%.

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Abstract

The invention discloses a preparation method of an EGFR molecular targeting antitumor drug. The EGFR molecular targeting antitumor drug is (E)-N-[4-(3-acetylenephenyl)-amino-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-buteneamide. The preparation method of the EGFR molecular targeting antitumor drug comprises the following step: carrying out a heating substitution reaction on N-(4-chloro-3-cyano-7-ethoxyquinoline-6-yl)acetamide and m-aminophenylacetylene under the condition that n-propanol is used as a reaction solvent. The method has the advantages of easily available raw materials, simple process, short reaction time, low impurity content, high yield, suitability for industrial production and the like.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxy The preparation method of -6-quinolyl]-4-(dimethylamino)-2-butenamide. Background technique [0002] (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenamide , whose structure is: [0003] [0004] (E)-N-[4-(3-ethynylphenyl)amino-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenamide (I) is a new type of EGFR molecular targeted anti-tumor drug jointly developed by Jiangsu Suzhong Pharmaceutical Group Co., Ltd. and Jiangsu Maidu Drug Research and Development Co., Ltd. It is an irreversible pan-ErbB receptor tyrosine kinase inhibitor , can effectively inhibit the activity of ErbB1 and ErbB2 tyrosine kinases, and is mainly used for the treatment of non-small cell lung cancer (Non Small Cell Lung Cancer, NSCLC). [0...

Claims

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Application Information

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IPC IPC(8): C07D215/54A61P35/00
CPCC07D215/54A61P35/00
Inventor 唐海涛葛海涛刘超刘美香夏崇亮王正俊崔志泽
Owner JIANGSU SUZHONG PHARM GRP CO LTD
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