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A kind of preparation method of EGFR molecular targeted anti-tumor drug

A cyano- and ethoxy-based technology, which is applied in antineoplastic drugs, drug combinations, organic chemistry, etc., can solve the problems of high impurity content, difficult quality control, and low conversion rate of Compound IV, and achieve easy-to-obtain raw materials and reduce The content of impurities and the effect of low production cost

Active Publication Date: 2022-06-21
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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  • A kind of preparation method of EGFR molecular targeted anti-tumor drug
  • A kind of preparation method of EGFR molecular targeted anti-tumor drug
  • A kind of preparation method of EGFR molecular targeted anti-tumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

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

[0066] In the 50L reaction kettle, add 1.155kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 18.48kg n-propanol, stir evenly; add 0.52kg m-aminophenylacetylene (molar ratio of compound III and compound II is: 1.1:1); be warmed up to 90 ℃~95 ℃, react 3 hours to reach the end point, cool down to 0 ℃~5 ℃, centrifuge, the solid is washed with n-propanol, and dried 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] Example 1-2: Preparation of Compound IV

[0068] In the 50L reaction kettle, add 1.500kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 18.00kg of n-propanol, stir evenly; add 0.789kg m-aminophenylacetylene (The molar ratio of compound III to compound II is 1.3:1); the temperature is raised to 85°C to 90°C, the reaction reaches the end point in 3 hours, the temperature is lowered to 10°C to 15°C, centrifuged, and the solid is washed with n-propanol and dried to obtain the product 2.015kg, the content is 99.46%, and the yield is 96%.

Embodiment 1-3

[0069] Preparation of Example 1-3 Compound IV:

[0070] In the 50L reaction kettle, add 1.00kg N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide, 15.00kg n-propanol, stir evenly; add 0.325kg m-aminophenylacetylene (molar ratio of compound III and compound II is: 0.8:1); be warmed up to boiling reflux, reacted to reach the end point in 2.7 hours, cooled to 0 ℃~10 ℃, centrifuged, and the solid was 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 molecule-targeted antitumor drug, and the EGFR molecule-targeted antitumor drug is (E)-N-[4-(3-ethynylphenyl)amino-3- Cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenamide. The preparation method of the EGFR molecular targeting antineoplastic drug comprises the following steps: N-(4-chloro-3-cyano-7-ethoxyquinoline-6-yl) acetamide and m-aminophenylacetylene Under the condition of n-propanol as reaction solvent, heating substitution reaction was carried out. The method has the advantages of easy-to-obtain raw materials, simple process, short reaction time, low impurity content, high yield, and suitability for industrialized production.

Description

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

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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