Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline

Abstract

The invention relates to a preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline, which comprises using 3,4-dimethoxybenzoic acid (II) as raw material, synthesizing 2-amido-4-methoxy-5-hydroxybenzoic acid (V), cyclizing to obtain 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (VI), directly chloridizing to obtain 4-chloro-hydroxy-7-methoxy-quinazoline (VII), reacting directly with 3-chloro-4-fluoroaniline, carrying out amination to obtain 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxy-quinazoline (VIII), finally reacting with morpholinyl chloropropane to obtain Geftinat (I).

Description

technical field [0001] The present invention relates to the preparation method of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline (gefitinib, I) . Background technique [0002] 4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline (gefitinib) (structural formula I, trade name: Yi Ressa, Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, and is currently clinically used for the treatment of non-small cell lung cancer. [0003] [0004] The synthetic route (WO9633980, CN96193526) reported by K H Gibson of Zenica Co., Ltd. is as follows: [0005] [0006] This route uses 6,7-dimethoxy-3,4-dihydroquinazolin-4-one as raw material, and selectively demethylates with methanesulfonic acid and L-methionine to obtain 6-hydroxy-7-methionine Oxy-3,4-dihydroquinazolin-4-one, followed by acetylation to protect the 6-hydroxyl group, chlorination, amination of 3-chloro-4-fluoroaniline, ...

AI Technical Summary

Problems solved by technology

Although this method overcomes the shortcomings of using a large amount of methanesulfonic acid and L-methionine demethylation in the original route, the price of the starting material 3-hydroxyl-4-methoxybenzaldehyde is expensive, which is the 3,4 used in the original route. - More than 20 times that of dimethoxybenzaldehyde

[0011] (Chinese Journal of Medicinal Chemistry, 2005, 15 (1): 39-41) although the method reported by Yuan Li of Shenyang Pharmaceutical University is slightly different from that of J.P. Gildai et al., the starting material used is 3-Hydroxy-4-methoxybenzoic acid methyl ester, its deficiency is similar to the method of J.P. Gilday et al.

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