Preparation method of 4-chloro-7-methoxyl quinazoline-6-alchol acetate

Abstract

The invention relates to the field of organic chemistry and medicinal chemistry, in particular to a preparation method of gefitinib intermediate 4-chloro-7-methoxyl quinazoline-6-alchol acetate. The method comprises the steps of adding 3, 4-dihydro-7-methoxyl-4-oxygen generation quinazoline-6-alchol acetate to organic solvents, adding chloro regents and N, N- dimethylformamide, reacting 5h in a backflow mode, adding solid carbonate or solid bicarbonate under room temperature, adjusting potential of hydrogen (PH) which is equal to 6-8, carrying out suction filtration, and evaporating and drying filtrate to obtain the 4-chloro-7-methoxyl quinazoline-6-alchol acetate. According to the method, the solid carbonate or solid bicarbonate is added, the problem that the chloro regents or acidic materials generated by reaction are remained is solved, generation of following reaction impurities is largely reduced, and meanwhile the defect that products are easy dissolve when meeting water in a post-processing process and the problem that certain alkaline conditions cause degradation of the products and falling-off of acetyl are solved. The preparation method is high in product yield, high in purity, simple in operation and suitable for commercial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of gefitinib intermediate 4-chloro-7-methoxyquinazolin-6-ol acetate. Background technique [0002] 4-Chloro-7-methoxyquinazolin-6-alcohol acetate is a key intermediate for the synthesis of gefitinib, with a structure as shown in formula I: [0003] [0004] The preparation method of gefitinib intermediate in the prior art mainly contains following several kinds: [0005] The patent CN1182421A applied by British Zenica Co., Ltd. discloses the preparation method of gefitinib, as shown in route 1: [0006] [0007] In this route, gefitinib intermediate 4-chloro-7-methoxyquinazolin-6-alcohol acetate adopts 3,4-dihydro-7-methoxyl-4-oxoquinazoline- 6-alcohol acetate is chlorinated with thionyl chloride and N, N-dimethylformamide, obtained by direct distillation of thionyl chloride, 4-chloro-7-methoxyquinazole Lin-6-alcohol acetate ...

AI Technical Summary

Problems solved by technology

[0008] The main problem that this method exists is: thionyl chloride is difficult to reduce steaming, can't evaporate thoroughly, and the acidic substance (hydrogen chloride etc.) that residual chlorinated reagent and its reaction generate can affect the carrying out of next step amination reaction, cause raw material reaction Incomplete and more impurities are generated, resulting in low yield and low product purity, which is not conducive to industrial production

[0010] The main problem that this method exists is: adopt sodium bicarbonate aqueous solution to carry out aftertreatment, the 4-chloro-7-methoxyquinazolin-6-alcohol acetate that obtains is unstable with water, decomposes faster, and regenerates For compound II, with the increase of production scale and the prolongation of operation time, the conversion of the product will be further accelerated, which will affect the yield and purity of the product, which is not conducive to the realization of industrial production

[0013] This method removes the process of reducing and distilling chlorinated reagents, and adopts the method of water treatment of excess chlorinated reagents and the acidic substances generated by the reaction. Because this method uses water, it is unavoidable to decompose the product, which is also unfavorable for realizing industrial production.

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