Method for preparing gemcitabine hydrochloride

Abstract

The invention relates to a compound in a formula (I), and discloses a method for preparing gemcitabine hydrochloride. The method includes preparing an intermediate type (III) compound by means of realizing Reformatsky reaction, removing a protecting group and realizing lactonization and double benzoylation; obtaining a compound in a formula (VI) via reduction, methyl sulfonylation and condensation; and finally removing a protecting group, saltifying and realizing crystallization to obtain a final product. The method is simple in process, high in yield and quite suitable for industrial production, the purity of the product is fine, and harsh reaction conditions are omitted.

Description

technical field [0001] The invention relates to the preparation of an antitumor active compound, in particular to a preparation method of gemcitabine hydrochloride. Background technique [0002] Gemcitabine hydrochloride is a cell cycle-specific anti-metabolite drug. It is used as an anti-tumor compound. In 1996, the US FDA approved gemcitabine hydrochloride produced by Eli Lilly and Company as a first-line drug for the treatment of pancreatic cancer. In 1998, it was approved as a drug for the treatment of non-small cell lung cancer. . [0003] Gemcitabine hydrochloride mainly acts on tumor cells in the DNA synthesis phase, that is, cells in the S phase. Under certain conditions, it can prevent the progression from the G1 phase to the S phase; it has obvious cytotoxic activity on various cultured human and mouse tumors. At non-lethal doses, it has good anticancer activity against various tumors in mice. [0004] Most of the synthesis of gemcitabine hydrochloride reported i...

AI Technical Summary

Problems solved by technology

This reaction utilizes the asymmetric Reformatsky reaction controlled by the substrate, but the selectivity is not high, and further processing with column chromatography is required to obtain chiral pure reaction products, which is not suitable for large-scale industrial production

[0005] People such as T.S.Chou have improved above-mentioned route (Synthesis, 1992,565), the mixture of the cis-trans products of asymmetric Reformatsky reaction is directly used in reaction, finally handles product with crystallization method, although this method has avoided using column chromatography, But the synthetic route is longer, and the total yield of product is not high, only 25%, making production cost improve

[0006] Osamu Kitagawa tried to use iododifluoroacetate as a raw material, and added trialkylchlorosilane in the reaction to improve the selectivity of cis-trans products, (Tetrahdron Lett., 1988, 29, 1803), Yasushi Matsumra, etc. People take (R)-2,3-O-cyclohexanone-glyceraldehyde as raw material, add Titanocene catalyst in reaction system, and then improve the selectivity of cis-trans product (J.Flurine chem., 1992,57,203 ), but these methods have used more expensive reagents, and the reaction conditions are harsh, and are still not suitable for industrial production

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