Preparation method of antitumor drug gemcitabine hydrochloride

Abstract

The invention discloses a preparation method of an antitumor drug gemcitabine hydrochloride. The preparation method specifically comprises the following processes: (1) preparing an antitumor drug gemcitabine hydrochloride intermediate: Step 1, synthesis of T1; Step2, synthesis of T2; Step3, synthesis of T3; Step4, synthesis of T4; Step5, synthesis of T5; and Step6, synthesis of T6; and (2) preparing gemcitabine hydrochloride from the gemcitabine hydrochloride intermediate: Step7, firstly reducing T6 with lithium tri (tert-butoxy) aluminum hydride, and then acylating with paratoluensulfonyl chloride to prepare T7, wherein T7 is 2-deoxy-2, 2-difluoro-D-ribofuranose-3, 5-dibenzoate; and Step8, reacting T7 with cytosine under the action of a catalyst to generate T8, wherein T8 is 2'-deoxy-2',2'-difluorocytidine-D-ribofuranose-3',5'-dibenzoate. The preparation method of the antitumor drug gemcitabine hydrochloride has the advantages of low production cost, favorability for industrial production and small environmental pollution.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis chemistry, in particular to a preparation method of antineoplastic drug gemcitabine hydrochloride. Background technique [0002] Gemcitabine hydrochloride is a new type of artificially synthesized difluoronucleoside antimetabolite and antitumor drug. This product was first developed by Eli Lilly Company of the United States, and its trade name is "Genza". Gemcitabine hydrochloride can inhibit DNA synthesis; as a prodrug, after gemcitabine hydrochloride is taken up by cells, it is phosphorylated by deoxycytidine kinase to gemcitabine monophosphate, and further converted into the active metabolite gemcitabine diphosphate or triphosphate. Gemcitabine triphosphate competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death, and this inhibitory activity is enhanced by the self-reinforcing properties of gemcitabine diphosphate and gemcitabine triphosphate. As a resul...

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Problems solved by technology

[0006] (1) The starting material D-mannitol is mainly extracted from kelp and seaweed due to the large pollution of chemical synthesis and low yield. Seafood is easily affected by the natural environment, the supply of raw materials cannot be fully guaranteed, and the price fluctuates greatly

[0007] (2), selectivity is very poor in B2 synthetic process, side reaction is many, and purity is not high, and product yield is very low

[0008] (3), B3 ketal glyceraldehyde oxidation synthesis process is very difficult to control, the oxidation reaction process exothermic violent, produce impurities, easy peroxidation, aldehyde content is relatively poor, the by-product sodium iodate produced by the reaction is easy to self-decompose, Iodine vapor is emitted, which poses a major safety hazard. At the same time, iodine is also extracted from seafood. The supply is unstable and the price fluctuates greatly. If it is oxidized with lead acetate, it will cause serious environmental pollution.

[0009] (4) The original patent for deprotection and ring closure of B4 is catalyzed by trifluoroacetic acid, the compound solvent of toluene and acetonitrile removes the isopropylidene protecting group, the ring closure is incomplete, and the distilled mixed solvent cannot be used mechanically, which is not friendly to the environment and the cost of raw materials is high

[0010] (5) After the key intermediate 2-deoxy-2,2-difluoro-D-erythro-1-furanulose-3,5-dibenzoyl ester (T6) was prepared, the Gemcitabine hydrochloride also has the shortcoming that the harvest rate is low

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