High-selectivity synthesis method for gemcitabine intermediate

Abstract

The invention discloses a high-selectivity synthesis method for a gemcitabine intermediate. The high-selectivity synthesis method specifically comprises the following process: Step 1, synthesis of T1;Step2, synthesis of T2, to be specific, 550kg of hydrogen peroxide is dropwise added into the T1, and a reaction is controlled to produce the T2; Step3, synthesis of T3, to be specific, sodium acetate trihydrate or sodium carbonate is added into a reaction kettle, the PH value is adjusted with glacial acetic acid, a 10%-15% sodium hypochlorite aqueous solution is dropwise added, and a reaction iscontrolled to produce the T3; Step 4, synthesis of T4; Step 5, synthesis of T5; Step 6, synthesis of T6; Step 7, synthesis of T7; Step 8, synthesis of T8; and Step9, T8 configuration transformation.The high-selectivity synthetic method for the gemcitabine intermediate can reduce the production cost, and meanwhile, can also increase the yield of the gemcitabine intermediate.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthetic chemistry, in particular to a highly selective synthesis method for gemcitabine intermediates. 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 result, h...

AI Technical Summary

Problems solved by technology

[0006] (1) The synthesis process of T6→T7 needs to be reacted at ultra-low temperature (below -60°C), which requires a lot of energy consumption and additional cryogenic equipment, such as liquid nitrogen refrigeration devices

[0007] (2) The reducing agent used in the synthesis process of T6→T7 is unstable lithium tri-tert-butylaluminum hydride, which needs to be prepared by yourself. Lithium aluminum hydride and tert-butanol are reacted in ether solvent. Lithium aluminum hydride is very easy to meet with water Combustion, ether is also easy to catch fire, there is a big safety risk in production

[0008] (3), T7→T8 synthesis process, the required isomer a content of product T8 is low, needs crystallization to obtain high-content isomer a use, contains about 20% product in the crystallization mother liquor and can't utilize, and as by-product The product is discarded, which not only leads to low yield, high cost but also great environmental pollution, which increases the treatment cost of the three wastes

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