Preparation, separation and purification method of Decitabine

Abstract

The invention relates to a preparation, separation and purification method of Decitabine, which adopts the following technical scheme: taking 2'-Deoxy-D-ribose and 5-Azacytosine as basic raw materials, and preparing the Decitabine by reactions of methylation, acylation, trimethyl silylation, condensation, deprotection and the like and chiral separation and purification. The method utilizes cheap chemical products as raw materials, has mild reaction conditions, adopts a simple and easy chiral separation method, and obtains a high purity product with the chemical purity of above 99.8% and optical purity of above 99.68%, thus greatly lowering production cost and being suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for chemically synthesizing anticancer drugs, in particular to a method for preparing, separating and purifying decitabine. Background technique [0002] Decitabine (also known as Dezocitadine), chemical name: 4-amino-1-(2-deoxy-β-D-erythrofuranose)-1,3,5-triazine-2(1H)- Ketone, is the analogue of 2'-deoxycytidine, structural formula is (I): [0003] [0004] Decitabine is a new anticancer drug developed by SuperGen Corporation of the United States. It can be converted into an analogue of 5′-monophosphate deoxycytidine in the body, and it can be incorporated into the four bases of DNA under the action of DNA polymerase. Among them, it inhibits DNA synthesis and methylation, leading to cell differentiation or apoptosis, thereby inhibiting the growth of tumor cells, has anti-tumor effects, and is suitable for various solid tumors. [0005] Literature reports some synthetic methods of decitabine. The synthetic route...

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Problems solved by technology

[0006] China Journal of Pharmaceutical Industry, 2007, 38(7): 468-469 provides another synthetic route of decitabine, they use 2-deoxy-D-ribose as raw material, react with acetic anhydride under the action of pyridine to obtain 1, 3,5-tris-D-acetyl-2-deoxy-D-ribose, which was condensed with 5-azacytosine activated with HMDS under the catalysis of trimethylsilyl trifluoromethanesulfonate, and then Ammonia deprotection, methanol recrystallization to obtain decitabine, the process of ammonia deprotection is cumbersome, and the reaction process is not easy to control

These reports do not disclose the final product α, how the two isomers of β are resolved (decitabine is β type), and simultaneously α, the separation of the two isomers of β is relatively difficult, how to obtain high The purity of the isomers is the key to the synthesis of decitabine

[0007] CN200810068816.2 provides a synthesis process of decitabine, its specific technical scheme is: with 2-deoxy-D-ribose, 10% HCl methanol solution, methoxyacetic anhydride, HDMDS, acetic anhydride, trimethylsilane Trifluoromethanesulfonate, ammonium acetate, etc. were used as raw materials, and decitabine was obtained through five reactions of methylation, acylation, trimethylsilylation, ammoniation, and deacylation, with a total yield of 18.4%. The defect of the process is that the obtained product is a racemate of decitabine, and the separation and purification methods of the isomers are not provided, and the decitabine of the β configuration is an active isomer, and the decitabine in the hydroxyl The use of methoxyacetic anhydride in the protection makes it difficult to carry out the deprotection process of the product

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