A kind of method utilizing chiral catalyst to prepare gemcitabine intermediate

Abstract

The invention relates to a method for preparing a Gemcitabine intermediate from a chiral catalyst, and belongs to the technical field of synthesis of medical intermediates. In order to solve the problem that the existing reaction is poor in stereoselectivity, the invention provides the method for preparing the Gemcitabine intermediate from the chiral catalyst; the method comprises the following steps: performing a condensation reaction on R-glyceraldehyde acetonide and difluoro halogenated ethyl acetate in an inert organic solvent under the combined catalytic action of active zinc powder and delta-amino alcohol ligands to obtain a corresponding intermediate; performing deprotection and lactonization treatment on the intermediate and performing a reaction on the intermediate and benzoyl chloride in the presence of an acid-binding agent to obtain the corresponding Gemcitabine intermediate. A product obtained with the method provided by the invention has an ee value being as high as 98% or above, the content of an erythro form product is high, and the obtained product does not need to be refined and can be directly used for next reaction.

Description

technical field [0001] The invention relates to a method for preparing a gemcitabine intermediate by using a chiral catalyst, and belongs to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Gemcitabine is a pyrimidine nucleoside anti-metabolism anti-tumor drug developed by Eli Lilly and Company of the United States. It can interfere with the synthesis of nucleic acids to prevent cancer cells from producing DNA or RNA, and finally stop the growth of cancer cells and cause them to die. Some mouse solid tumors and human tumor xenografts have good inhibitory effect. [0003] 2-Deoxy-2,2-D-erythro-pentofuranose-1-one-3,5-dibenzoate is the key intermediate of gemcitabine. At present, R-glyceraldehyde acetal and difluoro Ethyl bromoacetate was used as raw material, and zinc powder was added to initiate the reaction to obtain 2,2-difluoro-D-threo-3-hydroxyl-(2,2-dimethyl-1,3-dioxolane-4- base) ethyl propionate and 2,2-difluoro-D-eryth...

AI Technical Summary

Problems solved by technology

Although it did not clearly separate threo and erythro through its Rerormatsky reaction, its yield reached about 60%, which also shows that the selectivity to threo and erythro can not be very good when zinc powder is used to activate the reaction. Requirements, resulting in low red content

Therefore, in order to obtain qualified products, solvents must be added to refine again, and the by-product 2-deoxy-2,2-D-threo-pentofuranose-1-one-3,5-diphenyl Formate is removed by refining, which increases the cost of raw and auxiliary materials, and the separated by-products are treated as solid waste, causing pollution to the environment

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