A kind of preparation method of gemcitabine hydrochloride

Abstract

The present invention relates to a preparation method of gemcitabine hydrochloride. The present invention uses cytidine as raw material, firstly prepares 3', 5' and N-protected cytidine, and obtains 2'-ketocytidine intermediate after oxidation. Deoxyfluorinating reagent, a new process for preparing gemcitabine through catalytic deoxygenating difluoro. Compared with the currently widely used method of preparing gemcitabine by coupling fluorodeoxyribose and cytosine bases, this method completely eliminates the possibility of generating α isomers. Because it does not involve the reaction of cytosine base configuration, the possibility of generating α-isomer is eliminated, the product is easy to purify, the purification process is greatly reduced, and an efficient and practical new process method is provided for the preparation of gemcitabine. It has high industrial application value.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of gemcitabine hydrochloride, an antitumor active compound. Background technique [0002] Gemcitabine hydrochloride, as an antitumor compound, is widely used clinically in the treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer and other solid tumors. Gemcitabine hydrochloride was first developed by Eli Lilly Company of the United States. It was first listed in Australia, Finland and other countries in 1995. In 1996, it was approved by the US FDA as a drug for the treatment of pancreatic cancer. In 1998, it was approved by the US FDA for the treatment of non-small cell Lung cancer. Since then, gemcitabine has been clinically used in the treatment of bladder cancer, breast cancer, etc. Due to the excellent properties of gemcitabine in interfering with DNA replication and inhibiting ribonucleotide reductase, its ...

AI Technical Summary

Problems solved by technology

This method lays the foundation for the preparation of gemcitabine by the indirect introduction method, but the main disadvantage is that the separation of the β and α isomers produced when the sugar ring is coupled with the base is difficult, the yield is low, and it is not suitable for large-scale industrial production

In 1992, based on the work of L.W.Hertel and others, T.S.Chou et al. improved the reaction conditions and purification methods for the synthesis of 2-deoxy-D-erythro-2,2-difluoro-1-carbonyl ribose intermediates (Synthesis, 1992, 565-570), it can be produced on a large scale, but it does not solve the problem of β and α isomers produced when the sugar ring is coupled with the base, and the ratio of β and α isomers is almost 1:1 , When crystallization is used for separation, the product loss is large, the yield is reduced, and the cost is increased

In 2008, based on the work of T.S.Chou et al., Jingshan Shen et al. selected different protecting groups and optimized reaction and purification conditions, and improved the process for preparing gemcitabine (Organic Process Research & Development, 2008, 12, 888-891), and the yield increased , the total yield is about 10%, but it still does not improve and solve the problem of α and β isomers produced when the sugar ring is coupled with the base

In 2012, Hong Chengjie and others further improved the process of preparing gemcitabine (Chinese patent CN102617678), but still did not solve the problem of the α and β isomers produced when the sugar ring and the base are coupled, and the α and β isomers The ratio is 1.13:1

Even if separated, because the two isomers cross each other, the loss is large and the yield is low

Among the existing methods for preparing gemcitabine (Qilu Pharmacy, 2012, 31, 608-611), there is an improved method for preparing the intermediate 2-deoxy-2,2-difluoro-1-carbonyl ribose intermediate, and there is a method for changing the protecting group , in order to increase the yield, and also optimize the coupling reaction, these improvements cannot fundamentally solve the problem of α isomer formation

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