Synthesis process of the industrial production of gemcitabine hydrochloride

A technology of gemcitabine hydrochloride and synthesis process, applied in the field of synthesis technology of known compounds, can solve the problems of easy deprotection, unstable dibenzoyl protection, affecting product quality and yield, etc., and achieves improved stability and product quality. The effect of easy quality assurance

Active Publication Date: 2009-07-29
NENTER & CO
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0004] But in the above-mentioned known technology, because its intermediate bisbenzoyl protection is unstable, it is very easy to deprotect under alkaline conditions, which affects product quality and yield, which is an important defect of the above-mentioned technology.

Method used

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  • Synthesis process of the industrial production of gemcitabine hydrochloride
  • Synthesis process of the industrial production of gemcitabine hydrochloride
  • Synthesis process of the industrial production of gemcitabine hydrochloride

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Embodiment Construction

[0021] The industrial production of gemcitabine hydrochloride synthesis process is to use 2,3-oxo-isopentylidene-D-glyceraldehyde as raw material, through addition, ring opening, ring closure, and then protect the hydroxyl group with TBDPSCl and benzoyl chloride respectively. intermediate. The intermediate is reduced, mesylated, condensed with cytosine and then deprotected to form a salt to obtain gemcitabine hydrochloride.

[0022] The concrete preparation steps of its each step technique are as follows:

[0023] (1) Preparation of 3-(2,2-diethyl-1,3-dioxolyl)-2,2-difluoro-3-hydroxyl-propionic acid ethyl ester (1α / β):

[0024] Under the protection of nitrogen, put activated zinc powder (126g, 1.94mol) into the reaction bottle, THF (220ml) and stir for 10 minutes. 2,3-oxo-isopentylidene-D-glyceraldehyde (180g, 1.13mol), ethyl difluorobromoacetate (300g, 1.48mol) and THF (1000ml) were added dropwise at a temperature of 56-58°C and mixed uniformly Solution, add and keep warm ...

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Abstract

The invention relates to a synthesis process of industrial production of gemcitabine hydrochloride and pertains to the field of chemical product synthesis process. The invention takes 2, 3-oxygen-isopentylidene-D-glyceraldehyde as the raw materials and respectively uses TBDPSCl and benzoyl chloride to protect hydroxyl to produce an intermediate after addition, ring opening and cyclization. The intermediate is condensed with cytosine after reduction and methyl sulfonylation and then acquires gemcitabine hydrochloride after de-protection and salification. The invention has the advantage that TBDPSCl is adopted to protect one of hydroxyls, thus increasing the stability of the intermediate double benzoyl and facilitating the separation and purification of the product. The invention solves the problem in the prior gemcitabine hydrochloride production process that the intermediate double benzoyl protector is unstable and easily de-protected in alkalescence, thus affecting the product quality and yield. The total yield of the synthesis process is 17.9 percent and the purity is above 99.8 percent, thus being particularly applicable to the industrial production of gemcitabine hydrochloride.

Description

Technical field: [0001] The present invention relates to a synthesis process of known compounds, in particular to a synthesis process for industrial production of gemcitabine hydrochloride. Background technique: [0002] Gemcitabine hydrochloride is a known compound. Its chemical name is 2′-deoxy-2′, 2′-difluorocytidine hydrochloride, and its English name is gemcitabine hydrochloride. Gemcitabine hydrochloride is a cell cycle-specific anti-metabolite drug that mainly acts on tumor cells in the DNA synthesis phase, that is, cells in the S phase. Under certain conditions, it can prevent the progression from the G1 phase to the S phase; it can be used alone in clinical applications. It can also be used in combination with other drug treatments. The main process of producing gemcitabine hydrochloride at present is: [0003] [0004] However, in the above-mentioned known process, because the intermediate bisbenzoyl protected compound is unstable, it is very easy to deprotec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
CPCY02P20/55
Inventor 蔡东伟陈玉龙文兆峰
Owner NENTER & CO
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