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Preparation method of beta-configuration gemcitabine hydrochloride intermediate

A technology for gemcitabine hydrochloride and an intermediate, which is applied in the field of pharmaceutical synthesis, can solve the problems affecting the yield and purity of the target product, complicated post-processing steps, and many α-configuration by-products, etc., and achieves simple and simplified operation and post-processing steps. Processing steps, effects of improving yield and purity

Active Publication Date: 2021-03-30
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the prior art, the reaction selectivity of the preparation process of gemcitabine hydrochloride intermediate II is poor, and it is difficult to avoid the production of a large number of by-products in the α configuration, which seriously affects the yield and purity of the target product, and causes the post-processing steps to be more cumbersome
For example, Chinese patent document CN102617678A discloses a preparation method of gemcitabine hydrochloride, which involves the preparation of gemcitabine hydrochloride intermediate II. Dilution, hydrochloric acid treatment, beating, pH adjustment and other steps can obtain the target product. The post-processing steps are relatively cumbersome, and the ratio of α-configuration and β-configuration in the obtained target product is 1.13, and there are many by-products of α-configuration

Method used

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  • Preparation method of beta-configuration gemcitabine hydrochloride intermediate
  • Preparation method of beta-configuration gemcitabine hydrochloride intermediate
  • Preparation method of beta-configuration gemcitabine hydrochloride intermediate

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Experimental program
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Effect test

Embodiment 1

[0037] A preparation method of a beta configuration gemcitabine hydrochloride intermediate, the steps are as follows:

[0038] 3g α configuration content higher gemcitabine hydrochloride intermediate II ', 20g (molar weight 0.044mol) gemcitabine hydrochloride intermediate I, 22.4g (molar weight 0.088mol) silanized cytosine dropped into 170g toluene together, 120 ℃ for 6 hours; after the reaction, slowly add the reaction solution to 160 g of absolute ethanol that has been cooled to 15 ℃, stir and crystallize at 25 ℃ for 0.5 hours, filter; the obtained filter cake is washed with 6 wt% dilute hydrochloric acid, returned to alkali (neutralized by 10% aqueous sodium hydroxide solution), dried to obtain gemcitabine hydrochloride intermediate II in β configuration; the mother liquor obtained by filtration was concentrated until a large amount of solids were precipitated, cooled to 5° C. for crystallization, filtered, and dried to obtain 3.02 g of gemcitabine hydrochloride in α configu...

Embodiment 2

[0041] Put 2.5g of gemcitabine hydrochloride intermediate II' with higher alpha configuration content, 20g (molar weight 0.044mol) gemcitabine hydrochloride intermediate I, 22.4g (molar weight 0.088mol) silanized cytosine into 170g of toluene, React at 120°C for 6h; after the reaction, slowly add the reaction solution to 160g of absolute ethanol that has been cooled to 14°C, stir and crystallize at 26°C for 0.5 hour, filter; the obtained filter cake is washed with 6wt% dilute hydrochloric acid, returned to Alkali (neutralized by 10% aqueous sodium hydroxide solution), dried to obtain gemcitabine hydrochloride intermediate II in β configuration; the mother liquor obtained by filtration was concentrated until a large amount of solids were precipitated, cooled to 6°C for crystallization, filtered, and dried to obtain 2.92 g of hydrochloric acid in α configuration Gemcitabine intermediate II' (purity 95.89wt%), the obtained α-configuration gemcitabine hydrochloride intermediate II'...

Embodiment 3

[0044]Put 2.5g of gemcitabine hydrochloride intermediate II' with higher alpha configuration content, 20g (molar weight 0.044mol) gemcitabine hydrochloride intermediate I, 22.4g (molar weight 0.088mol) silanized cytosine into 170g of toluene, React at 130°C for 6 hours; after the reaction, slowly add the reaction solution to 160g of absolute ethanol that has been cooled to 13°C, stir and crystallize at 28°C for 0.5 hours, and filter; the obtained filter cake is washed with 6wt% dilute hydrochloric acid, returned to Alkali (neutralized by 10% aqueous sodium hydroxide solution), dried to obtain the β-configuration gemcitabine hydrochloride intermediate II; the mother liquor obtained by filtration was concentrated until a large amount of solids were precipitated), cooled to 5°C for crystallization, filtered, and dried to obtain 2.85 g of the α-configuration Gemcitabine hydrochloride intermediate II' (purity 95.5wt%), the obtained α-configuration gemcitabine hydrochloride intermedi...

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Abstract

The invention provides a preparation method of a beta-configuration gemcitabine hydrochloride intermediate, which comprises the following step: in a solvent, in the presence of an alpha-configurationgemcitabine hydrochloride intermediate II', reacting a gemcitabine hydrochloride intermediate I with silanized cytosine to prepare the beta-configuration gemcitabine hydrochloride intermediate II. Thebeta-configuration gemcitabine hydrochloride intermediate II is prepared in the presence of the alpha-configuration gemcitabine hydrochloride intermediate II', and the production of the alpha-configuration gemcitabine hydrochloride intermediate is effectively inhibited, so that the yield and the purity of a target product, namely the beta-configuration gemcitabine hydrochloride intermediate II, are improved, and post-treatment steps are simplified.

Description

technical field [0001] The invention provides a preparation method of a β-configuration gemcitabine hydrochloride intermediate, which belongs to the technical field of drug synthesis. Background technique [0002] Gemcitabine hydrochloride, the molecular formula is C 9 h 11 f 2 N 3 o 4 , the chemical name is 2'-deoxy-2,2-difluorocytidine hydrochloride (β isomer), and the structural formula is as follows. It is a pyrimidine nucleoside analog developed by Eli Lilly and Company of the United States. In 1995, it was released in Australia, Finland, etc. Listed in China, the trade name is Gemzar. Gemcitabine hydrochloride belongs to nucleoside anti-metabolism and anti-tumor drugs, and is suitable for the treatment of middle and advanced non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer, etc. [0003] [0004] β-1-(2'-deoxy-2',2'-difluoro-3',5'-di-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one is the preparation of gemcitabine hydrochloride The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
CPCC07B2200/07C07H1/00C07H19/06
Inventor 徐宝旺赵立凡孔改兰申新德
Owner 山东安弘制药有限公司