Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine

A compound, methylsulfonyl technology, applied in the field of drug synthesis, can solve the problems of low reaction yield, low selectivity, and low utilization rate of raw materials, and achieve high reaction efficiency, low isomer content, and high purity.

Active Publication Date: 2017-03-08
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route carries out α and β isomer purification after synthesizing gemcitabine, and selectivity is not high, and reaction yield is low, and raw material utilization rate is low, is not suitable for industrial large-scale production

Method used

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  • Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine
  • Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine
  • Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Add 45 mL of ethyl acetate and 15 mL of tetrahydrofuran into the reaction flask, add 10 g of 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-1-one-3,5-dibenzoate, and anhydrous Zinc chloride 1.8, stir to dissolve, add 2 g of tert-butanol, add 0.67 g of sodium borohydride under temperature control below 15°C, and react for 1 to 1.5 hours. After the reaction is complete, add 40 mL of dilute hydrochloric acid, stir for 10 minutes, let stand to separate layers, discard the water layer, and wash the organic layer with 20 mL of saturated brine and 20 mL of saturated aqueous sodium bicarbonate solution, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain 2- Deoxy-2,2-difluoro-D-ribofuranose-3,5-dibenzoate 10g, α / β=3.7, yield 100%.

Embodiment 2

[0035]

[0036] Add 45 mL of ethyl acetate and 15 mL of tetrahydrofuran into the reaction flask, add 10 g of 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-1-one-3,5-diacetate, anhydrous chlorine Zinc chloride 1.8, stir to dissolve, add 2 g of tert-butanol, add 0.67 g of sodium borohydride under temperature control below 15°C, and react for 1 to 1.5 hours. After the reaction is complete, add 40 mL of dilute hydrochloric acid, stir for 10 minutes, let stand to separate layers, discard the water layer, and wash the organic layer with 20 mL of saturated brine and 20 mL of saturated aqueous sodium bicarbonate solution, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain 2- Deoxy-2,2-difluoro-D-ribofuranose-3,5-diacetate 10g, α / β=3.1, yield 100%.

Embodiment 3

[0038]

[0039] Add 60 mL of ethyl acetate to the reaction flask, add 10 g of 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-1-one-3,5-dibenzoate, anhydrous zinc chloride 1.8, stir to dissolve, add 2 g of tert-butanol, add 0.67 g of sodium borohydride under temperature control below 15°C, and react for 1 to 1.5 hours. After the reaction is complete, add 40 mL of dilute hydrochloric acid, stir for 10 minutes, let stand to separate layers, discard the water layer, and wash the organic layer with 20 mL of saturated brine and 20 mL of saturated aqueous sodium bicarbonate solution, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain 2- Deoxy-2,2-difluoro-D-ribofuranose-3,5-dibenzoate 10g, α / β=3.1, yield 100%.

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Abstract

The invention relates to a preparation method for a compound represented by a formula (I) shown in the description, i.e., a key intermediate sulfonated saccharide of Gemcitabine. The final product is prepared through subjecting a compound represented by a formula (II) shown in the description to sodium borohydride reduction, hydroxyl protection and resolution. The method is simple in process, high in yield and high in product purity and has no need of harsh reaction conditions, thereby being very suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an industrial preparation process of sulfonated sugar, a key intermediate of gemcitabine. Background technique [0002] Gemcitabine hydrochloride is a cell cycle-specific anti-metabolite drug. It is used as an anti-tumor compound. In 1996, the US FDA approved gemcitabine hydrochloride produced by Eli Lilly and Company as a first-line drug for the treatment of pancreatic cancer. In 1998, it was approved as a drug for the treatment of non-small cell lung cancer. . [0003] Gemcitabine hydrochloride 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 has obvious cytotoxic activity on various cultured human and mouse tumors. At non-lethal doses, it has good anticancer activity against various tumors in mice. [0004] Most of the synthesis of gemcitabine hydro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H13/06C07H1/00C07H1/06C07H19/06
CPCY02P20/55C07H15/18C07H1/00C07H1/06C07H13/06C07H19/06
Inventor 张庆捷陈之峰
Owner 连云港恒运药业有限公司
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