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A kind of method for preparing gemcitabine hydrochloride

A technology of gemcitabine hydrochloride and its synthesis method, which is applied in the field of drug synthesis, and achieves the effects of high purity, simple and easy post-processing operation, high purity and high yield

Active Publication Date: 2016-08-10
NAT INST OF PHARMA R & D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to address the problems existing in the existing gemcitabine hydrochloride synthesis method, and propose a method for preparing gemcitabine hydrochloride that is simple in reaction steps, easy to purify after treatment, high in purity, and more suitable for industrial production

Method used

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  • A kind of method for preparing gemcitabine hydrochloride
  • A kind of method for preparing gemcitabine hydrochloride
  • A kind of method for preparing gemcitabine hydrochloride

Examples

Experimental program
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Embodiment 1

[0035] Add 500g of GE-0 into a 5L three-necked flask, then add 2.5L of ethyl acetate, and gradually add 500g of tri-tert-butoxy lithium aluminum hydride in batches under mechanical stirring at 0-10°C (the reaction temperature should not exceed 10°C when adding) , After about 1-2 h, the addition was completed, and then the reaction was continued at 0-10°C for 4 hours. TLC monitors the end point of the reaction. After the reaction is completed, add 200 ml of concentrated hydrochloric acid dropwise under mechanical stirring at 0-10°C (the temperature of the reaction solution should not exceed 10°C). After the addition is complete, filter with suction and wash the filter cake with 1.5L*3 , the filtrates were combined, washed twice with saturated brine 2L*2, the ethyl acetate layer was separated, and the organic layer was concentrated to dryness to obtain 475 g of light yellow oil with a yield of 94.5%.

Embodiment 2

[0037] Add 475g GE-1 into a 5L three-necked flask, then add it into 2.5L dichloromethane, cool down to 5-10°C with a low-temperature cooling circulation pump, add 261ml triethylamine under mechanical stirring, drop by drop under mechanical stirring at 0-10°C 117ml of methanesulfonyl chloride was added, and the addition was completed in about 1-2 hours, and then the reaction was continued at 5-10°C for 4 hours. After the reaction was completed, wash with 2 L of 1 mol / L hydrochloric acid aqueous solution, 2 L of 5% sodium bicarbonate aqueous solution, and 2 L of Hao water, respectively, and concentrate the organic layer to dryness to obtain 566 g of light brown oil (crystals precipitated after standing for 1-2 days). The yield was 98.8%.

Embodiment 3

[0039] Add 275g of cytosine and 0.5g of ammonium sulfate into the reaction flask, then add 1.65L of hexamethyldisilazane, heat to reflux (120-130°C), continue to stir for 2 hours after the reaction liquid is clarified, cool to room temperature, and filter with suction , and the filter cake was vacuum-dried to obtain 605 g of N, O-bis(trimethylsilane)cytosine with a yield of 95%.

[0040] Add 565g of N,O-bis(trimethylsilane)cytosine into a 5L three-necked flask, then add 1.15L of anisole, stir well, then add 1.15L of trimethylsilyl trifluoromethanesulfonate, heat After the reaction solution is completely dissolved at about 125°C, dissolve 565g of GE-2 in 1.15L of anisole and add it dropwise to the reaction solution for about 1-2 hours, then continue the reaction under reflux for 5 Hour. After the reaction is complete, add 2.3L ethyl acetate, extract 2 times with 100L purified water, concentrate the organic layer to dryness to obtain a wine-red viscous substance, then add 1.4L ...

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Abstract

The invention belongs to the field of drug synthesis and provides a new method for synthesizing gemcitabine hydrochloride. The present invention uses 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-1-one-3,5-dibenzoate (referred to as "difluoro sugar") as the starting material, and undergoes Reduction, mesylation, condensation, deprotection, salt formation, resolution and refining to obtain the final product. The method has the advantages of simple process, high yield and a purity of over 99.8%, and is more favorable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of an antitumor compound gemcitabine hydrochloride. Background technique [0002] Gemcitabine hydrochloride is a nucleoside homologue, which is a cell cycle-specific antineoplastic drug. 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, and in 1998 as a treatment for non-small cell lung cancer. The drug is suitable for the treatment of inoperable advanced or metastatic pancreatic cancer, the treatment of locally advanced or metastatic non-small cell lung cancer, the treatment of intermediate and advanced non-small cell lung cancer, non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer and other solid tumors. [0003] At present, there are not many reports about the synthesis of gemcitabine. The relevant reports mainly include Her...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00
Inventor 张淑兰于中生宗利斌黄茂华张力
Owner NAT INST OF PHARMA R & D CO LTD
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