Preparation method of 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: 2014-10-22
NAT INST OF PHARMA R & D CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

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  • Preparation method of gemcitabine hydrochloride
  • Preparation method of gemcitabine hydrochloride
  • Preparation method of gemcitabine hydrochloride

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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, and concentrate the organic layer to dryness to obtain a wine-red viscous substance, then a...

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Abstract

The invention belongs to the drug synthesis field, and provides a novel method for synthesizing gemcitabine hydrochloride. In the method, 2-deoxy-2,2-difluoro-D-erythro-pentafuranous-one-3,5-dibenzoate (bifluoro-sugar for short) is taken as the primary raw material, and then the primary raw material is subjected to steps of reduction, methyl-sulfonylation, condensation, deprotection, salt forming, separation, and refinement so as to obtain the finished product. The method has the advantages of simple technology, high yield, high purity (which can reach 99.8% or more), and more suitability for industrial 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 Applications(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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