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Preparation method for emtricitabine isomer

A technology of emtricitabine and isomers, which is applied in the field of drug synthesis, can solve the problems of incomplete synthesis, separation and separation of three isomers, etc., and achieve the effects of simple operation, easy purification operation, and high optical purity

Active Publication Date: 2019-04-02
JIANGXI FUSHINE PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The present invention aims at the problem that there are few and incomplete reports on the synthesis and separation of the three isomers in the existing emtricitabine synthesis process, and provides a process with simple operation, high yield, easy purification operation of intermediates, and product optics. A new method for the preparation of the three isomers of emtricitabine with high purity and suitable for large-scale synthesis, which provides a strong guarantee for the process and quality research of emtricitabine

Method used

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  • Preparation method for emtricitabine isomer
  • Preparation method for emtricitabine isomer

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Embodiment 1

[0069] Preparation of Compound II (R is benzoyl): 54g (1.0eq) of acetonide was dissolved in a solution of 300ml of dichloromethane and 62g (1.5eq) of triethylamine, cooled to 0-5°C, and added dropwise within 1h Dissolve 60g (1.05eq) of benzoyl chloride solution in 60ml of dichloromethane, add dropwise and keep warm for about 1h. After the reaction was completed, 200 ml of water was added to the reaction mixture for liquid separation, and the organic layer was washed with 100 ml of water. The organic phase was evaporated to dryness and concentrated to dryness to obtain 90 g of oil, which was directly put into the next reaction without purification.

Embodiment 2

[0071] Preparation of Compound III: Dissolve 90 g of the oil obtained in the previous step in 200 ml of tetrahydrofuran, add 40 ml of 2N hydrochloric acid dropwise, heat to 45-50° C., stir for 2 hours, and then stir overnight at room temperature. After the reaction, neutralize with 5g of sodium bicarbonate and filter. The filtrate was evaporated to dryness to obtain 85 g of oil, which was directly put into the next reaction without purification.

Embodiment 3

[0073] Preparation of Compound IV: Dissolve 85g of the above oil in 400ml of dichloromethane and 40ml of water, and add 80g of sodium periodate (1.0eq) in 8 batches at 20-25°C. The reaction was continued for 4 hours. The solid was filtered, and the filtrate was concentrated to obtain 75 g of oil, which was directly put into the next reaction without purification.

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Abstract

The invention discloses a preparation method for an embritabine isomer. The preparation method comprises the following steps: with Solketal as a starting material, allowing the Solketal to undergo a six-step reaction of esterification, hydrolysis, oxidation, condensation cyclization, acetylation and glycosylation condensation so as to synthesize four mixture intermediates of emtricitabine; and splitting the four isomer intermediates into a cis-isomer mixture and a trans-isomer mixture through a chiral reagent. According to the invention, by adoption of a simple starting material, a mixture forsplitting key intermediates of four optical isomers of the emtricitabine is synthesized through the six-step reaction, and chiral acid is utilized to split the four isomers into a mixture of cis andtrans isomers, so the preparation method provided by the invention has the advantages of simple and convenient operation, high yield and high isomer chiral purity.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing and separating emtricitabine isomers. Background technique [0002] Emtricitabine, chemical name: 5-fluoro-1-(2R,5S)-[2-hydroxymethyl-1,3-oxothiocyclic-5-yl]cytosine, English name: Emtricitabine Foreign trade name: Emtriva, English code name: FTC, its structure is as follows: [0003] [0004] Emtricitabine is a new type of nucleoside reverse transcriptase inhibitor developed by Gilead Sciences of the United States. It has good inhibitory activity against HIV-1, HIV-2, and HBV viruses. It was applied for marketing in the United States in 2003. Clinically, it can be used in combination with other antiretroviral drugs for the treatment of adult HIV infection, as well as for the treatment of chronic hepatitis B. [0005] At present, the synthesis process of emtricitabine is mainly divided into the following types according to differe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04
CPCC07B2200/07C07D411/04Y02P20/55
Inventor 杜峰周忠波龚杰余翔王静谢永居
Owner JIANGXI FUSHINE PHARMA CO LTD
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