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An improved sofosbuvir preparation method

A compound, Lewis acid technology, applied in the field of medicine and chemical industry, can solve problems such as unsafe

Active Publication Date: 2017-02-15
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The scheme provided by the present invention does not use flammable and explosive tert-butylmagnesium chloride, has the advantages of mild reaction conditions, convenient reagent storage, safe use, easy operation, convenient post-treatment, etc., and is easy to realize large-scale production of raw materials in factories, overcoming existing problems. There are disadvantages that the method of synthesizing Sofosbuvir is not safe

Method used

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preparation example Construction

[0034] Specifically, the improved sofosbuvir preparation method of the present invention may include:

[0035] a) adding compound I, compound II, Lewis acid and organic solvent into the reaction vessel, and adding alkali;

[0036] b) Control the reaction temperature of the system at 20°C to 40°C, and stir the reaction until the compound I content is ≤3.0%;

[0037] c) stop the reaction, extract the reaction solution, and then perform crystallization to obtain compound III.

[0038] Specifically, the method for preparing the improved sofosbuvir described in the present invention may include the following steps:

[0039] a) adding compound I, compound II, Lewis acid and organic solvent into the reaction vessel, and adding alkali;

[0040] b) Control the reaction temperature of the system at 20°C to 40°C, and stir the reaction until the compound I content is ≤3.0%;

[0041] c) Stop the reaction, extract the reaction solution with dichloromethane, wash with aqueous sodium carbo...

specific Embodiment approach

[0081] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0082] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0083] In the present invention, ml or mL refers to milliliter, L refers to liter, g refers to gram, kg refers to kilogram, mol / L refers to mole / liter, h refers to hour, min refers to minute, v / v refers to volume ratio, <a certain value is means below a certain value.

[0084] HPLC detection chromatographic conditions are as follows:

[0085] Chromatographic column: Waters XSELECT HSS T3 (4.6*100mm, 2.5um);

[0086] Flow rate: 1.5mL / min; Detection wavelength: 210nm; Column temperature: 25°C;

[0087] Running time: 29min; Injection volume: 2μl;

[0088] Mobile phase: Phase A: Dissolve 0.5mL of ...

Embodiment 1

[0092] Add 100g of compound Ⅰ, 51g of anhydrous magnesium chloride, 200g of compound Ⅳ, 600mL of tetrahydrofuran into the reaction flask, add 60g of DIPEA dropwise under stirring at a temperature of 30°C to 40°C, after the addition is completed, react at a temperature of 30°C to 40°C, and detect by HPLC Compound I content ≤ 3.0%, stop the reaction. Add 300 mL of 10% (v / v) dilute hydrochloric acid to the reaction solution, stir for 30 min, add 600 g of dichloromethane for extraction, and separate the aqueous phase; the organic phase is washed three times with 140 g of 10% sodium carbonate, and the aqueous sodium carbonate phase is combined , after extracting twice with 100 g of dichloromethane, combine all the dichloromethane phases, wash once with 100 mL of water, evaporate to dryness, then add 50 mL of isopropyl acetate, continue to evaporate to dryness, add 1.2 L of isopropyl acetate to the resulting product, After heating to 60°C to dissolve, cool down to 20°C, stir until s...

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Abstract

An improved sofosbuvir preparation method is provided. The method adopts (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine, and other raw materials and prepares the sofosbuvir through reacting in an organic solvent under existence of a Lewis acid and an alkali. The method has advantages of mild reaction conditions, safe agent using, simple and convenient operation, convenient after-treatment, and the like, and is prone to large-scale production in a factory.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to an improved preparation method of sofosbuvir. Background technique [0002] Sofosbuvir, chemical name (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine -1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester, its structural formula as follows: [0003] [0004] Sofosbuvir is an NS5B polymerase inhibitor developed by Gilead, which can be used to treat hepatitis C infection in mammals. The drug is currently on the market in many countries and is a drug with significant effects in the treatment of liver diseases. [0005] The prior art D-type amino acid compound (CN 104470939A) for liver diseases discloses a preparation method of Sofosbuvir, and the reaction mode of the method is as follows: [0006] [0007] The disclosed method requires the use of tert-butylmagnesium chloride, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00C07H1/06
CPCC07H1/00C07H1/06C07H19/10
Inventor 王海龙张德喜杨柱
Owner SUNSHINE LAKE PHARM CO LTD
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