Preparation method for sofosbuvir fluorofuran intermediate

An intermediate and temperature control technology, applied in the field of medicine, can solve the problems of large pollution, unfavorable industrial production, complex process, etc., and achieve the effects of high total yield, low cost and simple process

Active Publication Date: 2019-03-05
CHANGZHOU PHARMA FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This synthetic route has 8 steps of reaction, using a large amount of phosphorus-containing compound (triphenylphosphine), strong oxidant (potassium

Method used

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  • Preparation method for sofosbuvir fluorofuran intermediate
  • Preparation method for sofosbuvir fluorofuran intermediate
  • Preparation method for sofosbuvir fluorofuran intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (intermediate 18)

[0035] Under anhydrous conditions, disperse 180.0g (1.0mol, 1.0eq) of D-glucose in 250ml of absolute ethanol, add 60.0g (1.0mol, 1.0eq) of glacial acetic acid and stir for 30min, then add 33% dimethylamine dropwise 139.4g (1.02mol, 1.02eq) of ethanol solution, the temperature is controlled not to exceed 20°C. The reaction solution was heated to 75° C. for 2 hours, then cooled to 55° C., and kept for 2 hours. Concentrate under reduced pressure at 50°C to obtain a brown oil. Add 400ml of water to the oily substance, replace with nitrogen for 3 times, add 73.1g (1.3mol, 1.3eq) of calcium oxide, control the temperature not to exceed 20°C, after adding, stir at 20°C for 20min, then heat to 40°C for reaction 4h. Cool the reaction solution below 3°C, add concentrated sulfuric acid dropwise to adjust the pH between 3.0-3.2, and control the temperature not to exceed 3°C. ...

Embodiment 2

[0036] Example 2 ((2R,3R,4R)-3-(benzoyloxy)-4-hydroxyl-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (intermediate 19) Preparation of

[0037]

[0038] Dissolve 100g (0.62mol) of intermediate 18 in 800ml of dichloromethane, add 186.9g (1.85mol, 3.0eq) of triethylamine, lower to -20°C, add dropwise 177.7g (1.26mol, 2.05eq) of benzoyl chloride ), control the temperature not to exceed 0°C, and continue stirring for 3-5 hours after the dropwise addition is completed. After the reaction was completed, the reaction solution was washed successively with 5% aqueous sodium bicarbonate solution (500ml) and saturated brine (500mlx2). 10:1) stirred and crystallized, filtered and dried to obtain ((2R,3R,4R)-3-(benzoyloxy)-4-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl ) methyl benzoate (intermediate 19), 182.7g, off-white solid, yield 80%.

Embodiment 3

[0039] Example 3 ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (structural formula A ) preparation

[0040]

[0041] Add 180g (0.486mol, 1.0eq) of intermediate 19 and 1.5L of dichloromethane into a 3L reaction flask, stir to dissolve, cool down to -15°C, and slowly add 86.2g of diethylaminosulfur trifluoride (0.534mol , 1.1eq), control the temperature not to exceed -5°C, after the addition, naturally rise to room temperature, stir for 18h, after the reaction is completed, wash the reaction solution with 700ml of 1N hydrochloric acid and saturated brine (800x2) successively, dry the organic phase and concentrate To dryness, get ((2R, 3R, 4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (structural formula A), 164.7g, off-white solid, yield 91%.

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Abstract

The invention provides a preparation method for a sofosbuvir fluorofuran intermediate. The invention provides the preparation method for an important sofosbuvir intermediate, namely, ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxytetrahydrofuran-2-yl)methylbenzoate (a fluorofuran fragment, with a structural formula A which is described in the specification).

Description

technical field [0001] The present invention relates to a sofosbuvir intermediate ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) The preparation method of methyl benzoate belongs to the technical field of medicine. Background technique [0002] Viral hepatitis C, referred to as hepatitis C and hepatitis C for short, is a viral hepatitis caused by hepatitis C virus (HCV) infection, which is mainly transmitted through blood transfusion, acupuncture, mother to child, etc. According to the statistics of the World Health Organization, The global HCV infection rate is about 3%. It is estimated that about 180 million people are infected with HCV, and about 3.5 million new cases of hepatitis C occur each year. Hepatitis C is a global epidemic, which can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients can develop liver cirrhosis and even hepatocellular carcinoma (HCC). In the next 20 years, the mortality rate related to H...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33
Inventor 施世良殷学治唐井元马贯军巫美金
Owner CHANGZHOU PHARMA FACTORY
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