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Preparation method of sofosbuvir intermediate

A technology for intermediates and preparation steps, which is applied in the field of preparation of sofosbuvir intermediates, can solve problems such as cumbersome operations, high waste treatment costs, and high environmental protection pressure, and achieve high stereoselectivity, novel synthetic routes, and high yields. high effect

Inactive Publication Date: 2018-01-12
PHARMA SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this route has long steps, cumbersome operation and high production cost
Moreover, a large amount of hazardous solid waste such as triphenoxyphos, manganese salt and barium salt is produced, the pressure on environmental protection is very high, and the cost of waste treatment is quite high

Method used

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  • Preparation method of sofosbuvir intermediate
  • Preparation method of sofosbuvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Under the protection of nitrogen, the compound of formula II (50g, 0.31mol) was dissolved in dry tetrahydrofuran (1000mL), cooled to -50°C, and n-butyllithium (2.5M, 135mL, 0.34mol) was slowly added dropwise, controlled The inner temperature is not higher than -40 degrees. After dropping, stir at about -50°C for 30 minutes. Then the compound of formula III (72.9 g, 0.34 mol) was added dropwise, the internal temperature was controlled not to be higher than -40°C, and after the addition was completed, it was stirred at about -50°C for 1 hour. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (200 mL), and extracted twice with ethyl acetate (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was slurried by adding n-hexane (500 mL), filtered and dried to obtain the compound of formula IV.

[0071] Yield: 75.8 g, Yield: 83%.

Embodiment 2

[0073] Under the protection of nitrogen, the compound of formula II (50g, 0.31mol) was dissolved in dry tetrahydrofuran (1000mL), triethylamine (154.9g, 1.53mol), DMAP (3.7g, 0.031mol) were added, cooled to 0- At 5°C, the compound of formula III (99.3 g, 0.46 mol) was added dropwise. After the addition was complete, the mixture was raised to room temperature and reacted overnight. Quenched with saturated aqueous ammonium chloride (200 mL), extracted twice with ethyl acetate (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was subjected to column chromatography to obtain a compound of formula IV.

[0074] Yield: 71.3 g, Yield: 78%.

Embodiment 3

[0076] The compound of formula II (250 g, 1.53 mol) was added to toluene (3750 mL), and heated to 70 degrees. Sodium methoxide in methanol (29 wt%, 314 g, 1.68 mol) was added dropwise. After the addition, methanol was distilled off under normal pressure. Cool to 0-5°C, add the compound of formula III (364.4 g, 1.68 mol) dropwise, and control the temperature not higher than 20°C. After adding, react for 1-2 hours. After the reaction was completed, water (250 mL) was added, heated to 50-60° C., the layers were separated, and the water phase was separated. The organic phase was washed twice with water. The organic phase was concentrated to give crude product. Add n-hexane (1500mL) to the crude product to make a slurry, filter and dry to obtain the intermediate of formula IV.

[0077] Yield: 436 g, Yield: 95.4%.

[0078] Among the above-mentioned examples 1-3, the base n-BuLi or triethylamine or sodium methylate used can also be selected from iso-BuLi, t-BuLi, LDA, LiHMDS, K...

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Abstract

The invention discloses a preparation method of a sofosbuvir intermediate of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid-g-lactone 3,5-dibenzoate. The intermediate structure corresponds toa formula I shown as the description. The method comprises the step that the sofosbuvir intermediate shown as the formula I is finally obtained by using (D2) (S)-(+)-4-phenyl-2-oxazolidinone of a compound shown as a formula II as a raw material through six-step reaction of condensation, fluorination, Adol addition, oxidation cyclization, isomerization and benzoylation. The preparation method hasthe advantages that the raw materials are cheap and can be easily obtained; the reaction conditions are mild; the route is short; the yield is high; three wastes are few; the pollution is little; thepreparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a sofosbuvir intermediate. Background technique [0002] Sofosbuvir is a new drug developed by Gilead Inc. (Gilead Inc.) for the treatment of chronic hepatitis C. It was approved by the US Food and Drug Administration (FDA) on December 6, 2013. It is the first drug that does not require combination Interferons are safe and effective drugs for the treatment of the major hepatitis C subtypes. The intermediate is the key intermediate in the current synthetic route of Sofosbuvir, and its structural formula is as follows: [0003] [0004] WO2008045419 discloses a preparation method corresponding to an intermediate of formula I: using mannitol of formula 1 as a raw material, the intermediate of formula I is obtained through 9 steps of reaction, and the reaction is as follows: [0005] [0006] In current technology, intermediates o...

Claims

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Application Information

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IPC IPC(8): C07D307/33
Inventor 陈平彭少平李因强
Owner PHARMA SHANGHAI
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