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A kind of synthetic method of Sofosbuvir intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of high price of downstream raw materials, impact on the purity and quality of compound C, insufficient purity of compound B, etc., and achieve the prospect of large-scale industrial production, which is conducive to stable production , the effect of reducing production costs

Active Publication Date: 2020-06-02
上海西浦医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The initial raw material is mannitol, which is cheap and easy to get, but the disadvantages are more obvious: (1) the price of sodium periodate (KIO4) is very high, which directly restricts the cost of compound A and compound B; (2) the route consists of compound A The purity of the synthesized compound B is not enough, which will greatly affect the purity and quality of compound C, which will have an impact on the high price of downstream raw materials

Method used

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  • A kind of synthetic method of Sofosbuvir intermediate
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  • A kind of synthetic method of Sofosbuvir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of intermediate product (III)

[0029] Add 300mL of acetone and 0.3mL of boron trifluoride diethyl ether into a clean 500mL three-necked bottle, stir, cool down to 0°C, and slowly add 18.5g (R)-epichlorohydrin to it dropwise, and the dropwise addition is completed within 30 minutes. After 13 hours, the reaction was stopped, the acetone was distilled off, and 24 g of pure product was obtained by distillation under reduced pressure, with a yield of 80%.

Embodiment 2

[0030] Embodiment 2: the synthesis of intermediate product (IV)

[0031] Add 200mL triethyl phosphite into a clean 500mL three-neck flask, add 24g of intermediate product (III) to it, heat to 65°C, reflux for 24h, stop the reaction, remove excess triethyl phosphite by distillation, and distill the three-necked The remaining liquid in the bottle was purified by a silica gel column to obtain 36.2 g of the product with a yield of 89.2%.

Embodiment 3

[0032] Embodiment 3: the synthesis of intermediate (I)

[0033] Add the intermediate product (IV) to 500mL of toluene, cool down to 0°C, add 18g of potassium tert-butoxide in batches, stir for 30min, add 17g of ethyl pyruvate dropwise, control the reaction temperature at 0-5°C, and finish the dropwise Complete, react for 12 hours, stop the reaction, lower the temperature to 5°C, add 2N hydrochloric acid dropwise to adjust the pH to 6-7, add 300mL of water, stir and separate layers, wash the organic layer with water, dry, concentrate, and distill to obtain the pure intermediate product (I) 24g, yield 79.1%, purity 99.82%. 1H-NMR (400Hz, CDCl3), δ=6.66(dd, J=6.8, 8.0Hz, 1H), 4.81-4.86(m, 1H), 4.11-4.21(m, 3H), 3.60(t, J=8.4 Hz, 1H), 1.87 (d, J = 1.2 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H).

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Abstract

The invention provides a synthetic method of sofosbuvir intermediate (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolame-4-yl]-2-methyl-2-ethyl acrylate. The synthetic method adopts (R)-epoxy chloropropane as a raw material, and the sofosbuvir intermediate can be obtained by virtue of the acetonylidene protection and phosphorylation of triethyl phosphite, and the reaction with ethyl pyruvate. According to thesynthetic method, the (R)-epoxy chloropropane is used as the raw material and is low in price and easy to obtain; and other raw materials are conventional products in the market, so that the industrialized production cost is greatly decreased, the production cost of the intermediate can be reduced by 30 percent or more, the purity of a prepared target product is high, and the industrialized production prospect is great.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to a sofosbuvir intermediate (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]- Synthetic method of ethyl 2-methyl-2-acrylate. Background technique [0002] Hepatitis C is a liver disease caused by the hepatitis C virus. Like hepatitis B, it can also cause cirrhosis or liver cancer, threatening the health of many infected people. According to the latest World Health Organization (WHO) statistics, 130-150 million people worldwide are living with chronic hepatitis C infection. It is estimated that 80% of patients infected with hepatitis C will develop chronic infection. In chronic hepatitis C, 20% of patients will develop liver cirrhosis, and 25% may develop liver cancer. Between 350,000 and 500,000 people die each year from hepatitis C-related liver disease. Hepatitis C virus is a blood-borne virus. The most common ways of infection include unsafe medical procedures and sexual tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/30
CPCC07D317/30
Inventor 秦勇陈悦
Owner 上海西浦医药科技有限公司
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