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Synthesis method of intermediate compound of sofosbuvir

A synthesis method and intermediate technology, which are applied to the synthesis field of intermediate compounds, can solve the problems of low atom economy, long production cycle, and many three wastes, etc., and achieve the effects of simple and easy synthesis route, low cost and simple steps.

Inactive Publication Date: 2015-10-21
SHANGHAI TWISUN BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, this method has problems such as long route, long production cycle, more three wastes, and low atom economy.

Method used

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  • Synthesis method of intermediate compound of sofosbuvir
  • Synthesis method of intermediate compound of sofosbuvir
  • Synthesis method of intermediate compound of sofosbuvir

Examples

Experimental program
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preparation example Construction

[0041] The synthetic method comprises the following steps:

[0042] (1) Starting with (3R,4R,5R)-3-fluoro-dihydro-4-hydroxy-5-hydroxymethyl-3-methylfuran-2(3H)-one, and pivaloyl chloride A reaction occurs to generate an intermediate product (Ⅻ);

[0043] (2) reduction of intermediate product (XII) to intermediate product (XIII);

[0044] (3) reacting the intermediate product (XIII) with pivaloyl chloride to generate the intermediate product (XIV);

[0045] (4) reacting the intermediate product (XIV) with hydrobromic acetic acid solution to generate the intermediate product (XV);

[0046] (5) performing a Silyl-Hilbert-Johnson reaction on the intermediate product (XV) with uracil to generate the intermediate product (XVI);

[0047] (6) Reacting the intermediate product (XVI) with sodium methoxide to obtain the target product: an intermediate compound of sofosbuvir represented by formula (I).

[0048] In a preferred embodiment, in the synthesis method, the step (1) is: adding ...

Embodiment 1

[0057] The synthesis of embodiment 1 intermediate product (XII)

[0058] Add (3R,4R,5R)-3-fluoro-dihydro-4-hydroxy-5-hydroxymethyl-3-methylfuran-2(3H)-one 200.0g and acetonitrile into a dry 3.0L reaction flask 1.4L. The temperature of the reaction liquid was lowered to 0°C, and 368.0 g of pivaloyl chloride was added dropwise. During the dropwise addition, the temperature was controlled at 0°C. After the dropwise addition, 8.0 g of 4-dimethylaminopyridine was added. Then, the temperature was raised to 10-15° C., and the reaction was stirred for 1 hour. Add 296.0 g of triethylamine dropwise, and control the temperature at 10-15°C during the dropwise addition. After the dropwise addition, the temperature was raised to normal temperature to react for 1 hour. After completion of the reaction, 1000.0 g of ethyl acetate was added, followed by stirring for 30 minutes. After filtering, the filter cake was washed twice with 1000.0 g of ethyl acetate. The two filtrates were combin...

Embodiment 2

[0061] The synthesis of embodiment 2 intermediate product (XIII)

[0062] Under nitrogen protection, 261.0 g of red aluminum and 500.0 g of toluene were added to a dry and anhydrous 1.0 L reaction flask. The temperature was lowered to about -12°C, and 84.0 g of trifluoroethanol was slowly added dropwise. When adding dropwise, control the temperature at about -10°C. After the dropwise addition, the temperature was raised to room temperature and stirred for one hour.

[0063] Under nitrogen protection, 200.0 g of intermediate product (Ⅻ), 400.0 g of toluene and 260.0 g of butyl acetate were added to a dry and anhydrous 3.0 L reaction flask. Lower the temperature to about -12°C, and slowly add the activated red aluminum solution dropwise. During the dropwise addition, the temperature was controlled at about -10°C. After dropping, stir for 15 minutes. HPLC analysis of a sample showed that the reaction was complete. After the reaction was completed, the reaction solution was ...

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Abstract

The invention provides a synthesis method of an intermediate compound of sofosbuvir as shown in formula (I) (see specification). The synthesis method of the intermediate compound of sofosbuvir, a synthetic route of which is as follows: (see specification) the synthesis method comprises the following steps: taking (3R, 4R, 5R)-3-fluoro-dihydro-4-hydroxl3-methyl furan-2(3H)-ketone as an initial raw material to react with pivaloyl chloride to generate an intermediate product (XII); reducing the intermediate product to obtain an intermediate product (XIII); enabling the intermediate product (XIII) to react with pivaloyl chloride to generate an intermediate product (XIV); generating an intermediate product (XV) by virtue of the reaction of the intermediate product (XIV) and a hydrogen bromide; performing silyl-hilbert-johnson reaction for the intermediate product (XV) and uracil to generate an intermediate product (XVI); enabling the intermediate product (XVI) to react with sodium methoxide to obtain a target product. The synthesis method of the intermediate compound (I) is moderate in reaction condition, simple in procedure, low in cost, environment-friendly and favorable for the industrialized production.

Description

technical field [0001] The present invention relates to a kind of synthetic method of medicine intermediate, relate in particular to a kind of synthetic method of the intermediate compound of sofosbuvir. Background technique [0002] Sofosbuvir is an anti-hepatitis C patent drug newly developed by Gilead Sciences of the United States. Its chemical name is: (S)-2-[(((2R,3R,4R,5R)-5-(2,4-di Oxo-3,4-dihydropyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino]propionic acid Isopropyl ester, the structural formula is as follows: [0003] [0004] It is the first drug approved for an all-oral treatment regimen for hepatitis C. The product was approved by the US Food and Drug Administration in December 2013 and the European Union in January 2014. Currently, Sofosbuvir is regarded as a breakthrough drug in the treatment of hepatitis C, with a cure rate of over 90%. [0005] According to the "Hepatitis C Screening and Treatment Guide...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
Inventor 王其安叶方国叶敏
Owner SHANGHAI TWISUN BIO PHARM
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