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Preparation method of sofosbuvir intermediate

A technology for intermediates and compounds, applied in the field of pharmaceuticals, can solve the problems of excessive reduction, generation of by-products, inconvenient reaction, etc., and achieve the effects of improving product purity, reducing by-product generation, and improving purity.

Active Publication Date: 2021-09-07
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The modified red aluminum and the passivating agent trifluoroethanol used in the process have poor selectivity to the reaction, and are prone to excessive reduction, resulting in by-products, which in turn cause inconvenience to subsequent reactions

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2～5

[0058] According to the method disclosed in Example 1, only the feeding ratio of compound a-1 and 70% red aluminum in the preparation of compound b-1 from compound a-1 was changed, and the results are shown in Table 1.

[0059] Table 1 Different reaction conditions and results

[0060] Example no a-1 :n 红铝

Embodiment 6～16

[0062] According to the method disclosed in Example 1, only the chlorinated reagent, the feed ratio of compound b-1 and the chlorinated reagent, and the reaction temperature in the operation of preparing compound c-1 by chlorinated reaction of compound b-1 were changed respectively. The results are shown in the table 2.

[0063] Note: blank spaces in the table indicate that this parameter is the same as in Example 1.

[0064] Table 2 Different reaction conditions and results

[0065]

[0066]

Embodiment 17～24

[0068] According to the method disclosed in Example 1, only the feed ratio and reaction temperature of compound c-1 and e-1 in the operation of preparing target compound d-1 with compound c-1 as substrate were changed respectively. The results are shown in Table 3.

[0069] Note: blank spaces in the table indicate that this parameter is the same as in Example 1.

[0070] Table 3 Different reaction conditions and results

[0071]

[0072]

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PUM

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Abstract

The invention relates to the technical field of biopharmacy, in particular to preparation of a sofosbuvir intermediate, and more particularly relates to a preparation method of the sofosbuvir intermediate ((2R, 3R, 4R)-3-benzoyloxy-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) methyl benzoate; and a compound shown in a formula a reacts with modified red aluminum to prepare a compound shown in a formula b, then the compound shown in the formula b is subjected to a chlorination reaction in an oxalyl chloride / chlorobenzene solution to prepare a compound shown in a formula c, and finally the compound shown in the formula c reacts with a compound with a structure shown in a formula e to prepare a target compound shown in a formula d. The preparation process is simple in reaction condition, easy to operate and low in cost; the hydrolysis operation is reduced in the post-treatment process of the chlorination stage, so that the wastewater amount is reduced, and the method is more environment-friendly; and the preparation process disclosed by the invention is high in yield, high in product purity, more stable in product and suitable for large-scale production.

Description

technical field [0001] The present invention relates to the field of pharmacy, in particular to the preparation of Sofosbuvir intermediates, more specifically to Sofosbuvir intermediates ((2R, 3R, 4R)-3-benzoyloxy-4-fluoro - the preparation method of 5-chloro-4-methyltetrahydrofuran-2-yl) methyl benzoate. Background technique [0002] Sofosbuvir, the chemical name is (2S)-isopropyl-2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-di Hydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid ethyl ester, CAS number It is 1190307-88-0, and its structural formula is as follows: [0003] [0004] Sofosbuvir is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, suitable for the treatment of chronic hepatitis C (CHC) infection as a combination component in a combined antiviral therapy regimen. It is a new drug developed by Gilead for the treatment of chronic hepatitis C. It was approved by the US Food and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00
CPCC07H19/067C07H1/00C07B2200/07
Inventor 石利平陈本顺叶金星李大伟江涛钱若灿张维冰杨武林邱磊于娜娜
Owner JIANGSU ALPHA PHARM CO LTD
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