Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug

A technology of coupling reaction and reaction temperature, applied in the field of compounds, can solve problems such as difficult treatment of HCV-I virus infection

Active Publication Date: 2014-06-11
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, the treatment of HCV-...

Method used

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  • Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug
  • Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug
  • Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1 3',5'- O -Dibenzoyl-2'-deoxy-2'-fluoro-2'- C -Methyl-N 4 -Preparation of p-benzoyl-5-fluorocytidine

[0134] 1) Add 49g of trifluoroethanol dropwise to 240ml of toluene and 150g of 70% reduced aluminum (Red-Al) / toluene mixed solution under anhydrous, anaerobic, -15°C and stirring conditions. Stir at room temperature for 0.5h to prepare reduced aluminum (Red-Al(OCH 2 CF 3 )) solution;

[0135] 2) Under anhydrous, anaerobic, -10°C and stirring conditions, add dropwise the trifluoroethanol-modified reduced aluminum (Red-Al(OCH 2 CF 3 )) solution; after the dropwise addition, continue to stir at -10°C for 0.5h, and TLC detects that the reaction is complete;

[0136] 3) Maintain anhydrous, anaerobic, -10 ℃, stirring conditions, after adding 12g of tetrabutylammonium bromide, dropwise add 138g of sulfuryl chloride (SO 2 Cl 2 ), after the dropwise addition was completed, stir at room temperature for 16 h, after TLC de...

Embodiment 2

[0143] Example 2 3',5'- O -Dibenzoyl-2'-deoxy-2'-fluoro-2'- C - Preparation of methyl-5-fluorouridine

[0144] Weigh the 3', 5'- prepared in Example 1 O -Dibenzoyl-2'-deoxy-2'-fluoro-2'- C -Methyl-N 4 - 100 grams of p-benzoyl-5-fluorocytidine, put it into 1.5L of 70% acetic acid aqueous solution, stir, heat to reflux for 20h, after TLC detects that the reaction is complete, cool to room temperature, add 400ml of water, and stir at room temperature 2h, suction filtration under reduced pressure, the filter cake was washed with water and dried to obtain 3',5'- O -Dibenzoyl-2'-deoxy-2'-fluoro-2'- C -Methyl-5-fluorouridine 72g, in the form of off-white solid.

[0145] δ( 1 HNMR, DMSO- d 6 ): 1.50 (d, J =22.4Hz, 3H), 4.59(m, 2H), 5.05(m, 1H), 5.95(m, 1H), 6.47(d, J =20.0Hz, 1H), 7.45(m, 2H), 7.57(m, 2H), 7.60(m, 1H), 7.71(m, 1H), 7.92(m, 2H), 8.01(m, 2H), 8.01 (d, J=7.8Hz, 1H), 11.40 (s, 1H) ppm; δ( 19 FNMR, DMSO- d 6 ): -167.8(s), -172.2(...

Embodiment 3

[0146] Example 3 3',5'- O -Dibenzoyl-2'-deoxy-2'-fluoro-2'- C - Preparation of methyl-5-fluorouridine

[0147] 1) Add 8.16g of trifluoroethanol dropwise to 40ml of toluene and 25g of 70% reduced aluminum (Red-Al) / toluene mixed solution under anhydrous, anaerobic, -15°C and stirring conditions. After the dropwise addition, Stir at room temperature for 0.5h to obtain trifluoroethanol-modified reduced aluminum (Red-Al(OCH 2 CF 3 )) solution;

[0148] 2) Add the trifluoroethanol-modified reduced aluminum (Red-Al(OCH 2 CF 3 )) solution; after the dropwise addition, continue to stir at -10°C for 0.5h, and TLC detects that the reaction is complete;

[0149] 3) Maintain anhydrous, anaerobic, -10°C, stirring conditions, add 2g of tetrabutylammonium bromide, drop 23g of SO 2 Cl 2 ；

[0150] 4) After the dropwise addition, stir at room temperature for 16 hours. After TLC detects that the reaction is complete, cool the reaction mixture to 0°C, add 200m...

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Abstract

The invention relates to a nucleoside phosphamide prodrug as well as a preparation method and application of the nucleoside phosphamide prodrug. The nucleoside phosphamide prodrug is selected from any one of a compound I and a compound II, wherein in the formulas of the compound I and the compound II, X is selected from any one of F, Cl, Br and I. Compared with GS7977andGS7851, The compound I or II disclosed by the invention has more excellent resistance to hepatitis C virus, wherein the formulas I and II are respectively as shown in specifications.

Description

[0001] technical field [0002] The invention relates to the field of compounds, in particular to a nucleoside phosphoramide prodrug, a preparation method thereof and an application thereof. Background technique [0003] Hepatitis C virus (HCV) infection can directly lead to liver cirrhosis and liver cancer, seriously threatening human health. The World Health Organization (WTO) survey results show that more than 200 million people in the world are infected with hepatitis C virus, of which about 20% of the infected people rely on their own immune system to clear the HCV virus, while the rest of the HCV virus infected people are HCV The virus stays dormant for the rest of its life, and about 10-20% of infected people develop liver cirrhosis or liver cancer and die. [0004] At present, the combination of peginterferon (alfa-2a or alfa-2b) and ribavirin (Ribavirin), Boceprevir or Telaprevir has become the standard treatment for acute or chronic hepatitis C, of ​​which about ...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H19/073C07H1/00C07H1/02A61K31/7072A61P31/14
Inventor 岳祥军钟晓锋王志邦
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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