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Method for preparing antiviral medicinal entecavir intermediate

An antiviral drug, entecavir technology, applied in organic chemistry and other directions, can solve the problems of extreme sensitivity to air and water vapor, high price, and complicated and complicated homemade process.

Active Publication Date: 2010-06-09
SHANGHAI QINGSONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Dess-Martin oxidant is expensive and sensitive to air and water vapor, so it is not suitable for storage
Nysted reagent is also expensive, extremely sensitive to air and water vapor, not suitable for storage, and the self-made process is cumbersome and complicated, requiring harsh conditions such as low temperature, so it is not suitable for industrial production

Method used

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  • Method for preparing antiviral medicinal entecavir intermediate
  • Method for preparing antiviral medicinal entecavir intermediate
  • Method for preparing antiviral medicinal entecavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Preparation of (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[[(4-methoxyphenyl)diphenylmethyl]amino]- 9H-purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanone (Formula II)

[0028] Add (1S, 2S, 3S, 5S)-3-benzyloxy-5-[-6-benzyloxy-2-[[(4-methoxyphenyl)benzhydryl] into a 500ml three-necked flask -amino]-9H-purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanol (formula III) (20g, 24.3mmol) and dichloromethane (300ml), stirred to dissolve, stirred Saturated aqueous sodium bicarbonate solution (60 ml) was added thereto, followed by stirring for 10 minutes. Then iodine (13 g, 51.2 mmol) and TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl radical) (0.5 g, 3.2 mmol) were added, and the reaction solution was stirred at 20° C. for 5 hours. Cool to 0°C, add 10% sodium sulfite solution (100ml), and stir for 15 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate (80ml), and the organic phases were combined and washed with saturated potassium bicarbonate...

Embodiment 2

[0029] Example 2 Preparation of (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[[(4-methoxyphenyl)diphenylmethyl]amino]- 9H-purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanone (Formula II)

[0030] The saturated aqueous sodium bicarbonate solution (60ml) in Example 1 was replaced with saturated aqueous sodium carbonate solution (60ml), and other operations were the same as in Example 1, with a yield of 90%.

Embodiment 3

[0031] Example 3 (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[[(4-methoxyphenyl)diphenylmethyl]amino]-9H -Purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanone (Formula II)

[0032] The saturated aqueous sodium bicarbonate solution (60ml) in Example 1 was replaced with a saturated 2M aqueous sodium hydroxide solution (150ml). Other operations were the same as in Example 1, and the yield was 75%.

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PUM

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Abstract

The invention relates to a method for preparing an antiviral medicinal entecavir intermediate compound with a formula I. An oxidation system formed by TEMPO and iodine under an alkali condition is adopted to oxidize a compound with a formula III to obtain a compound with a formula II, and methylenation is carried out on the formula II by a methylenation system formed by titanium tetrachloride, magnesium, methylene chloride and tetrahydrofuran to obtain the compound with the formula I. The invention has easy acquirement of raw materials and simple and convenient method and is suitable for industrialized production.

Description

Technical field: [0001] The present invention relates to medicine preparation. In particular, it relates to an improved method for preparing an antiviral drug entecavir intermediate. Background technique: [0002] The chemical name of Entecavir is: (1S, 3R, 4S)-9-[4-hydroxyl-(3-hydroxymethyl)-2-methylenecyclopentyl]-guanine. The structural formula is; [0003] [0004] Molecular formula is C 12 h 15 N 5 o 3 , with a molecular weight of 277.3 [0005] Entecavir is a deoxyguanosine analogue that effectively and selectively inhibits the replication of hepatitis B virus. It has a strong effect of inhibiting the replication of hepatitis B virus and reducing the level of serum viral DNA. At the same time, the compound has relatively high selectivity, and its cytotoxicity is 1 / 8000 of the anti-hepatitis B virus activity, can effectively treat chronic hepatitis B without interfering with influenza virus and HIV virus, and is safe to use and well tolerated. [0006] US Pat...

Claims

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Application Information

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IPC IPC(8): C07D473/18
Inventor 杨守宁张磊谭宙宏杨琍苹
Owner SHANGHAI QINGSONG PHARMA
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