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Improved method for preparing entecavir

A technology of entecavir and compounds, applied in the field of improved preparation of antiviral drug entecavir, can solve the problems of excessive waste water and waste solvent, low total yield, unfavorable environmental protection, etc., and achieve high application value, good reproducibility, and easy operation Effect

Active Publication Date: 2011-11-02
SHANGHAI QINGSONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The disadvantages of the above method: ① two-step reaction is required, and the first step reaction intermediate needs to be separated and purified by post-treatment before the second step reaction can be carried out, and the reaction cycle is longer; ② more waste water and waste solvent are produced, which is not conducive to environmental protection ; 3. total yield is lower 35~50%, is not suitable for industrialized production

Method used

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  • Improved method for preparing entecavir
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  • Improved method for preparing entecavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[[(4-methoxyphenyl) diphenylmethyl]amino]-9H Preparation of -purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanone

[0026]

[0027] Among them, MMT represents 4-methoxytrityl, Bn represents benzyl

[0028] Add (1S, 2S, 3S, 5S)-3-benzyloxy-5-[-6-benzyloxy-2-[[(4-methoxyphenyl)benzhydryl] into a 1000ml three-necked flask -Amino]-9H-purin-9-yl]-2-[(benzyloxy)methyl]-cyclopentanol (40g, 48.6mmol) and dichloromethane (600ml), stirred and dissolved, and saturated carbonic acid was added under stirring Aqueous sodium hydrogen solution (120ml), stirred for 10 minutes. Then iodine (26 g, 102.4 mmol) and TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl radical) (1.0 g, 6.4 mmol) were added, and the reaction solution was stirred at 20° C. for 5 hours. Cool to 0°C, add 10% sodium sulfite solution (200ml), and stir for 15 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate (160ml), the organic phase...

Embodiment 2

[0029] Example 2 (1S, 3R, 4S)-6-benzyloxy-9-[[2-methylene-4-benzyloxy-3-(benzyloxy)methyl]-cyclopentyl]-N - Preparation of [(4-methoxyphenyl)benzhydryl]-9H-purin-2-amine (formula II, R=4-methoxytrityl)

[0030]

[0031] Formula II

[0032] Wherein, MMT represents 4-methoxytrityl, and Bn represents benzyl.

[0033] Under nitrogen atmosphere, magnesium (8.14g, 334.8mmol) and dichloromethane (184ml, 2872mmmol) were added to the three-necked flask, cooled to 0°C, and titanium tetrachloride (18.4ml, 167.4mmol) was added with stirring. (2R, 3S, 5S)-3-benzyloxy-5-[6-benzyloxy-2-[[[(4-methoxyphenyl)diphenylmethyl]amino]-9H-purine -9-yl]-2-[(benzyloxy)methyl]-cyclopentanone (prepared in Example 1) (38.4g, 46.8mmol) in dichloromethane (184ml, 2872mmol) and tetrahydrofuran (154ml, 1900mmol) ) was added dropwise into the reaction solution, the rate of addition was controlled so that the internal temperature was not higher than 5°C, and the mixture was stirred at 0°C for 20 minutes a...

Embodiment 3

[0035] Example 3 Preparation of Entecavir

[0036]

[0037] Formula II (R=4-methoxytrityl) Formula I

[0038] Add the compound of formula II (R=4-methoxytrityl)(1S,3R,4S)-N-[(4-methoxyphenyl)benzhydryl to a 1L three-necked flask under nitrogen protection ]-6-benzyloxy-9-[2-methylene-4-benzyloxy-3-(benzyloxy)methyl]cyclopentyl]-9H-purin-2-amine (from Example 2 Prepared) (15.58g, 0.019mol) and dichloromethane (450ml), stirred and dissolved, cooled the reaction solution to -75~-80°C, added dropwise 1mol / l boron trichloride dichloromethane solution (228ml, 0.228 mol), gradually warm up to -25~-30°C and stir for 1 hour after dropping.

[0039]The reaction solution was cooled to -60~-65°C, methanol (300ml, 7.406mol) and water (30.8ml, 1.710mol) were added dropwise, the temperature was gradually raised while stirring, and dichloromethane was distilled off under reduced pressure. The temperature of the reaction solution was raised to 55-60°C and stirred for 1 hour. After distil...

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Abstract

The invention provides an improved method for preparing an antiviral medicine, i.e., entecavir. The method comprises the following steps of: taking a compound in a formula II shown as the specification as a raw material and carrying out further reaction under the action of a boron chloride dichloromethane solution, methyl alcohol and water to obtain entecavir. A formula II is shown as the specification; R in the formula II and I is used for representing 4-methoxyl triphenylmethyl or triphenylmethyl, and the Bn is used for representing benzyl. The method has the advantages of simpleness and convenience for operation, good repeatability, high yield, suitability for industrial production and higher application value.

Description

technical field [0001] The invention relates to a method for preparing medicine. In particular, it relates to an improved method for preparing antiviral drug entecavir. Background technique [0002] Entecavir chemical name: 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro- 6H-Purin-6-one monohydrate. The structural formula is: [0003] [0004] Formula I [0005] Molecular formula is C 12 h 15 N 5 o 3 ·H 2 O with a molecular weight of 295.3 [0006] Entecavir is a cyclopentanoyl guanosine analogue, which is the first-line drug against hepatitis B virus. It has a strong effect of inhibiting the replication of hepatitis B virus and reducing the level of serum viral DNA, and its antiviral effect is better than that of lamivudine. The curative effect is significant when the virus replication is active in hepatitis B patients, the serum transaminase ALT continues to rise, or the liver histology shows active lesions. Entecavir was f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
Inventor 张磊杨守宁谭宙宏
Owner SHANGHAI QINGSONG PHARMA
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