Preparation process of entecavir

A technology of entecavir and compounds, which is applied in the field of drug preparation, can solve the problems of harsh reaction conditions, high price, and high cost, and achieve the effects of high reaction efficiency, low price, and easy operation

Active Publication Date: 2006-11-15
SHANGHAI QINGSONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this preparation method has some defects: 1. expensive chiral boron reagents should be used as starting materials; 2. highly toxic raw material boron trichloride should be used fo...

Method used

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  • Preparation process of entecavir
  • Preparation process of entecavir
  • Preparation process of entecavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 (1S, 2R, 3R, 4S)-2-amino-6-benzyloxy-9-[4-benzyloxy-3-benzyloxymethyl-2-(2,2-dimethyl- [1,3]dioxolane)-cyclopentyl]-9H-purine (Formula IV)

[0028] (1R, 2R, 3R, 4S)-3-benzyloxymethyl-2-[2-(1-methoxy-1-methyl-ethoxy)-ethyl]-4-benzyloxy- Cyclopentanol (formula II) (41.2g, 0.1mol) and triphenylphosphine (12.6g, 0.05mol) were dissolved in anhydrous tetrahydrofuran (500ml), cooled to 0°C, and 2-amino-6-benzyloxy Ethyl-9H-purine (Formula III) (29.0 g, 0.12 mol). Keeping at 0°C, a solution of diethyl diazodicarboxylate (20.9 g, 0.12 mol) in tetrahydrofuran (200 ml) was added dropwise. After the dropwise addition, the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness under reduced pressure to obtain formula IV (53 g), with a yield of 83%.

Embodiment 2

[0029] Example 2 (1S, 2R, 3R, 4S)-[5-(2-amino-6-benzyloxy-purine-9-generation-)-3-benzyloxy-2-benzyloxymethyl-cyclopentyl Base]-methanol (Formula V)

[0030] Concentrated hydrochloric acid (10 ml, 0.12 mol) was added dropwise to a solution of Formula IV (63.5 g, 0.1 mol) in methanol (500 ml), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Add methanol (500ml), cool to 0°C, add sodium periodate (25.7g, 0.12mol) in water (500ml), and stir at room temperature for 1 hour. Add sodium borohydride (7.6 g, 0.20 mol) and stir at room temperature for 1 hour. After filtration, the filtrate was concentrated, and then extracted with dichloromethane (300ml×3). The extracts were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to obtain formula V (44g), with a yield of 78%.

Embodiment 3

[0031] Example 3 (1S, 3R, 4S)-2-amino-6-benzyloxy-9-(4-benzyloxy-3-benzyloxymethyl-2-methylene-cyclopentyl)-9H- Purine (formula VI)

[0032] Add dichloromethane (500ml) to formula V (56.5g, 0.1mol), then add 4-dimethylaminopyridine (25g, 0.2mol), cool to 0°C, then add p-toluenesulfonyl chloride (23g, 0.12mol ), stirred at 0°C for 2 hours. Warm to room temperature and stir for 3 hours. Dichloromethane (500ml) was added for dilution, washed with water (500ml) and saturated sodium bicarbonate solution (500ml) respectively, and the organic layer was dried over anhydrous sodium sulfate. Filter and evaporate the filtrate to dryness. To the residue was added N,N-dimethylformamide (500ml).

[0033] 60% sodium hydride (12 g, 0.3 mol) was added to N,N-dimethylformamide (100 ml), then 2-methoxyethanol (40 ml, 0.5 mol) was added dropwise, and stirred for 1 hour. Cool to 0°C, slowly add the solution obtained above, and continue stirring at 0°C for 4 hours after the addition is complet...

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Abstract

A deoxy guanonucleoside analog able to effectively suppress the duplication of HBV, its structure formula, and its preparing process are disclosed.

Description

Technical field: [0001] The present invention relates to the preparation method of medicine. Specifically relates to a preparation method of entecavir. Background of the invention: [0002] Entecavir is a deoxyguanosine analog that can effectively inhibit the replication of hepatitis B virus. Its chemical name is: (1S, 3R, 4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-sub Methylcyclopentyl]-guanine, the structural formula is as follows formula I: [0003] [0004] Formula I [0005] A large number of clinical trials have shown that it has a direct inhibitory effect on reverse transcriptase and hepatitis B virus DNA polymerase in liver cells, and has strong antiviral ability. At the same time, the selectivity of the compound is relatively high. Its cytotoxicity is anti-hepatitis B virus 1 / 8000 of the activity, it can effectively treat chronic hepatitis B without interfering with influenza virus and HIV virus. And because of their different mechanisms of a...

Claims

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Application Information

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IPC IPC(8): C07D473/18
Inventor 张磊曾振亚杨琍苹郭理维
Owner SHANGHAI QINGSONG PHARMA
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