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Preparation method of antiviral drug Entecavir

An antiviral drug, Entecavir technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of distance from reaction conditions, difficulty in separation and purification, unstable yield, etc., and achieve low cost, wide source of raw materials, and product purification method simple effect

Active Publication Date: 2012-04-18
HAINAN PULIN PHARMA +1
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0005] The structure of entecavir contains a chiral carbocycle and guanine core, which is a biologically active carbocyclic nucleoside analogue. In the synthetic methods of the prior art, complex reactions, unstable yields, and distances from reaction conditions generally exist. , separation and purification difficulties, etc.

Method used

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  • Preparation method of antiviral drug Entecavir
  • Preparation method of antiviral drug Entecavir
  • Preparation method of antiviral drug Entecavir

Examples

Experimental program
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Embodiment 1

[0045] (1), preparation compound I:

[0046] Feeding:

[0047]

[0048] Reaction formula:

[0049]

[0050] D-Glucose Compound-I

[0051] reaction process:

[0052] Anhydrous glucose (257g) was stirred and suspended in 5000ml of acetone, and the temperature of the system was cooled to below 5°C in an ice bath, and the concentrated H 2 SO 4 (205.6ml) was placed in the dropping funnel, added dropwise to the stirring system, and the temperature was controlled below 10°C. After the concentrated sulfuric acid was added, the temperature was naturally raised to room temperature and reacted overnight. Cool the system below 5°C with an ice bath, and neutralize it by adding 33.3% NaOH dropwise. The reaction solution was filtered, the filtrate was concentrated by rotary evaporation, and after cooling, the 2 Cl 2 Extraction, H 2 O washes the organic phase, anhydrous Na 2 SO 4 Drying, rotary evaporation, and recrystallization from ethyl acetate and petroleum ether gave com...

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Abstract

The invention relates to a preparation method of an antiviral drug Entecavir. Taking D-glucose and acetone as starting materials, the method has advantages of easy operation, high yield, easy separation and purification, wide source of raw materials and low cost. The selectivity and stereospecificity are controlled at the beginning of a reaction to effectively inhibit the production of chiral isomer. The purification method of product is simple with high yield. A key intermediate of the reaction is 4- methylol-5- methylene cyclopentane-1,3-diol, of which 4- methylol is selectively protected by trityl chloride, and the intermediate combines with 2-amino-6-chloropurine by mitsunobu. Because of the steric hinderance effect, the protecting group can effectively protect target group and the operation is easy to carry out while removing the protecting group.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of an antiviral drug, in particular to a preparation method of an antiviral drug entecavir. Background technique [0002] Entecavir is a guanosine analog with the chemical name 2-amino-9-[(1s,3s,4s)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl ]-1,9-dihydro-6H-purin-6-one monohydrate, the molecular structure is as follows: [0003] [0004] Molecular formula C12H15N5O3 H2O, molecular weight 295.3. US Patent No. 5,206,244 discloses entecavir, its preparation and its use in the treatment of hepatitis B. Studies have shown that entecavir can selectively inhibit HBV DNA polymerase and prevent all three stages of viral replication. Clinical trials have shown that Entecavir has excellent anti-HBV activity, is not prone to clinical drug resistance, and is still effective against Adefovir and Lamivudine treatment failures. [0005] The structure ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 范敏华毛建丰司秉坤冯静
Owner HAINAN PULIN PHARMA
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