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Preparation method of zanamivir

A zanamivir and compound technology, applied in the field of preparation of antiviral drug zanamivir, can solve problems affecting application, etc., and achieve the effects of simplifying operation, reducing cost, and convenient operation

Inactive Publication Date: 2012-05-23
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Above-mentioned method all will use resin, has influenced the application of these methods in industry

Method used

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  • Preparation method of zanamivir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 (4S, 5R, 6R)-5-acetylamino-4-guanidino-6-((1R, 2R)-1,2,3-trihydroxy-propyl)-5,6-dihydro- Preparation of 4H-pyran-2-carboxylic acid methyl ester

[0040]

[0041] 45.6 g of (4S, 5R, 6R)-5-acetylamino-4-amino-6-((1R, 2R)-1,2,3-trihydroxy-propyl)-5,6-dihydro- Methyl 4H-pyran-2-carboxylate was dissolved in 500 mL of methanol, and then 108 g of triethylenediamine and 44 g of 1-formamidine pyrazole hydrochloride were added to the above reaction solution. Reacted at 50°C for 26h, and the resulting methanol solution was concentrated to dryness and used directly for the next reaction.

Embodiment 2

[0042] Example 2 Preparation of Zanamivir

[0043]

[0044] 300 mL of water was added to the solid prepared in Example 1, stirred to dissolve, then 120 mL of triethylamine was added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, it was concentrated to dryness. Then add water to dissolve at 50°C, add 900mL of methanol to cool down and slowly precipitate solid. Stir overnight, filter to obtain 36g zanamivir crude product, recrystallize 2 times with isopropanol-water (1: 1), dry under reduced pressure at 30 ℃, obtain white solid zanamivir (27.9g, total yield 56%) , purity>96%).

Embodiment 3

[0045] Example 3 (4S, 5R, 6R)-5-acetylamino-4-guanidino-6-((1R, 2R)-1,2,3-trihydroxy-propyl)-5,6-dihydro- Preparation of 4H-pyran-2-carboxylic acid methyl ester

[0046]

[0047] 4.56 g of (4S, 5R, 6R)-5-acetylamino-4-amino-6-((1R, 2R)-1,2,3-trihydroxy-propyl)-5,6-dihydro- Methyl 4H-pyran-2-carboxylate was dissolved in 50 mL of methanol, and then 10.8 g of triethylenediamine and 4.4 g of 1-formamidine pyrazole hydrochloride were added to the above reaction solution. Reaction at 50°C for 26h. The resulting methanol solution was concentrated to dryness, and subjected to column chromatography with 200-300 mesh silica gel, gradient elution, eluting with methanol:dichloromethane=1:5-1:3 to obtain 4.67 g of the title compound , yield 90%.

[0048] ESIMS m / z calcd for C 13 h 22 N 4 o 7 ;[M+H] + :347.15, found: 347.2;

[0049] 1 H-NMR (500MHz, DMSO-d 6 ): δ7.87 (1H, d, J = 9Hz, NH), 5.71 (1H, d, J = 2.5Hz, 3-H), 4.71 (1H, d, J = 4Hz, OH), 4.67-4.65 ( 2H, m, OH, 4-H), 4....

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Abstract

The invention relates to a preparation method of an antiviral drug zanamivir, which comprises the following steps: amino in an intermediate neuraminic acid methyl ester derivative is conversed to guanidine, then ester group is subjected to hydrolyzation, so that zanamivir is prepared. Compared with current synthesis technology of zanamivir, the method of the invention has the advantages that the usage of resin can be avoided, the cost is reduced, no separation or purification is required after each step of the reaction, the next step reaction can be directly carried out, the loss of the intermediate during the purifying process can be avoided, the yield is high, the operation is convenient, and the preparation method of the zanamivir is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular the invention relates to a preparation method of an antiviral drug zanamivir. Background technique [0002] Zanamivir (zanamivir) is a kind of influenza virus sialic acid inhibitor developed by Australia Biota Company, which can be used for the prevention and treatment of A and B influenza, and is currently one of the effective candidate drugs for the treatment of highly pathogenic avian influenza . Its chemical name is (4S,5R,6R)-5-acetylamino-4-guanidino-6-((1R,2R)-1,2,3-trihydroxy-propyl)-5,6-di Hydrogen-4H-pyran-2-carboxylic acid, having the structure of formula I. It was launched in Australia, the United States and the United Kingdom in 1999 under the product name Relenza. [0003] [0004] Formula I [0005] In order to simplify the operation steps and reduce the synthesis cost, people have carried out in-depth research on the preparation method of zanamivir. Most of the cu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/28
Inventor 朱益忠张喜全顾红梅刘飞
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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