Method for preparing zanamivir intermediate serving as compound resisting highly pathogenic avian influenza

A technology of zanamivir and high pathogenicity, which is applied in the field of preparation of Zanamivir intermediates against highly pathogenic avian influenza compound, can solve the problems such as difficult control of the reaction, and achieve separation and purification, easy Amplified production, specific effect

Inactive Publication Date: 2010-05-12
NANJING SIMCERE DONGYUAN PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It solves the problem that the reaction is not easy to control and improves the post-reaction treatment, which is conducive to the classification and purification of products and facilitates the operation

Method used

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  • Method for preparing zanamivir intermediate serving as compound resisting highly pathogenic avian influenza
  • Method for preparing zanamivir intermediate serving as compound resisting highly pathogenic avian influenza
  • Method for preparing zanamivir intermediate serving as compound resisting highly pathogenic avian influenza

Examples

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Effect test

Embodiment 1

[0025] Embodiment 1: An anti-highly pathogenic avian influenza compound zanamivir intermediate (5-acetylamino-3,5-dideoxy-D-glycerol base-D-galactose-2-enoic acid Synthesis of methyl ester) (intermediate I)

[0026]

[0027] 20g of acetyl chloride was added to 1980g of methanol, stirred and reacted for 30 minutes to obtain a methanolic hydrogen chloride solution.

[0028] Add 300g of sialic acid (compound 1, also known as N-acetylneuraminic acid, NANA) to the methanol solution of the above-mentioned acetyl chloride, stir and heat to 40°C, after 3 hours of reaction, add 10g of sodium acetate, adjust the pH=6~ 7. Continue to stir for 10 minutes, stop the reaction, and distill under reduced pressure at a vacuum degree of -0.085--0.095MPa and a temperature of 30-70°C until it is basically dry. Recrystallize with 600g of ethyl acetate and 60g of water, then filter and dry in vacuum with a vacuum degree of -0.065--0.095MPa and a drying temperature of 30-70°C to obtain 265g of in...

Embodiment 2

[0029] Embodiment 2: An anti-highly pathogenic avian influenza compound zanamivir intermediate (5-acetylamino-3,5-dideoxy-D-glycerol base-D-galactose-2-enoic acid Synthesis of methyl ester) (intermediate I)

[0030] 132g of acetyl chloride was added to 39600g of methanol, stirred and reacted for 30 minutes to obtain a methanolic hydrogen chloride solution.

[0031] 2000.0g of sialic acid (compound 1, also known as N-acetylneuraminic acid, NANA) was added to the methanol solution of acetyl chloride, stirred and heated to 45°C, after 4 hours of reaction, 66.7g of sodium acetate was added to adjust the pH= 6-7, continue to stir for 10 minutes, stop the reaction, and distill to dryness under reduced pressure at a vacuum degree of -0.085--0.095MPa and a temperature of 30-70°C. Recrystallize with 20,000 g of ethyl acetate and 400 g of water, then filter and dry in vacuum with a vacuum degree of -0.065-0.095 MPa and a drying temperature of 30-70°C to obtain 1948.0 g of Intermediate ...

Embodiment 3

[0032] Embodiment 3: An anti-highly pathogenic avian influenza compound zanamivir intermediate (5-acetylamino-3,5-dideoxy-D-glycerol base-D-galactose-2-enoic acid Synthesis of methyl ester) (intermediate I)

[0033] 132g of acetyl chloride was added to 132000g of methanol, stirred and reacted for 30 minutes to obtain a methanolic hydrogen chloride solution.

[0034] Add 2000.0g of sialic acid (Compound 1, also known as N-acetylneuraminic acid, NANA) to the above-mentioned methanol solution of acetyl chloride, stir and heat to 55°C, after reacting for 6 hours, add 66.7g of sodium acetate to adjust the pH= 6-7, continue to stir for 10 minutes, stop the reaction, and distill to dryness under reduced pressure at a vacuum degree of -0.085--0.095MPa and a temperature of 30-70°C. Recrystallize with 20000g of ethyl acetate and 400g of water, then filter and dry in vacuum with a vacuum degree of -0.065-0.095MPa and a drying temperature of 30-70°C to obtain 1938.0g of intermediate I. ...

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Abstract

The invention relates to a method for preparing zanamivir intermediate serving as compound resisting highly pathogenic avian influenza (5-acetylamino-3,5-didehydro-D-glycerol-D-galactose-2-enol methyl palmitate). The method comprises: obtaining hydrogen chloride solution of methanol through the reaction of acyl chloride and methanol, wherein the weight ratio of the acyl chloride to the methanol is 1:100-1,000; adding sialic acid to the hydrogen chloride solution of methanol, stirring, heating, performing reaction at the temperature between 20 and 60 DEG C for 2 to 8 hours, adding 0.1 equivalent (mol) of sodium acetate, adjusting pH between 6 and 7, continuing to stir for 10 minutes and stopping reaction, wherein the weight ratio of the sialic acid to the hydrogen chloride solution of methanol is 1:2-20, and reaction temperature is 20 to 60 DEG C; performing concentration under reduced pressure, performing distillation under reduced pressure till drying the obtained product and using water and ethyl acetate for recrystallization, wherein the weight ratio of the water to the ethyl acetate is 1:10-100; and filtering, drying under vacuum and obtaining the zanamivir intermediate serving as compound resisting highly pathogenic avian influenza.

Description

technical field [0001] The invention relates to an anti-highly pathogenic avian influenza compound zanamivir intermediate (5-acetylamino-3,5-dideoxy-D-glycerol-D-galactose-2-enoic acid methyl Ester) preparation method, choose to use sialic acid through acid catalyzed esterification, concentration, crystallization to obtain zanamivir intermediate. The intermediate I can be obtained according to the disclosed method to obtain the anti-highly pathogenic avian influenza compound zanamivir. The method has the characteristics of convenient operation, easy control, and easy scale-up and industrialization. Background technique [0002] Compound I, zanamivir, Chinese name zanamivir, chemical name 5-acetylamino-4-guanidino-2,6-dihydro-3,4,5-trideoxy-D-glycerol-D -Galactose-2-nonenoic acid, developed by Australia Biota Company, and listed in Australia, the United States and the United Kingdom by GSK Company in 1999, with the trade name Relenza, is used for the prevention and treatmen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H7/02C07H1/00
Inventor 葛宗明彭素琴梁西周骆宏鹏罗丰茂沈超
Owner NANJING SIMCERE DONGYUAN PHARM CO LTD
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