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Preparation method of zanamivir intermediate and preparation method of zanamivir

A technology of zanamivir and body acetyl, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high price, high price, and difficult industrialization of silicon trimethyl azide, and achieve the goal of being suitable for large-scale industrialization Production, reduction of production cost, and the effect of shortening the synthesis steps

Active Publication Date: 2017-05-10
湖北浩信药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method is not easy for industrialization, because azide is used in the process from cyclic compound (III) to (II), trimethyl silicon azide is expensive, which increases the production cost, and azide The explosion hazard of intermediates and intermediates has brought great danger to large-scale industrial production
In addition, according to the calculation of sialic acid in this patent, the total mass yield is only less than 20%, and the yield is very low
[0010] CN101704851A relates to an anti-highly pathogenic avian influenza compound zanamivir intermediate (5-acetylamino-3,5-dideoxy-D-glycerol-D-galactose-2-enolate methyl ester ) preparation method, but only optimized the methyl ester protection step of sialic acid (V), but no substantial progress on the basis of patent ZL96107757.3
This method does not conform to atomic economics because the price of imidylpyrazole is expensive, and the amount of imidylpyrazole must be more than that of the latter, so the cost of this method will inevitably increase. raised

Method used

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  • Preparation method of zanamivir intermediate and preparation method of zanamivir
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  • Preparation method of zanamivir intermediate and preparation method of zanamivir

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Synthesis of acetylated protected amino compounds (formula II)

[0094] To 120 g of cyclic compound (formula III), add 1200 g of anhydrous tetrahydrofuran, and slowly add 20 g of potassium amide. Stir, heat, and react at the reflux temperature of tetrahydrofuran for 7 hours. 80 g of water was added to quench the reaction. Concentrate, add ethyl acetate to dissolve, wash with 300g water three times each time, concentrate ethyl acetate to dryness. Recrystallize with 550g of isopropanol, filter and dry to obtain 123g of acetylated amino compound (Formula II). Yield: 93.1%.

Embodiment 2

[0096] (1) Synthetic sialic acid (formula IV) with protective group

[0097]Sialic acid (formula V) 100g, methanol 1000g, strong acid ion exchange resin 5g; stirring at room temperature for 12 hours, the reaction solution was a dissolved and clear solution. As detected by HPLC, the normalized content of sialic acid was 1.2%. After filtration, the filtrate was concentrated in methanol to dryness to obtain methyl sialic acid.

[0098] 1000 g of pyridine and 3 g of p-dimethylaminopyridine (DMAP) were added, and 250 g of acetic anhydride was added under ice-water cooling. Stir at room temperature for 15 hours. As detected by HPLC, the normalized content of methyl sialic acid was 0.3%. Pyridine was concentrated to dryness. Dissolve with 1000g ethyl acetate, wash with 300g water three times each time, and concentrate ethyl acetate to dryness. 169 g of sialic acid (formula IV) with protective groups was obtained. Yield: 97.9%.

[0099] (2) Synthetic ring compound (formula III)...

Embodiment 3

[0109] (1) Synthetic sialic acid (formula IV) with protective group

[0110] In a 30L glass reactor, add 2 kg of sialic acid (formula V), 20 kg of methanol, and 100 g of strong acid ion exchange resin; stir at room temperature for 10 hours, and the reaction solution becomes a dissolved and clear solution. HPLC detection, sialic acid normalization method content is 1.0%. After filtration, the filtrate was transferred to a 30L glass reactor, and the methanol was concentrated to dryness to obtain methyl sialic acid.

[0111] Add 20kg of pyridine, 80g of p-dimethylaminopyridine (DMAP), and add 5kg of acetic anhydride under ice-water cooling. Stir at room temperature for 15 hours. As detected by HPLC, the normalized content of methyl sialic acid was 0.3%. Pyridine was concentrated to dryness. Add 20kg of ethyl acetate to dissolve, wash with 6L of water three times each time, and concentrate the ethyl acetate to dryness. 3.4 kg of sialic acid (formula IV) with protective groups...

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Abstract

The invention relates to a preparation method of a zanamivir intermediate, namely an acetylation protected amino compound, and a preparation method of zanamivir. The preparation method of the zanamivir, provided by the invention, comprises the following steps: performing cyclization by taking sialic acid as a raw material and through group protection to produce a cyclization substance, treating the cyclization substance by a metal amino substance at one step to obtain the acetylation protected amino compound, and removing a hydroxyl protective agent acetic acid ester and removing guanidyl from imipyrozole reaction to obtain the zanamivir, wherein the process of treating the cyclization substance by the metal amino substance at one step to obtain the acetylation protected amino compound is great substantial breakthrough in preparation of the zanamivir, the synthesis steps are greatly shortened and the process operation is simplified. Ring opening is conducted by the cheap metal amino substance instead of expensive trimethylsilyl azid, so that the cost is reduced and the safety of the production process is guaranteed. According to thepreparation method of the zanamivir, provided by the invention, the total mass yield can reach 50 percent or above and is greatly increased as compared with that in the prior art.

Description

technical field [0001] The invention relates to a new preparation method of a zanamivir intermediate, and also relates to a preparation method of zanamivir, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Zanamivir (Zanamivir) is the first class of neuraminidase inhibitors synthesized based on drug design, and it and Osel tamivir (Osel tamivir) are two of the few currently on the market approved for the treatment of Drugs for type and B influenza viruses. [0003] Zanamivir was discovered by scientists from Biota, Australia in 1989, and was authorized to GlaxoSmithKline for clinical treatment in 1990. In 1999, it was approved by the FDA and launched in the United States. The product name of the inhalant sold in China is Leganqing. [0004] Zanamivir, chemical name (4S,5R,6R)-5-acetylamino-4-guanidino-6-((1R,2R)-1,2,3-trihydroxy-propyl)-5,6 -Dihydro-4H-pyran-2-carboxylic acid, the chemical structural formula is as follo...

Claims

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Application Information

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IPC IPC(8): C07D309/28C07D498/04
CPCY02P20/55C07D309/28C07D498/04
Inventor 金鹏潘亚金王贡献
Owner 湖北浩信药业有限公司
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