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Preparation method of peramivir

An intermediate, selected technology, applied in the field of preparation of antiviral drug peramivir, can solve the problems of long route, low total yield, complicated operation and the like

Inactive Publication Date: 2012-08-15
FUAN PHARM (GRP) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In order to solve the shortcomings in the existing key technology of preparing peramivir, such as long route, low total yield, cumbersome operation, and heavy environmental pollution of the reagents involved, the present invention has carried out key steps such as ring opening, cyclization, and reduction. Improvement, a new process for preparing peramivir is provided, and its process route is as follows:

Method used

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  • Preparation method of peramivir

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Embodiment 1: Preparation of L-tartaric acid (1S, 4R) 4-aminocyclopent-2-ene-1-acid methyl ester (intermediate 1)

[0047] (±)-2-Azabicyclo[2.2.1]hept-5-en-3-one (100.0g, 0.916mol) was dissolved in 150g methanol, the temperature was controlled at 60-70°C, and thionyl chloride ( 65.4g, 0.6 equivalents), after dropping, reflux for 30min, and cool the reaction solution to 20-25°C. Add 84g of L-tartaric acid and 65.0g of water in sequence, add 62.2g of triethylamine under temperature control at 35-40°C, stir for 10-15min, add a small amount of L-tartaric acid (1S, 4R) 4-aminocyclopent-2-ene-1 - Methyl carboxylate crystals as seeds. The mixture was cooled to 22-25°C and filtered. The solid was washed with cold methanol and dried under reduced pressure at 40°C under vacuum.

[0048] 122.5 g of the target compound was obtained with a yield of 91.8%, ee > 99.5% by HPLC; mp: 175.0-175.5°C; [α] D20°C=-41.8° (c=1g / dL, H2O).

Embodiment 2

[0049] Example 2: Preparation of (1S, 4R) 4-aminocyclopent-2-en-1-acid methyl ester (intermediate 2)

[0050] 110 g of methyl L-tartaric acid (1S,4R) 4-aminocyclopent-2-ene-1-carboxylate and 86.7 g of Boc anhydride were suspended in 143.0 g of methanol. Add 88.0 g of triethylamine at 30-35°C, and after adding half of the amount of amine, the reaction liquid is clear and starts to emit CO2 gas. After all the amine had been added, the solution was stirred for 2 h. Cool the solution to 5-10°C, keep the temperature of the reaction solution not exceeding 10°C, add 5.5g of 25% ammonia water and 420ml of water. A small amount of (1S,4R) methyl 4-[[1,1-dimethylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylate crystals were added as seed crystals to give a white precipitate. The mixture was stirred at 5-10°C for 2h, filtered, and the filtered solid was washed with water and dried under reduced pressure (35-40°C). The target compound was obtained 82.5g, 90.5%, mp51.3-52.0°C; [α]D20...

Embodiment 3

[0051] Embodiment 3: the preparation of 2-ethyl butyraldehyde oxime (intermediate 3)

[0052] Dissolve 52.0g of hydroxylamine hydrochloride in 400ml of water, then add 65.0g of potassium carbonate to it, stir at 20-25°C for 1 hour, and slowly add 2-ethylbutyraldehyde 65.0g dropwise under temperature control at 0-5°C g, 350ml of ethanol solution. After the dropwise addition, stir at 20-25°C for 1h. Concentrated under reduced pressure, the resulting oil was added with 325 g of dichloromethane, washed with water, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give 52.6 g of a colorless oil with a yield of 70.

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Abstract

The invention discloses a preparation method of an antiviral drug of peramivir, which is characterized in that 2-diazabicyclo [2.2.1] hept-5-en-3-one is used as an initial raw material for peramivir synthesis, and the overall yield is up to 35%. Compared with the prior art, the method has the advantages of high yield, fewer 'three wastes', safe and convenient operations, high purity of the obtained finished products, easy realization of industrial production, and the like.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of an antiviral drug peramivir. Background technique [0002] Peramivir (Peramivir), the chemical name is (1S, 2S, 3R, 4R)-3-[(1S)-1-(acetylamino)-2-ethyl-butyl]-4-guanidine and -2 -Hydroxycyclopentane-1-carboxylic acid trihydrate (as shown in structural formula 1), is a kind of cyclopentane neuraminidase inhibitor developed by American Biocrystal Company, and is the world's first intravenous route of influenza medicine. The drug can effectively inhibit the replication and spread of various influenza virus strains, and has the advantages of good tolerance and low toxicity. (Type B) treatment of influenza virus infection. [0003] [0004] At present, there are few reports on the synthesis process of peramivir. Patent CN1282316A discloses a technical scheme for preparing peramivir crude product (see route 1). The scheme is to use chiral 2-azab...

Claims

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Application Information

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IPC IPC(8): C07C279/16C07C277/08
Inventor 陈小勇李佩杰梁杰
Owner FUAN PHARM (GRP) CO LTD
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