Synthetic method of peramivir intermediate

A synthesis method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of low yield, increase production cost, low total yield of peramivir finished product production, etc., and achieve lower production cost, simple processing, and improved reaction. Yield effect

Inactive Publication Date: 2015-12-30
GUANGZHOU NANXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO2012145932A1 also describes a similar reaction with a high yield, but the product needs to be subjected to column chromatography, which is not suitable for industrial scale production
Due to the low yield of this step, the total yield of peramivir finished product production in the existing process is low, which increases the production cost

Method used

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  • Synthetic method of peramivir intermediate
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  • Synthetic method of peramivir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 34.5 g (496 mmol) of hydroxylamine hydrochloride, 33.0 g of water, and 105.0 g of toluene were mixed, and 47.4 g (473 mmol) of 2-ethylbutyraldehyde was added with stirring. At 10 to 25°C, 79.4 g of a 30% sodium hydroxide solution (containing 23.8 g of sodium hydroxide) was added over 1 hour. After addition, continue to stir for 1.5h. Leave to stand for stratification, take the upper toluene layer, and use it directly for the next step. Will N - 63.2 g (473 mmol) of chlorosuccinimide (NCS) were suspended in 75 g of dimethylformamide, and cooled to 0-10°C. The toluene solution of the above oxime was added in 2.5 hours, and the reaction temperature did not exceed 25°C during the dropwise addition. After the addition was complete, stirring was continued for 1.5 hours. After completion of the reaction, 83 g of water was added, stirred for 30 minutes, and the reaction temperature was controlled not to exceed 30°C. The layers were allowed to stand, the aqueous...

Embodiment 2

[0030] Example 2 Will (1 S ,4 R )-(-)-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl ester (compound I) 38.0g (157mmol), toluene 78g, 48g of triethylamine was mixed and heated to 50°C-55°C to dissolve. Then add PdCl 2 (PPh 3 ) 2 2.2 g (3.14 mmol), CuI 1.2 (6.28 mmol) g. To this solution, 120 g of a toluene solution containing 70.8 g (473 mmol) of 2-ethyl-N-hydroxybutyrimide chloride (compound II) was added dropwise. After the addition was complete, the reaction mixture was stirred at 60-65°C for about 9 hours. Add 80 g of water to the reaction solution to dissolve the solid, let stand to separate the toluene layer, and wash the toluene layer with water for 3 times. Then, the toluene layer was concentrated to remove 45 g of toluene. Add 63 g of 15% sodium hydroxide solution (containing 9.6 g of sodium hydroxide) to the concentrated toluene layer, and stir at room temperature for 10 hours. The toluene layer was washed with 15 g of water....

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Abstract

The invention relates to a synthetic method of a peramivir intermediate, in particular to a synthetic method of a key intermediate by adopting an anti-influenza drug, namely peramivir, wherein the key intermediate is (3aR,4R,6S,6aS)-4-[[(1,1-dimethyl ethoxy) carbonyl] amino]-3-(1'-ethyl propyl)-3a,5,6,6a-tetralin-tetrahydro-4H-cyclopentano[d]isoxazole-6-carboxylic acid ammonium tertiary butyl (compound IV). According to the synthetic method of peramivir intermediate, provided by the invention, (1S,4R)-(-)-[[(1,1-dimethyl ethoxy)carbonyl]amino]cyclopentyl-2-alkenyl-1- carboxylic acid methyl ester (compound I) is taken as the raw material (preparation reference patent is CN101367750B) to be subjected to ring-closure reaction with butyric imine acyl chloride under catalyzation of a metal catalyst, so that the target compound is formed. According to the synthetic method of peramivir intermediate, provided by the invention, the low-cost, easily available and efficient metal catalyst is used, in addition, compared with the conventional technological process, the synthetic method is obviously increased in the yield, the technological process is simple, and industrial large-scale production is facilitated.

Description

technical field [0001] The present invention relates to a kind of preparation peramivir key intermediate (3a R, 4 R, 6 S, 6a S )-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta A new method of tert-butylammonium alkano[d]isoxazole-6-carboxylate (compound IV, see the figure below), which belongs to the field of drug synthesis. [0002] Background technique [0003] Peramivir, English name Peramivir, chemical name (1S,2S,3S,4R)-3-[(1S)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2- Hydroxy-cyclopentyl-1-carboxylic acid. The drug is a cyclopentanol derivative-like neuroacidase inhibitor developed by Biocryst Pharmaceutical Company of the United States, which can effectively inhibit the replication of various influenza viruses, has the advantages of good tolerance, low toxicity, and can be injected. It is a promising broad-spectrum anti-influenza drug. In China, Li Song of the Chinese Academy of Military Pharmaceutical Scien...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20
CPCC07D261/20
Inventor 林寨伟罗军奇朱建平
Owner GUANGZHOU NANXIN PHARMA
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