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Preparation method of peramivir key intermediate

An intermediate and key technology, applied in the direction of organic chemistry, can solve the problems of low production yield, many steps, consumption, etc.

Pending Publication Date: 2022-08-02
重庆恩联生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chemical reaction formula is as follows: (reaction formula 1.) steps are many, and operating procedure is many, and yield is low
The main reason is that the refining and purification of compound Ⅲ consumes too much
Lead to the low total yield of peramivir finished product production in the existing process, increasing production costs

Method used

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  • Preparation method of peramivir key intermediate
  • Preparation method of peramivir key intermediate
  • Preparation method of peramivir key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Step 1: get 90g (0.43mol) of (1S,4R)-(-)-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl Ester, 600g toluene and 130g (1.28mol) triethylamine were added to the reaction flask, mixed and heated to 60-70°C to obtain a mixed solution, and the previously prepared 2-ethyl-N-hydroxybutanimine was added to the mixed solution. The toluene solution of the acid chloride was subjected to cyclization reaction. After 3 hours, the temperature of the mixed solution in the reaction flask was cooled to room temperature and 200 g of water was added. The organic layer is removed;

[0068] Step 2: add 400g of n-heptane to the product after the cyclization reaction described in step 1 and keep stirring at a temperature of 60-70 ° C until it is dissolved, add 4.5g of activated carbon to the product after the dissolution and decolorize for 0.5h, after the decolorization The product was filtered for the first time, cooled to 0-5 °C for stirring, filtered for the ...

Embodiment 2

[0071] Step 1: get 30g (0.14mol) of (1S,4R)-(-)-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl Ester, 200g of toluene and 43.3g (0.43mol) of triethylamine were added to the reaction flask, mixed and heated to 60-70°C to obtain a mixed solution, and into the mixed solution was added the 2-ethyl-N-hydroxybutanimine prepared above. The toluene solution of the acid chloride was subjected to cyclization reaction. After 3 hours, the temperature of the mixed solution in the reaction flask was cooled to room temperature and 70 g of water was added. The organic layer is removed;

[0072] Step 2: add 140g of n-heptane to the product after the cyclization reaction described in step 1 and keep stirring at a temperature of 60-70 ° C until it is dissolved, add 1.5g of activated carbon to the product after the dissolution and decolorize for 0.5h, after decolorization The product was filtered for the first time, cooled to 0-5 °C for stirring, filtered for the s...

Embodiment 3

[0075] Step 1: get 30g (0.14mol) of (1S,4R)-(-)-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl Ester, 200g of toluene and 43.3g (0.43mol) of triethylamine were added to the reaction flask, mixed and heated to 60-70°C to obtain a mixed solution, and into the mixed solution was added the 2-ethyl-N-hydroxybutanimine prepared above. The toluene solution of the acid chloride was subjected to cyclization reaction. After 3 hours, the temperature of the mixed solution in the reaction flask was cooled to room temperature and 70 g of water was added. The organic layer is removed;

[0076] Step 2: add 140g of n-heptane to the product after the cyclization reaction described in step 1 and keep stirring at a temperature of 60-70 ° C until it is dissolved, add 1.5g of activated carbon to the product after the dissolution and decolorize for 0.5h, after decolorization The product was filtered for the first time, cooled to 0-5 °C for stirring, filtered for the s...

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Abstract

The invention discloses a preparation method of a key intermediate (3aR, 4R, 6S, 6As)-4-[[(1, 2, 3, 4-triazole-3-yl)-1, 3, 4-triazole-3-yl]-1, 3, 4-triazole-3- The invention relates to a synthesis method of (1S, 4R)-(-)-[[(1, 1-dimethyl ethyoxyl) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5, 6, 6a-tetrahydro-4H-cyclopenta [d] isoxazole-6-carboxylic acid methyl ester, which comprises the following steps: taking (1S, 4R)-(-)-[[(1, 1-dimethyl ethyoxyl) carbonyl] amino] cyclopent-2-ene-1-carboxylic acid methyl ester as an initial raw material; the preparation method comprises the following steps: under the catalysis of triethylamine, carrying out cyclization reaction on (3aR, 4R, 6S, 6As)-4-[[(1, 2, 4-triazine-2-yl)-1, 3-diketone]-1, 3-diketone and a toluene solution containing 2-ethyl-N-hydroxybutyrimidyl chloride, and directly obtaining (3aR, 4R, 6S, 6As)-4-[[(1, 2, 4-triazine-2-yl)-1, 3-diketone]-1, 3-diketone through solvent treatment, impurity removal and Compared with the prior art, the preparation method disclosed by the invention has the advantages that the yield is high, the operation is safe and simple, the purity of a finished product is high, and industrial large-scale production is convenient to realize. The preparation method disclosed by the invention has the advantages that the preparation method disclosed by the invention can be used for preparing the 3-(1, 1-dimethyl ethyoxyl) carbonyl] amino]-3-(1 '-ethyl propyl)-3a, 5, 6, 6a-tetrahydro-4H-cyclopenta [d] isoxazole-6-carboxylic acid methyl ester.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a key intermediate for preparing peramivir (3aR, 4R, 6S, 6As)-4-[[(1,1-dimethylethoxy)carbonyl]amino] - The preparation method of methyl 3-(1'-ethylpropyl)-3a,5,6,6a-tetrahydro-4H-cyclopentano[d]isoxazole-6-carboxylate. Background technique [0002] Peramivir is a cyclopentane-derivative neuraminidase inhibitor developed by American Biocrystal Pharmaceuticals Co., Ltd. It was successfully developed after zanamivir and oseltamivir and was launched in 1999. Another new type of anti-influenza virus drug after that is used for the treatment and prevention of influenza A and B in adults and children. [0003] The chemical name of peramivir is (1S,2S,3R,4R,1'S)-(-)-3-[(1'-acetylamino-2'-ethyl)butyl]-4-[[(aminoidene Amino) methyl] amino]-2-hydroxycyclopentane-1-carboxylic acid trihydrate, the chemical structural formula is as follows: [0004] [0005] The product inj...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20
CPCC07D261/20C07B2200/07
Inventor 陈顺祥付飞杨杰彭启灯
Owner 重庆恩联生物科技有限公司
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