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A kind of synthetic method of peramivir trihydrate

A technology of peramivir trihydrate and a synthesis method, which is applied in the field of drug synthesis, can solve problems such as difficulty in material transfer, difficulty in post-processing, increase in processing cost, etc. rate increase effect

Active Publication Date: 2018-06-29
GUANGZHOU NANXIN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method has been greatly improved compared with the original research and previous methods, the process obtains the final product through more than ten steps of reaction, which not only has long steps and low yield (total yield is less than 15%), resulting in the production of peramivir High cost and high price of listed preparations
Moreover, NiCl 2 .6H 2 O / NaBH 4 As a reducing agent, the post-processing of the product is more difficult, such as the reduction time is relatively long, the solid-liquid separation time is long, the material is viscous, and the material transfer is difficult.
At the same time, due to the NiCl 2 .6H 2 O uses molar equivalents in the actual process, and the waste liquid must contain a large amount of heavy metal Ni ions, which increases the treatment cost and is not conducive to environmental protection.

Method used

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  • A kind of synthetic method of peramivir trihydrate
  • A kind of synthetic method of peramivir trihydrate
  • A kind of synthetic method of peramivir trihydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 (3a R, 4 R, 6 S, 6a S )-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta Synthesis of Alkano[d]isoxazole-6-carboxylic Acid (Compound II)

[0041] Add (3a R, 4 R, 6 S, 6a S )-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5,6,6a-tetrahydro-4H-cyclopenta Alkano[d]isoxazole-6-carboxylic acid 1,1-dimethylethylammonium (compound I) 39.0g (94.3mmol), potassium carbonate 0.66g, acetone 48g, stirred at room temperature; then added Sodium hydroxide 3.89g (97.2mmol) aqueous solution 13.0g, stirring; Then at 45-50 0 Acetone and tert-butylamine were evaporated under vacuum at C. 80 g of water was added to dissolve the residue, and acetic acid was added dropwise with stirring until the pH was about 7.0. Add 200 g of ethyl acetate and stir to separate the layers. The organic layer was washed with 80 g of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and cooled to room ...

Embodiment 2

[0042] Example 2 (1S,2S,3S,4R,1'S)-3-[(1-amino-2'-ethyl)butyl]-4-[[(1,1-dimethylethoxy)carbonyl Synthesis of ]amino]-2-hydroxycyclopentane-1-carboxylic acid (compound III)

[0043] 28.9g (84.9mmol) of compound II and 2.0g of 10%Pd-C were dissolved in 100mL of methanol under a nitrogen atmosphere and filled into a pressure reactor, and then 0.12mL of concentrated hydrochloric acid was added. After replacing the air in the kettle with nitrogen for 3 times, fill it with hydrogen until the pressure is 0.8Mpa. Heat the reaction mixture to 50-60 0 C stirred the reaction for 18h. The reaction liquid was cooled to room temperature, and the hydrogen in the kettle was removed. The reaction liquid was taken out from the kettle, and the solvent was distilled off. The residue was dissolved in 40 mL of methanol, purified by silica gel, and the solution was concentrated to obtain 24.8 g of solid product, namely compound III, with a yield of 89%. 1 H NMR (500 MHz, DMSO- d 6 ), 7.06–7.0...

Embodiment 3

[0044]Example 3 (1S,2S,3S,4R,1'S)-3-[(1-Acetamido-2'-ethyl)butyl]-4-[[(1,1-Dimethylethoxy) Synthesis of Carbonyl]Amino]-2-Hydroxycyclopentane-1-Carboxylic Acid (Compound IV)

[0045] Put (1S,2S,3S,4R,1'S)-3-[(1-amino-2'-ethyl)butyl]-4-[[(1,1-dimethylethoxy Base) carbonyl] amino] -2-hydroxycyclopentane-1-carboxylic acid (compound III) 24.8g (72.0mmoL), 16% sodium hydroxide solution 18mL (containing sodium hydroxide 2.9g, 72.0mmol), stirring Form a mix. Under stirring at room temperature, 7.3 g (72.0 mmol) of acetic anhydride and 9 mL of 32% sodium hydroxide solution (containing 2.9 g, 72.0 mmol) of sodium hydroxide were added dropwise to the mixture simultaneously. Control the reaction temperature not to exceed 30 0 C, and the pH value is around 10.0. Half an hour later, 7.3 g (72.0 mmol) of acetic anhydride and 9 mL of a 32% sodium hydroxide solution (containing 2.9 g, 72.0 mmol) of sodium hydroxide were added dropwise to the reaction solution simultaneously. After the a...

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Abstract

The invention relates to a synthesis method of peramivir trihydrate, an anti-influenza medicine. The present invention uses (3aR,4R,6S,6aS)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5, 6,6a-tetrahydro-4H-cyclopenta[d]isoxazole-6-carboxylic acid 1,1-dimethylethylammonium (compound I, prepared by referring to CN101367750B method) as raw material, through five steps Synthetic procedure Preparation of peramivir trihydrate. Compared with the methods reported in existing documents, the present invention designs a shorter, more effective and practical process route, and the total yield of finished product preparation is significantly improved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing peramivir trihydrate, an anti-common influenza and avian influenza virus drug. Background technique [0002] Peramivir trihydrate, English name is Peramivir trihydrate, chemical name is (1 S, 2 S, 3 R, 4 R,1'S ) -3-[(1'-acetylamino-2'-ethyl)butyl)]-4-[[(aminoimino)methyl]amino]-2-hydroxycyclopentane-1-carboxylic acid Trihydrate, whose structural formula is shown in the following formula, is a stable hydrate of the drug "Peramivir" originally developed by Biocryst Pharmaceuticals in the United States. Peramivir itself is a cyclopentane derivative neuraminidase inhibitor. The drug can effectively inhibit the replication and transmission process of various influenza virus strains, has the advantages of good tolerance, low toxicity, practical application for injection, etc., and is a promising anti-influenza drug. A team headed by researcher Li Song from ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C279/16C07C277/08
CPCY02P20/55
Inventor 林寨伟冯玉欢邓成斌朱建平
Owner GUANGZHOU NANXIN PHARMA
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