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Preparation method of peramivir intermediate

An intermediate and amino technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as long solid-liquid separation time, difficult material transfer, and increased processing costs, achieving significant social and economic benefits, reduced production costs, and side effects The effect of less product content

Active Publication Date: 2022-03-15
ZENJI RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has been greatly improved compared with the previous method, but the post-treatment of this system is more difficult, the reduction time is longer, the solid-liquid separation time is longer, the material is more viscous, and the material transfer is difficult. In addition, due to the use of Nickel chloride hexahydrate is the equivalent, and there is a large amount of heavy metal Ni in the waste liquid, which increases the treatment cost and is not conducive to environmental protection.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1 (1.1eq nickel chloride hexahydrate)

[0024] Add 0.18g of sodium hydroxide, 6.41g of sodium borohydride, and 60mL of methanol into the beaker, and stir to dissolve.

[0025] Add 20.00 g of compound 1, 14.75 g of nickel chloride hexahydrate, 60 mL of dichloromethane, and 20 mL of methanol into the reaction flask, and cool down to -5°C. Keep the internal temperature at -5°C ~ 5°C and add the sodium borohydride and sodium hydroxide methanol solution prepared above dropwise, then react at -5°C ~ 5°C for 15 minutes, and stop the reaction when the compound disappears at 1 point as detected by TLC.

[0026] Add 19.79 g of ethylenediamine tetraacetic acid, 11.68 g of sodium nitrite, 20 mL of ammonia water, and 100 mL of water into a beaker, and stir to dissolve.

[0027] The above-mentioned prepared ethylenediaminetetraacetic acid, sodium nitrite, and aqueous ammonia solution were added to the reaction solution to quench the reaction, extracted with 200 mL of dich...

Embodiment 2

[0028] Embodiment 2 (0.05eq nickel chloride hexahydrate)

[0029] Add 0.17g of sodium hydroxide, 6.44g of sodium borohydride, and 60mL of methanol into the beaker, and stir to dissolve.

[0030] Add 20.00 g of compound 1, 0.67 g of nickel chloride hexahydrate, 60 mL of dichloromethane, and 20 mL of methanol into the reaction flask, and cool down to 20°C. Keep the internal temperature at -5°C ~ 5°C and add the sodium borohydride and sodium hydroxide methanol solution prepared above dropwise, then react at -5°C ~ 5°C for 15 minutes, and stop the reaction when the compound disappears at 1 point as detected by TLC.

[0031] Add 1.98g of ethylenediaminetetraacetic acid, 3.89g of sodium nitrite, 20mL of ammonia water, and 100mL of water into a beaker, and stir to dissolve.

[0032] The above-mentioned prepared ethylenediaminetetraacetic acid, sodium nitrite, and aqueous ammonia solution were added to the reaction solution to quench the reaction, extracted with 200 mL of dichloromet...

Embodiment 3

[0033] Embodiment 3 (0.2eq nickel chloride hexahydrate)

[0034] Add 0.17g of sodium hydroxide, 6.47g of sodium borohydride, and 60mL of methanol into the beaker, and stir to dissolve.

[0035] Add 20.00 g of compound 1, 2.68 g of nickel chloride hexahydrate, 60 mL of dichloromethane, and 20 mL of methanol into the reaction flask, and cool down to -5°C. Keep the internal temperature at -5°C-5°C and add the sodium borohydride and sodium hydroxide methanol solution prepared above dropwise, then react at -5°C-5°C for 15 minutes, and stop the reaction when the compound disappears at 1 point as detected by TLC.

[0036] Add 3.63g of ethylenediaminetetraacetic acid, 3.92g of sodium nitrite, 20mL of ammonia water, and 100mL of water into a beaker, and stir to dissolve.

[0037] The above-mentioned prepared ethylenediaminetetraacetic acid, sodium nitrite, and aqueous ammonia solution were added to the reaction solution to quench the reaction, extracted with 200 mL of dichloromethane,...

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Abstract

The invention discloses a preparation method of a peramivir intermediate, which comprises the following steps: adding (3aR, 4R, 6S, 6aS)-4-((t-butyloxycarboryl) amino)-3-(pentane-3-yl)-3a, 5, 6, 6a-tetrahydro-4H-cyclopentane [d] isoxazole-6-carboxylic acid methyl ester and nickel chloride into a mixed solution of methanol and dichloromethane, then adding a methanol solution of sodium borohydride and sodium hydroxide, stirring, filtering, washing, and drying to obtain the peramivir intermediate. And after the reaction is completed, adding an aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid and ammonia water, stirring, quenching, extracting, concentrating under reduced pressure, and crystallizing by using a mixed solvent of alcohol and water to obtain the peramivir intermediate (1S, 2S, 3S, 4R)-3-((S)-1-amino-2-ethylbutyl)-4-((t-butyloxycarboryl) amino)-2-hydroxycyclopentane-1-carboxylic acid methyl ester.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, specifically a peramivir intermediate (1S, 2S, 3S, 4R)-3-((S)-1-amino-2-ethylbutyl) - a preparation method of methyl 4-((tert-butoxycarbonyl)amino)-2-hydroxycyclopentane-1-carboxylate. Background technique [0002] Peramivir, English name: Peramivir trihydrate, chemical name (1S, 2S, 3R, 4R, 1'S)-3-[(1'-acetylamino-2'-ethyl)]-4-[[( Aminoimino)-methyl]amino]-2-carboxycyclopentane-1-carboxylic acid is a cyclopentane derivative neuraminidase inhibitor developed by American Biocryst Pharmaceuticals, which inhibits influenza neuraminidase The interaction between the virus particles of the organization progeny in the host cell release and increase in value to achieve the role of prevention and treatment of type A and type B influenza, has the advantages of good tolerance, low toxicity, suitable for injection, etc., is a promising drug Anti-influenza drugs. However, the current...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/24
CPCC07C269/06C07C2601/08C07B2200/07C07C271/24Y02P20/55
Inventor 邹晓东胡锦亮郭辉付明伟罗林葛敏林峰
Owner ZENJI RES LAB
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