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Preparation method for fosamprenir intermediate

A technique for the preparation of fosamprenavir and intermediates, which is applied in the field of preparation of fosamprenavir intermediates, -1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane, and can solve the problem of preparation The method solves problems such as complex process, low safety, and difficult separation, and achieves the effects of reasonable process, improved production efficiency, and simple operation

Inactive Publication Date: 2015-07-29
SHANGHAI INSTITUTE OF TECHNOLOGY
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  • Abstract
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  • Claims
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Problems solved by technology

[0020] Aiming at the above technical problems in the prior art, the invention provides a method for preparing a fosamprenavir intermediate, which prepares (2R,3S)-1,2-epoxy-3-tert-butoxycarbonyl The method of amino-4-phenylbutane solves the technical problems of complex preparation process, difficult separation, high cost and low safety in the prior art

Method used

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  • Preparation method for fosamprenir intermediate
  • Preparation method for fosamprenir intermediate
  • Preparation method for fosamprenir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Adjust the pH of phenylacetonitrile 1 (60g, 0.512mol), potassium phosphate buffer (100ml), enzyme (20mg), and the mixture to 6, control the reaction temperature to 30°C, and stir for 12 hours. Then it was acylated with methoxymethylamine (31.3g, 0.512mol) at room temperature and stirred for 0.5h. After the reaction, extract with dichloromethane (2×250ml), dry, filter, concentrate under reduced pressure, column chromatography (ethyl acetate: hexane = 1:2) to give colorless oily liquid 2 (90.3g, 98.5% ). 1 H NMR (300MHz, CDCl 3 ):7.36-7.21(5H),3.78(s,2H),3.61(s,3H),3.2(s,3H). 13C NMR (75MHz, CDCl 3 ):172.5,135.1,129.4,128.6,126.9,61.4,39.5,32.3.

[0048] (2) Control the reaction temperature of N-methoxy-N-methyl-phenylacetamide 2 (90.3g, 0.504mol), bromovinyl Grignard reagent (66.3g, 0.51mol), tetrahydrofuran (250ml) mixture to 0 °C, stop the reaction after 1h. After the reaction, it was extracted with hexane (2×150ml), dried, filtered, concentrated under reduce...

Embodiment 2

[0055] (1) Adjust the pH of phenylacetonitrile 1 (60g, 0.512mol), potassium phosphate buffer (100ml), enzyme (20mg) and the mixture to 7, control the reaction temperature to 35°C, and stir for 13h. Then it was acylated with methoxymethylamine (46.8 g, 0.768 mol) at room temperature and stirred for 1 h. After the reaction, it was extracted with dichloromethane (2×250ml), dried, filtered, concentrated under reduced pressure, and column chromatography (ethyl acetate:hexane=1:2) gave colorless oily liquid 2 (90.5g, 98.7% ).

[0056] (2) Control the reaction temperature of N-methoxy-N-methyl-phenylacetamide 2 (90.5g, 0.505mol), bromovinyl Grignard reagent (98.4g, 0.757mol), tetrahydrofuran (250ml) mixture to 0 °C, stop the reaction after 1.5h. After the reaction, it was extracted with hexane (2×150ml), dried, filtered, concentrated under reduced pressure, and column chromatography (ethyl acetate:hexane=1:9) gave colorless oily liquid 3 (68.2g, 92.5%) .

[0057] (3) 4-phenyl-1-b...

Embodiment 3

[0062] (1) Adjust the pH of phenylacetonitrile 1 (60g, 0.512mol), potassium phosphate buffer (100ml), enzyme (20mg), and the mixture to 8, control the reaction temperature to 40°C, and stir for 14 hours. Then it was acylated with methoxymethylamine (62.5g, 1.024mol) at room temperature and stirred for 1.5h. After the reaction, it was extracted with dichloromethane (2×250ml), dried, filtered, concentrated under reduced pressure, column chromatography (ethyl acetate: hexane = 1:2) to obtain a colorless oily liquid 2 (89.9g, 98% ).

[0063](2) Control the reaction temperature of N-methoxy-N-methyl-phenylacetamide 2 (89.9g, 0.502mol), bromovinyl Grignard reagent (130.4g, 1.004mol), tetrahydrofuran (250ml) mixture to 0 °C, stop the reaction after 1.5h. After the reaction, it was extracted with hexane (2×150ml), dried, filtered, concentrated under reduced pressure, and column chromatography (ethyl acetate:hexane=1:9) gave colorless oily liquid 3 (68.9g, 94%) .

[0064] (3) 4-phe...

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Abstract

The invention provides a preparation method for a fosamprenir intermediate. The preparation method comprises the following steps: taking benzyl cyanide as a raw material, and performing steps of nitrile hydrolysis, acylation, reaction with a Grignard reagent, ammonization, cyclizing and the like for synthesizing (2R,3S)-1,2-epoxy-3-t-butyloxycarborylamino-4-phenyl butane. The method is reasonable in process, simple to operate, low in cost and high in yield; with the method, industrialization can be well realized and the production efficiency is improved.

Description

technical field [0001] The invention belongs to the field of chemical industry, and relates to a fosamprenavir intermediate, specifically a kind of (2R,3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane Preparation. Background technique [0002] HIV-1 protease inhibitors are an important part of highly active antiretroviral therapy (HAART), and (2R,3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane is prepared An important synthetic intermediate of the HIV-1 protease inhibitor fosamprenavir, its molecular formula is as follows: [0003] [0004] The preparation methods of (2R,3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane that have been reported to have industrial application value mainly contain the following four kinds: [0005] The first method (Tetrahedron Lett.1995, 36 (31), 5453-5456) takes L-phenylalanine as raw material, obtains compound 7 through four-step reaction, and synthetic route is as follows: [0006] [0007] Although the synthes...

Claims

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Application Information

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IPC IPC(8): C07D303/36
CPCC07D301/14C07D303/36Y02P20/55
Inventor 许鹏余焓韩生李亮
Owner SHANGHAI INSTITUTE OF TECHNOLOGY
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