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Preparation method of darunavir intermediate

A technology of darunavir and intermediates, applied in the direction of organic chemistry and the like, can solve the problems of low safety, difficult separation, complicated process and the like, and achieve the effects of reasonable process, simple operation and low cost

Inactive Publication Date: 2015-09-16
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Aiming at the above-mentioned technical problems in the prior art, the invention provides a kind of preparation method of darunavir intermediate, the preparation method of described this darunavir intermediate solves preparation (2R, 3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane has the technical problems of complex process, difficult separation, high cost and low safety

Method used

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  • Preparation method of darunavir intermediate
  • Preparation method of darunavir intermediate
  • Preparation method of darunavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] (1) Dissolve L-phenylalanine 1 (85g, 0.515mol) in methanol (250ml), and add thionyl chloride (182.1g, 1.545mol) dropwise under a controlled temperature of 0°C under nitrogen atmosphere , control the reaction temperature at 30°C, and stir the reaction for 12h. After the reaction, it was extracted with ethyl acetate (2×150ml) and sodium bicarbonate (2×150ml), dried, filtered, and concentrated under reduced pressure to obtain white solid 2 (84.8g, 92%). Mp:158-162℃.IR(KBr):3374,3028,2952,1732,1538,1263cm -1 . 1H NMR (300MHz, CDCl 3 ):δ7.42-7.30(m,5H,ArH),4.80-4.60(t,1H,J=7.0Hz,CH),3.83(s,3H,OCH 3 ),3.33-3.23(dd,2H,J1=J2=5.12Hz,CH 2 ) ppm. 13 C NMR (75MHz, CDCl 3 ): δ169,133,129,128,127,58,54,36ppm.

[0047] (2) The mixture of L-phenylalanine methyl ester 2 (84.8g, 0.474mol), benzyl chloride (179.2g, 1.422mol) and tetrahydrofuran (250ml) was reacted at room temperature for 10h. After the reaction, it was basified with potassium carbonate (2×150ml), extracted, dried,...

Embodiment 2

[0054] (1) Dissolve L-phenylalanine 1 (85g, 0.515mol) in methanol (250ml), and add thionyl chloride (212.1g, 1.8mol) dropwise under a controlled temperature of 0°C under nitrogen atmosphere , control the reaction temperature at 40°C, and stir the reaction for 13h. After the reaction, it was extracted with ethyl acetate (2×150ml) and sodium bicarbonate (2×150ml), dried, filtered, and concentrated under reduced pressure to obtain white solid 2 (85.4g, 92.6%).

[0055] (2) The mixture of L-phenylalanine methyl ester 2 (85.4g, 0.476mol), benzyl chloride (210.4g, 1.67mol) and tetrahydrofuran (250ml) was reacted at room temperature for 11h. After the reaction, it was basified with potassium carbonate (2×150ml), extracted, dried, filtered, concentrated under reduced pressure, column chromatography (ethyl acetate:hexane=1:50→1:5) to obtain a colorless oily liquid 3 (163.8 g, 95.8%).

[0056] (3) N, N-dibenzyl-L-phenylalanine methyl ester 3 (163.8g, 0.456mol), bromochloromethane (87....

Embodiment 3

[0062] (1) Dissolve L-phenylalanine 1 (85g, 0.515mol) in methanol (250ml), and add thionyl chloride (242.9g, 2.06mol) dropwise under a controlled temperature of 0°C under nitrogen atmosphere , control the reaction temperature at 50°C, and stir the reaction for 14h. After the reaction, it was extracted with ethyl acetate (2×150ml) and sodium bicarbonate (2×150ml), dried, filtered, and concentrated under reduced pressure to obtain white solid 2 (86.7g, 94%).

[0063] (2) The mixture of L-phenylalanine methyl ester 2 (86.7g, 0.484mol), benzyl chloride (244g, 1.936mol) and tetrahydrofuran (250ml) was reacted at room temperature for 12h. After the reaction, it was basified with potassium carbonate (2×150ml), extracted, dried, filtered, concentrated under reduced pressure, column chromatography (ethyl acetate:hexane=1:50→1:5) to obtain a colorless oily liquid 3 (167.4g, 96.3%).

[0064] (3) N, N-dibenzyl-L-phenylalanine methyl ester 3 (167.4g, 0.466mol), bromochloromethane (119.2g...

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Abstract

The invention provides a preparation method of a darunavir intermediate. The method adopting L-phenylalanine as a raw material comprises the steps of esterification, alkylation, acylation, palladium-carbon reduction and cyclization to synthesize (2R,3S)-1,2-epoxy-3-tertbutyloxycarbonylamino-4-phenylbutane. The method adopting a cheap benzyl group to protect an amino group has the advantages of reasonable technology, simple operation, low cost, high yield, industrialization realization, and production efficiency improvement.

Description

technical field [0001] The invention belongs to the field of chemical industry, and in particular relates to a darunavir intermediate, specifically (2R,3S)-1,2-epoxy-3-tert-butoxycarbonylamino-4-phenylbutane method of 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 darunavir, 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) uses L-phenylalanine as a raw material, and obtains compound 8 through four-step reactions, and the synthetic route is as follows: [0006] [0007] Alth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/36C07D301/26
CPCC07D303/36C07D301/26
Inventor 余焓何慧红韩生许鹏
Owner SHANGHAI INST OF TECH
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