A synthetic method of a critical intermediate of darunavir

A synthetic method, the technology of darunavir, applied in the field of intermediates for the preparation of darunavir, can solve the problems of high discharge of three wastes and low chiral purity, and achieve the effects of low cost, high optical purity and simple route

Active Publication Date: 2016-11-09
LIANYUNGANG DUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The purpose of the present invention is to provide a new preparation method of darunavir key intermediate 1S, 2S-(1-benzyl-3-chloro-2-hydroxypropyl)carbamate

Method used

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  • A synthetic method of a critical intermediate of darunavir
  • A synthetic method of a critical intermediate of darunavir
  • A synthetic method of a critical intermediate of darunavir

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1, a synthesis method of a darunavir key intermediate: In a clean 150ml autoclave, put 20.0 grams of 1S, 2S-(1-benzyl-3-halo-2-carbonylpropyl) carbamic acid tert-butyl ester, 0.2 g of carbonyl reduction catalyst {N-[3-(η6-phenyl)propyl]-[(1S-2S)-1,2-diphenyl-1-4-methylbenzenesulfonamide (kN)-Ethyl-2-amino-(kN)]}ruthenium (II), add 100ml of methanol for hydrogen replacement 3 times, hydrogen pressure 0.5 MPa, stir, control the reaction at 30 ℃, react for 3h. Release the pressure and filter to obtain the filtrate and filter cake. The filter cake is rinsed with a small amount of methanol and applied mechanically again. The filtrate was distilled under reduced pressure, methanol was recovered, and applied mechanically again. The crude product was obtained with a yield of 95.2% and a content of 98.1%. MS(+1)=337.5.

Embodiment 2

[0034]Example 2, a synthesis method of a darunavir key intermediate: In a clean 150ml autoclave, put 20 grams of 1S, 2S-(1-benzyl-3-halo-2-carbonylpropyl) carbamic acid tert-butyl ester, 0.5 g of carbonyl reduction catalyst {N-[3-(η6-phenyl)propyl]-[(1S-2S)-1,2-diphenyl-1-4-methylbenzenesulfonamide (kN)-Ethyl-2-amino-(kN)]} ruthenium (II), add 100ml of methanol for hydrogen replacement 3 times, hydrogen pressure 0.5MPa, control the reaction at 30°C, and react for 3h. Release the pressure and filter to obtain the filtrate and filter cake. The filter cake is rinsed with a small amount of methanol and applied mechanically again. The filtrate was distilled under reduced pressure, methanol was recovered, and applied mechanically again. The crude product was obtained with a yield of 95.6% and a content of 98.3%. MS(+1)=337.94.

Embodiment 3

[0035] Example 3, a synthesis method of a darunavir key intermediate, put 20 grams of 1S, 2S-(1-benzyl-3-halo-2-carbonylpropyl) carbamic acid into a clean 150ml autoclave tert-butyl ester, 0.2 g of carbonyl reduction catalyst {N-[3-(η6-phenyl)propyl]-[(1S-2S)-1,2-diphenyl-1-4-methylbenzenesulfonamide (kN)-Ethyl-2-amino-(kN)]} ruthenium (II), add 100 ml of methanol for hydrogen replacement 3 times, hydrogen pressure 1.0 MPa, control the reaction at 30°C, and react for 3 hours. Release the pressure and filter to obtain the filtrate and filter cake. The filter cake is rinsed with a small amount of methanol and applied mechanically again. The filtrate was distilled under reduced pressure, methanol was recovered, and applied mechanically again. The crude product was obtained with a yield of 95.2% and a content of 97.5%. MS(+1)=337.94.

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Abstract

A synthetic method of a critical intermediate of darunavir is disclosed. The critical intermediate which is tert-butyl 1S,2S-(1-benzyl-3-chloro-2-hydroxy propyl)carbamate is prepared by adopting tert-butyl 1S-(1-benzyl-3-chloro-2-carbonyl propyl)carbamate as a raw material through catalytic hydrogenation by using a chiral carbonyl reducing catalyst that is {N-[3-(Eta6-phenyl)propyl]-[(1S,2S)-1,2-diphenyl-1-4-methyl benzsulfamide (kN)-ethyl-2-amino-(kN)]}ruthenium (II). The method is simple in route and mild in reaction conditions. Through test verification, the yield is high and optical purity is high. After-treatment of tert-butyl 1S,2S-(1-benzyl-3-halogen-2-hydroxy propyl)carbamate after the reaction is finished is simple, and the chiral carbonyl reducing catalyst can be separated by filtering. A solvent is recovered and reutilized, and the catalyst can be recycled, and therefore the cost is low, an idea of green chemistry is met, and a three-waste discharge problem of the tert-butyl 1S,2S-(1-benzyl-3-halogen-2-hydroxy propyl)carbamate in the prior art is overcome, and the cost is reduced.

Description

technical field [0001] The present invention relates to an intermediate used in the preparation of darunavir, more particularly to a kind of tert-butyl 1S,2S-(1-benzyl-3-chloro-2-hydroxypropyl)carbamate The preparation method belongs to the technical field of pharmaceutical intermediate synthesis. technical background [0002] Darunavir, trade name Prezista, chemical name: [(1S,2R)-3-[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxyl-1 -Benzylpropylcarbamate (3R,3As,6aR)-hexahydrofuro[2,3-b]furan-3-ester-ethanolate, the English name is: [(1S,2S)-3- [[4-aminophenyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl] [0003] -carbamic acid (3R,3As,6aR)-hexahydrofuro[2,3-b]furan-3-yl estermonoethanolate. CAS number: 618109-00-5. [0004] [0005] Darunavir [0006] Darunavir is a non-peptide HIV protease inhibitor developed by Tibotec, the Icelandic subsidiary of Johnson & Johnson. Darunavir has strong antiviral activity in vitro, including HIV strains th...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/16
CPCY02P20/584C07C269/06C07C271/16
Inventor 黄朋勉王笃政谢建新王川民郑晓斌
Owner LIANYUNGANG DUXIANG CHEM
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