One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound

A compound and asymmetric technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of low-efficiency chromatographic purification steps, cumbersome and inconvenient synthesis process operations, etc., and achieve easy large-scale industrialization, fewer steps, and mild process conditions Effect

Active Publication Date: 2014-03-26
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0014] In summary, the above methods for synthesizing benzoxazinone compounds all use highly toxic or difficult-to-handle reagents and expensive ligand raw materials, the synthesis process is cumbersome and inconvenient, and in addition to low-efficiency chromatographic purification steps or low-yield (S)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (Efavirenz, formula 1) overall synthetic route, therefore, it is urgent to find a new synthetic process for benzoxazinone compounds that can be adapted to large-scale industrial production. Such a synthetic process can not only avoid or improve the above-mentioned constraints, but also efficiently provide Desired benzoxazinone compound

Method used

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  • One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound
  • One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound
  • One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Preparation of (1R,2R)-2-N,N-dimethylamino-3-p-nitrophenyl-1,3-propanediol:

[0135] References Jiang, B; Chen, Z.L.; Tang, X.X. Org. Lett., 2002, 4, 3451.

[0136] synthesis

Embodiment 2

[0138] Preparation of (1R,2R)-3-tert-butoxy-2-N,N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0139] At 0-5°C, add 0.8 g of concentrated sulfuric acid dropwise into (1R,2R)-2-N,N-dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.8 g, 7.5 mmol) in CH 2 Cl 2 (20mL) solution. Keep isobutene gas at 0-5°C. Then 0.2 g of concentrated sulfuric acid was added dropwise, the mixture was returned to room temperature and stirred vigorously for 5-7 h, and isobutene gas was continuously introduced. Cool the mixture to 0-5°C and add saturated K 2 CO 3 solution. The organic phase was dried (Na 2 SO 4 ) was concentrated and purified by recrystallization to obtain 1.44 g of the ligand with a yield of 65%. Mp100.0–101.3℃;[α] d 20 =+23.5(c,1.00,CHCl 3 )δ8.19(d,J=8.8Hz,2H),7.60(d,J=8.4Hz,2H),4.59(d,J=9.9Hz,1H),3.34(dd,J=3.0,9.9Hz, 1H),3.21 (dd,J=6.5,10Hz,1H),2.56(m,1H),2.47(s,6H),1.06(s,9H); 13 CNMR (75MHz, CDCl 3 )δ150.6, 147.6, 128.46, 123.49, 73.3, 70.3, 69.8, 56.0, 41.8, 27.4; MS ...

Embodiment 3

[0141]Preparation of (1R,2R)-3-tert-butyldimethylsilyloxy-2-N,N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0142] (1R,2R)-2-N,N-Dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.95 g, 8.1 mmol) was dissolved in CH 2 Cl 2 (30 mL), a mixture of TBDMSCl (1.28 g, 5.3 mmol) and imidazole (1.4 g, 20.6 mmol) was added at 0°C and stirred overnight to obtain 2.72 g of the post-treated product, with a yield of 94%. FTIR (KBr) 3344, 2954, 1606, 1525, 1349cm -1 ; 1 HNMR (300MHz, CDCl 3 )δ8.25-8.20(d,J=8.5Hz,2H),7.6-7.55(d,J=8.5Hz,2H),4.65(d,J=9.7Hz,1H),3.77-3.6(dd,J =11.3,2.7Hz1H),3.5-3.45(dd,J=11.3,6.0Hz1H),2.50(m,7H),1.85(s,8H),0.1(s,6H); 13 CNMR (75MHz, CDCl 3 )δ150.2, 147.4, 128.0, 123.3, 69.0, 57.1, 41.6, 25.7, 17.9, -5.9; MS(EI)m / e297(M +- 57,0.3),209(8.2),202(100).Anal.calcd.For C 17 h 30 N 2 o 4 Si;C,57.60;H,8.53;N,7.90.Found:C,57.82;H,8.18;N,7.77.

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Abstract

The invention relates to a novel one-pot asymmetric synthetic process of (S)-6-chloro-4-cyclopropyl acetenyl-4-trifluoromethyl-1, 4-dihydro-2H-1, 3-benzoxazine-2-one (Efavirenz) compounds. The invention is the divisional application of a one-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compounds, wherein the application number is 201110001621.8 and the application date is 6th, January, 2011. The compounds can be used as the reverse transcriptase inhibitor of HIV. The invention further relates to a novel alkamine ligand for the process.

Description

[0001] The application of the present invention is a divisional application with the application number 201110001621.8, the application date is January 06, 2011, and the invention name is "One-pot asymmetric synthesis process of HIV reverse transcriptase inhibitor efavirenz compounds". Technical field: [0002] The present invention relates to (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (ifavir Lun Efavirenz, formula I) a new one-pot asymmetric synthesis process, that is, the enantioselective addition of terminal alkynes to trifluoromethyl ketones to generate propargyl tertiary alcohols, the addition products are synthetic anti-HIV reverse transcription The key intermediate of the enzyme inhibitor Efavirenz (DMP266), which is not separated and purified, is obtained by one-step ring closure under the promotion of alkali in a continuous one-pot reaction. The invention also relates to novel aminoalcohol ligands for use in this process. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/18C07C215/44
CPCY02P20/55C07D265/18C07C215/44
Inventor 姜标李金华张琛李晓贤
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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