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One pot method asymmetric synthesis process of HIV reverse transcriptase inhibitor Efavirenz compound

A compound, asymmetric technology, applied in the direction of organic compound/hydride/coordination complex catalyst, compound of periodic table group 4/14 elements, chemical/physical process, etc., can solve the complex operation, low synthesis efficiency, problems such as low-efficiency chromatographic purification steps, to achieve the effect of easy large-scale industrialization, mild process conditions, and simple operation

Active Publication Date: 2012-07-18
然晟(上海)实业发展有限公司
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AI Technical Summary

Problems solved by technology

In addition, Young et al. also discussed the clinical effect of benzoxazinone as an HIV reverse transcriptase inhibitor in the treatment of HIV in Antimicrobial Agents and Chemotherapy (Antimicrobial Agents and Chemotherapy, 1995, 39, 2602-2605), In vitro activity and his kinetic activity, and also discloses a simplified method for the synthesis of benzoxazinones corresponding to EP582455A1, wherein the cyclized precursor tertiary alcohol is added by the corresponding amine to the cyclopropylethynyllithium reagent Obtained, not only still there are above-mentioned defects, but also the synthesis efficiency is still very low
[0013] U.S. Patent No. 5,922,864 describes a method for the preparation of benzoxazinones through a cyclization reaction involving alkyl chloroformate and aryl chloroformate, which involves the protection of the methoxybenzyl group first, and then Symmetrical addition, followed by removal of benzyl protection and then protection with alkyl chloroformate or aryl chloroformate, the separated and purified product was ring-closed under alkaline conditions to obtain benzoxazinone, although the use of severe Phosgene and phosgene analogues that are toxic and difficult to store and operate, but there are multi-step up-protection deprotection and corresponding separation and purification work, the operation is complicated, and the difficulty and cost of industrial production are increased
[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) general synthetic route, therefore, be badly in need of seeking new synthetic technique that can adapt to the benzoxazinone compound of large-scale industrial production, such synthetic technique can not only avoid or improve above-mentioned limiting condition, but also can provide efficiently Desired benzoxazinone compound

Method used

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  • One pot method asymmetric synthesis process of HIV reverse transcriptase inhibitor Efavirenz compound
  • One pot method asymmetric synthesis process of HIV reverse transcriptase inhibitor Efavirenz compound
  • One pot method asymmetric synthesis process of HIV reverse transcriptase inhibitor Efavirenz compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] (1R, 2R)-2-N, the preparation of N-dimethylamino-3-p-nitrophenyl-1,3-propanediol:

[0139] References Jiang, B; Chen, Z.L.; Tang, X.X. Org. Lett., 2002, 4, 3451.

[0140] synthesis

Embodiment 2

[0142] (1R, 2R)-3-tert-butoxy-2-N, the preparation of N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0143] 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%. Mp 100.0-101.3°C; [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...

Embodiment 3

[0145] Preparation of (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0146] (1R,2R)-2-N,N-Dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.95 g, 8.1 mmol) was dissolved in CH 2 Cl2 (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, 2.7Hz 1H), 3.5-3.45(dd, J=11.3, 6.0Hz 1H), 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 / e 297 (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 method asymmetric synthesis process of a (S)-6-chlorine-4-cylopropyl ethylnen-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone (Efavirenz) compound, the compound can be used as an reverse transcriptase inhibitor for human immunodeficiency virus (HIV). The invention also relates to a novel aminoalcohol ligand used for the process.

Description

Technical field: [0001] The present invention relates to (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (ifavir Lun Efavirenz, a new one-pot asymmetric synthesis process of formula I), that is, the enantioselective addition of terminal alkynes to trifluoromethyl ketones generates propargyl tertiary alcohols, and the addition products are synthetic anti-HIV reverse transcription The key intermediate of the enzyme inhibitor Efavirenz (DMP266), without separation and purification, adopts a continuous one-pot reaction method to obtain Efavirenz by one-step ring closure under the promotion of alkali. The invention also relates to novel aminoalcohol ligands for use in this process. Background technique: [0002] Reverse transcription is unique to retroviral replication. Viral replication requires the reverse transcription of the viral RNA genome by a virally encoded reverse transcriptase to produce a DNA copy of the viral sequence. Since...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06C07D413/06C07D265/18A61P31/18C07C215/30C07C217/48C07F7/18C07C317/34C07D295/092C07C219/22C07C215/38C07C225/12C07D213/64C07C225/22B01J31/22
CPCY02P20/55
Inventor 姜标李金华张琛李晓贤
Owner 然晟(上海)实业发展有限公司
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