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Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone

A chiral amino alcohol, asymmetric technology, applied in the preparation of amino hydroxy compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of difficult industrialization and harsh conditions.

Inactive Publication Date: 2003-10-22
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These have been reported to synthesize Efavirenz (Sustiva TM ) method needs to use a large excess of chiral ligands and a large excess of strong base (lithium alkyl and LHMDS), and the reaction needs to be carried out at minus 50 degrees, the conditions are harsh, and it is not easy for industrialization

Method used

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  • Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1R, 2R)-2-N, the preparation of N-dimethylamino-3-p-nitrophenyl-1,3-propanediol:

[0033] Reference Jiang, B.; Chen, Z.L.; Tang, X.X.Org.Lett.2002, 4, 3451. Synthesis

Embodiment 2

[0035] (1R, 2R)-3-tert-butoxy-2-N, the preparation of N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0036] 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. Isobutene gas was maintained at 0-5°C for one hour. 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 ligand 1.44g (65%).mp100.0-101.3°C; [α] D 20 =+23.5(c, 1.00, CHCl 3 ); FTIR (KBr) 3333, 2972, 1606, 1523, 1357, 1197, 861cm -1 ; 1 HNMR (300MHz, CDCl 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=3.0Hz, and9. 9Hz, 1H), 3.21(dd, J=6.5Hz, and 10Hz, 1H), 2....

Embodiment 3

[0037] Preparation of (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol:

[0038] (1R,2R)-2-N,N-Dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.946 g, 8.1 mmol) was dissolved in CH 2 Cl 2 (30mL), TBDMSCl (1.28g, 5.3mmol) and imidazole (1.4g, 20.6mmol) mixture was added at 0°C and stirred overnight to obtain product 2.72g. 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 =11.3Hz, 2.7Hz 1H), 3.5-3.45(dd, J=11.3Hz, 6.0Hz 1H), 2.50(m, 7H), 0.90(s, 9H), 0.01(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 present invention provides a kind of chiral ligand (1R, 2R)-2-N,N-substituted amino-1-(4-substituted phenyl)-1-ethanol or its enantiomorph and a method using the above-mentioned chiral ligand or its enantiomorph as catalyst for asymmetric addition of acetylene copper or acetylene zinc to trifluoromethylarylketone. Said invention provides its structural general formula. Said invention adopts the asymmetric addition process so as to can high-effectively and high enantiomeric-selectively create the chiral quanternary carbon center in HIV transfrase high-activity inhibitor Efavirenz (Sustiva TM), so that it can high-effectively synthesize Efavirenz (Sustiva TM).

Description

technical field [0001] The invention relates to a method for asymmetric addition of a chiral ligand to a terminal alkyne to a fluorine-containing alkyl aryl ketone. Background technique [0002] Human immunodeficiency virus (HIV, Human immunodeficiency virus) is prone to mutations, which can lead to drug resistance. As we all know, some transferase inhibitor drugs have been discovered and used for the treatment of HIV and similar diseases, such as azidothymidine or AZT. Efavirenz (Sustiva TM ), DPC961 and DPC083 are second-generation HIV non-nucleoside transferase inhibitors (NNRTIs, non-nucleoside reverse transcriptase inhibitors), among which Efavirenz (Sustiva TM ) is already listed. DPC-961 and DPC083 are currently undergoing clinical research testing (Journal of Medicinal Chemistry vol.43, NO.10, 2000, 2019-2030). [0003] Some methods have been used in Efavirenz (Sustiva TM ) synthesis (Angew.Chem.Int.Ed.no.5, 1999, 711-713; Journal of Organic Chemistry vol.63, no...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B01J31/02C07C213/06C07C215/70
Inventor 姜标司玉贵
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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