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Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine

A technology of chiral amino alcohols and ligands, applied in asymmetric synthesis, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve problems such as difficult industrialization and harsh conditions

Inactive Publication Date: 2003-09-17
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this method, a large excess of chiral ligands and a large excess of strong bases (lithiumalkyl and LHMDS) must be used, and the reaction must be carried out at minus 20 degrees, which is harsh and difficult for industrialization.

Method used

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  • Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of (1R, 2R)-2-N,N-dimethylamino-3-p-nitrophenyl-1,3-propanediol:

[0031] Reference Jiang, B.; Chen, Z.L.; Tang, X.X. Org. Lett. 2002, 4, 3451. Synthesis

Embodiment 2

[0033] Preparation of (1R, 2R)-3-tert-butoxy-2-N,N dimethylamino-1-p-nitrophenyl-1-propanol:

[0034] At 0-5°C, 0.8 g of concentrated sulfuric acid was added dropwise to (1R, 2R)-2-N,N-dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.8g, 7.5mmol) in CH 2 Cl 2 (20mL) in solution. Keep isobutylene gas 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 hours, and isobutylene gas was continuously introduced. Cool the mixture to 0-5℃ and add saturated K 2 CO 3 Solution. Organic phase drying (Na 2 SO 4 ) Concentrated and recrystallized to obtain the ligand 1.44g (65%).mp 100.0-101.3℃; [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, and 9.9 Hz, 1H), 3.21 (dd, J=6.5 Hz, and 10 Hz, 1H), 2.56 (m, 1H), 2.47 (s, 6H), 1.06 (s, 9H); 13...

Embodiment 3

[0035] Example 3 Preparation of (1R, 2R)-3-tert-butyldimethylsiloxy-2-N,N dimethylamino-1-p-nitrophenyl-1-propanol: (1R, 2R)- 2-N,N-Dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.946g, 8.1mmol) dissolved in CH 2 Cl 2 (30mL), add TBDMSCl (1.28g, 5.3mmol) and imidazole (1.4g, 20.6mmol) mixture at 0°C and stir overnight. After processing, the product is 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), 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 O4 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

A novel chiral ligand (1R, 2R)-2-N,N-substituent-1-(4-substituted phenyl)-3-O- substituent-1-propanol is disclosed, which can be used for asymmetrical synthesis of the precursors of DPC961 and DPC083, which are high-activity inhibitor of HIV transferase.

Description

Technical field [0001] The invention relates to a new chiral ligand and its use for the asymmetric addition of terminal alkynes to imine. 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 in the treatment of HIV and similar diseases, such as azidothymidine or AZT. DPC 961 and DPC 083 are the second-generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs, non-nucleoside reverse transcriptaseinhibitors), which are compatible with the already marketed transferase inhibitor drugs Efavirenz (Sustiva TM ) Has stronger activity than that. DPC-961 and DPC 083 are currently undergoing clinical research tests (Journal of Medicinal Chemistry vol. 43, NO. 10, 2000, 2019-2030). [0003] Some methods have been used for the synthesis of DPC 961 and DPC 083. These methods have been reported to synthesi...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07C215/28C07C217/48C07C317/26C07D239/70C07D239/80C07F7/18
Inventor 姜标司玉贵
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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