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4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof

A ketone compound, compound technology, applied in 4 fields, can solve problems such as harsh process conditions

Inactive Publication Date: 2006-09-06
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This directly leads to harsh process conditions

Method used

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  • 4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof
  • 4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof
  • 4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of (+ / -)-6-chloro-4-(2-oxopropyl)-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 2 = methyl)

[0061]

[0062] At room temperature, 250 mg (1 mmol) of compound 1 was dissolved in a mixed solution of 2 ml of acetone and 8 ml of anhydrous DMSO, and 23 mg (0.2 mmol) of racemic proline was added. The reaction can be tracked by TLC (petroleum ether: ethyl acetate 1:1), and can also be judged according to the color of the reaction system (from yellow to colorless), and the reaction is complete within 1 h. Add 10ml of water, extract with 10ml*3 ethyl acetate, combine the extracts, spin off the solvent, perform flash column chromatography (petroleum ether: ethyl acetate 2:1), and obtain 300mg (quantitative) of compound 2.

[0063] 1 HNMR (300MHz, acetone-d6 (deuterated acetone)) δ: 9.09 (br, s, NH), 7.11 (br, s, NH), 7.41 (s, 1H), 7.31 (dd, 1H, J=9, J=2), 6.98(d, 1H, J=9), 3.80(d, 1H, J=18), 3.47(d, 1H, J=18), 2.14(s, 3H);

[0064] 13 CNMR (75MHz, DMSO...

Embodiment 2

[0069] (+ / -)1-(4-methoxybenzyl)-6-chloro-4-(2-oxopropyl)-4-trifluoromethyl-3,4-dihydro-2(1H )-The preparation of quinazolinone (R 2 = methyl, P = 4-methoxybenzyl)

[0070]

[0071] At room temperature, 370 mg (1 mmol) of compound 1 was dissolved in a mixed solution of 2 ml of acetone and 8 ml of anhydrous DMSO, and 23 mg (0.2 mmol) of racemic proline was added. The reaction can be tracked by TLC (petroleum ether: ethyl acetate 3:1), and can also be judged according to the color of the reaction system (from bright yellow to colorless), and the reaction is complete within 2 hours. Add 10ml of water, extract with 10ml*3 ethyl acetate, combine the extracts, spin off the solvent, perform flash column chromatography (petroleum ether: ethyl acetate 3:1), and obtain 420mg, (99%) of compound 2a.

[0072] 1 HNMR (300MHz, CDCl3) δ: 7.16-7.20(m, 4H), 6.84-6.89(m, 3H), 6.76(d, 1H, J=9), 5.11(s, 2H), 3.77(s, 3H) , 3.33(d, 1H, J=17), 3.16(d, 1H, J=17), 2.20(s, 3H);

[0073] 13 CNMR ...

Embodiment 3

[0078] Preparation of (+ / -)-6-chloro-4-(2-oxobutyl)-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 2 = ethyl)

[0079]

[0080] At room temperature, 250 mg (1 mmol) of compound 1 was dissolved in a mixed solution of 2 ml butanone and 8 ml anhydrous DMSO, and 23 mg (0.2 mmol) of racemic proline was added. The reaction can be tracked by TLC (petroleum ether: ethyl acetate 1:1), and can also be judged according to the color of the reaction system (from yellow to colorless), and the reaction is complete within 24 hours. Add 10ml of water, extract with 10ml*3 ethyl acetate, combine the extracts, spin off the solvent, perform flash column chromatography (petroleum ether: ethyl acetate 2:1), and obtain 280mg (85%) of compound 3.

[0081] 1 HNMR (300MHz, acetone-d6) δ: 8.93 (br s, NH), 7.19 (br s, NH), 7.41 (s, 1H), 7.31 (dd, 1H, J=9, J=2), 6.98 ( d, 1H, J=8), 3.75(d, 1H, J=18.0), 3.48(d, 1H, J=18), 2.52(m, 2H), 0.907(t, 3H, J=7);

[0082] 13 CNMR (75MHz, DMSO-d6) δ: 204...

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Abstract

The invention relates to a 4, 4-disubstitutional-3,4-dihydro-2(one hydro)-quinaldinicketones compound and its method for synthesizing and its application. The said compound can be a compound with its constitutional formula on tha right, or its stereoisomer, its stereoisomeric mixture or a salt which can be accepted in the pharmacy. The method for synthesizing chiral pure isomer is carried out mainly by the asymmetric additive reaction between substrates of methyl ketone and trifluoromethylketone imine. Additionally, we can construct the most critical trifluoromethyl quaternary carbon chiral center of the target compound DPC083 easily and efficiently. Afterwards, the synthesis of the target compound DPC083 is realized by the transformation of the function group.

Description

technical field [0001] The invention relates to a 4,4-disubstituted-3,4-dihydro-2(1H)-quinolinone compound, a synthesis method and application. 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. DPC 961 and DPC 083 are the second-generation HIV non-nucleoside transferase inhibitors (NNRTIs, non-nucleoside reverse transcriptase inhibitors), and the already marketed transferase inhibitor drug Efavirenz (Sustiva TM ) has a stronger activity than DPC-961 and DPC 083 are currently undergoing clinical research testing (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. The reported methods for the synthesis of DPC 961 and DPC 083 ar...

Claims

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Application Information

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IPC IPC(8): C07D239/80B01J31/02A61K31/498A61P31/18
Inventor 姜标董佳家
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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