Chiral 3, 4-dihydrogen-2(1H)-quinolinone compound and preparation method

A technology for quinolinones and compounds, which is applied in the field of chiral 3,4-dihydro-2-quinolinones and their preparation, and achieves the effects of a wide range of substrates, convenient and easy-to-obtain raw materials, and mild reaction conditions

Active Publication Date: 2019-02-19
BEIJING UNIV OF TECH
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Problems solved by technology

At present, the stereoselective synthesis of chiral 3,4-dihydro-2(1H)-quinolinone has been reported in the literature; There are still many deficiencies and limitations

Method used

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  • Chiral 3, 4-dihydrogen-2(1H)-quinolinone compound and preparation method
  • Chiral 3, 4-dihydrogen-2(1H)-quinolinone compound and preparation method
  • Chiral 3, 4-dihydrogen-2(1H)-quinolinone compound and preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Weigh 1a (17.5mg, 0.1mmol), 2a (19.2mg, 0.12mmol), palladium catalyst (5.2mg, 0.005mmol) and ligand PPh 3 (2.6mg, 0.01mmol) was dissolved in 1.0mL of dichloromethane, added benzoic acid (2.4mg, 0.02mmol) and stirred for 4 hours (detected the reaction with TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluted The solvent is selected as petroleum ether / ethyl acetate mixed solution with a volume ratio of 1:1) to obtain the target product 3aa (23.9 mg), with a yield of 82%.

[0035] Characterization and analysis of the target object: yellow solid, 1 H NMR (400MHz, CDCl 3 ):δ8.72(s,1H),7.84–7.82(m,2H),7.55–7.50(m,1H),7.46–7.42(m,2H),7.23-7.20(m,2H),7.09-7.05 (m,1H),6.95(d,J=8.2,1H),6.87-6.85(m 1H),6.04-5.95(m,1H),5.38(dd,J=10.0Hz,1H),5.26(dd, J=17.2Hz, 1H), 5.00(dd, J=13.2 1H), 3.69(dd, J=13.2 1H) ppm; HRMS(ESI) m / z: C 18 h 16 N 2 o 2 [M+H] + The theoretical calculation value is 293.1285, and the measured ...

Embodiment 2

[0037]

[0038] Weigh 1b (19.3mg, 0.1mmol), 2a (19.2mg, 0.12mmol), palladium catalyst (5.2mg, 0.005mmol) and ligand PPh 3 (2.6mg, 0.01mmol) was dissolved in 1.0mL of dichloromethane, added benzoic acid (2.4mg, 0.02mmol) and stirred for 4 hours (detected the reaction with TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluted The solvent is selected as petroleum ether / ethyl acetate mixed solution with a volume ratio of 1:1) to obtain the target product 3ba (21.7 mg), with a yield of 70%.

[0039] Characterization and analysis of the target object: yellow solid, 1 H NMR (400MHz, CDCl 3):δ8.86(s,1H),7.85-7.83(m,2H),7.56-7.51(m,1H),7.49-7.44(m,2H),7.20-7.16(m,1H),6.86(d ,J=8.0,1H),6.77(td,J=8.4,1H),6.63(dd,J=9.2,1H),6.01-5.92(m,1H),5.40(dd,J=10.0Hz,1H) ,5.28(d,J=17.2Hz,1H),4.99(m,1H),3.66(dd,J=13.2 1H)ppm; HRMS(ESI)m / z:C 18 h 15 FN 2 o 2 [M+H] + The theoretically calculated value is 311.1190, and the measured value is 311...

Embodiment 3

[0041]

[0042] Weigh 1c (20.9mg, 0.1mmol), 2a (19.2mg, 0.12mmol), palladium catalyst (5.2mg, 0.005mmol) and ligand PPh 3 (2.6mg, 0.01mmol) was dissolved in 1.0mL of dichloromethane, added benzoic acid (2.4mg, 0.02mmol) and stirred for 4 hours (detected the reaction with TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluted The agent is selected as petroleum ether / ethyl acetate mixed solution with a volume ratio of 1:1) to obtain the target product 3ca (17.9 mg), with a yield of 55%.

[0043] Characterization and analysis of the target object: yellow solid, 1 H NMR (400MHz, CDCl 3 ):δ8.62(s,1H),7.83(d,J=7.6,2H),7.56-7.52(m,1H),7.50-7.44(m,2H),7.17(d,J=8.0 1H), 7.07(d, J=7.21H), 6.90(s, 1H), 6.81(d J=8.0 1H), 6.02-5.93(m, 1H), 5.43(d, J=10.0Hz, 1H), 5.00(dd ,J=17.2Hz,1H),5.05-4.98(m,1H),3.70-3.65(m,1H)ppm; HRMS(ESI)m / z: C 18 h 15 ClN 2 o 2 [M+H] + The theoretically calculated value is 327.0895, and the measured value ...

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Abstract

The invention discloses a chiral 3, 4-dihydrogen-2(1H)-quinolinone compound and a preparation method and belongs to the technical field of compound preparation. The preparation method includes: takingvinyl benzoxazinone and oxazolone as a synthetic building block, adding a metal palladium catalyst, phosphorus-ligand and acid-alkali additive, and allowing reaction at room temperature to obtain thecompound. The preparation method is mild in reaction condition, high in reaction speed, simple in aftertreatment and wide in substrate range. A method for selective synthesis of diastereomer of 3, 4-dihydrogen-2(1H)-quinolinone having extensive physiological and pharmacological activities like resistance to tumor, high blood pressure and tuberculosis and pain stopping is brand-new and efficient.

Description

technical field [0001] The invention relates to a chiral 3,4-dihydro-2(1H)-quinolinone compound and a preparation method thereof, belonging to the technical field of compound preparation. Background technique [0002] 3,4-Dihydro-2(1H)-quinolinone is an important class of benzo nitrogen-containing heterocyclic compounds. As a dominant drug skeleton structure, it widely exists in active natural products and drug molecular structures. 3,4-dihydro-2(1H)-quinolinones with complex chemical structures and diverse stereochemical structures have a wide range of physiological and pharmacological activities such as anti-tumor, anti-hypertensive, anti-tuberculosis, and analgesic. It has important application and research value in medicine and pharmacy. At present, the stereoselective synthesis of chiral 3,4-dihydro-2(1H)-quinolinone has been reported in the literature; There are still many deficiencies and limitations. Therefore, it has become an important research to construct 3,4-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/38
CPCC07D215/38
Inventor 赵洪武丁晚秋郭家明王立茹汤喆范晓祖吴慧慧毕晓帆
Owner BEIJING UNIV OF TECH
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