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Method for highly enantioselective catalytic synthesis of chiral quinolinone compound

An enantioselective compound technology, applied in the field of high enantioselective catalytic synthesis of chiral quinolinone compounds, can solve the problems hindering the application of drug synthesis research and pharmaceutical industry production, and the asymmetric synthesis method is not popular enough and not very extensive and other problems, to achieve the effect of simplifying the chiral control steps, wide application range and high reaction efficiency

Active Publication Date: 2019-07-05
YANGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the current research on the synthesis of optically pure quinolinone compounds using asymmetric catalysis is not very extensive (see J.Pedroni, T.Saget, P.A.Donets, N.Cramer, Chem.Sci., 2015, 6, 5164.), Its efficient asymmetric synthesis method is not popular enough, which obviously hinders the synthesis research of this class of drugs and the application of pharmaceutical industry production

Method used

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  • Method for highly enantioselective catalytic synthesis of chiral quinolinone compound
  • Method for highly enantioselective catalytic synthesis of chiral quinolinone compound
  • Method for highly enantioselective catalytic synthesis of chiral quinolinone compound

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Embodiment 1

[0046]

[0047] Add bromoarylamide (0.1 mmol) to a 10 mL Schlenk-type sealed tube equipped with a magnetic stirring bar, (C 3 h 5 )PdCp (10mol%, 2.13mg), L5 (25mol%, 24.7mg), K 2 CO 3 (0.2mmol, 27.6mg), AdCOOH (50mol%, 9.01mg), in N 2 Dry toluene (1 mL) was added under atmosphere. The tube was sealed and reacted at 100°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated to obtain a crude product, which was purified by column chromatography, petroleum ether / ethyl acetate=10:1, Rf=0.3, to obtain quinolinone compounds 2a (70% yield, 93% ee).

[0048] white solid. 70% yield. The ee value was analyzed using Daicel Chiralpak ID column, the mobile phase was n-hexane / isopropanol=90 / 10, and the flow rate was 1.0 mL / min. Retention time: 13.2min[(S)-enantiomer], 15.0min[(R)-enantiomer]. 93% ee. [α] 20 D =+73.0(c 0.1,CH 2 Cl 2 ).

[0049] 1 H NMR (400MHz, Chloroform-d) δ7.31(t, J=7.6Hz, 1H), 7.17(d, J=7.6H...

Embodiment 2

[0051]

[0052] Add bromoarylamide (0.1 mmol) to a 10 mL Schlenk-type sealed tube equipped with a magnetic stirring bar, (C 3 h 5 )PdCp (5mol%, 1.06mg), L1 (10mol%, 5.68mg), K 2 CO 3 (0.15mmol, 20.7mg), AdCOOH (30mol%, 5.41mg), in N 2 Dry toluene (1 mL) was added under atmosphere. The tube was sealed and reacted at 100°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated to obtain a crude product, which was purified by column chromatography, petroleum ether / ethyl acetate=10:1, Rf=0.3, to obtain quinolinone compounds 2a (0yield).

Embodiment 3

[0054]

[0055] Add bromoarylamide (0.1 mmol) to a 10 mL Schlenk-type sealed tube equipped with a magnetic stirring bar, (C 3 h 5 )PdCp (5mol%, 1.06mg), L2 (10mol%, 6.80mg), K 2 CO 3 (0.15mmol, 20.7mg), AdCOOH (30mol%, 5.41mg), in N 2 Dry toluene (1 mL) was added under atmosphere. The tube was sealed and reacted at 100°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated to obtain a crude product, which was purified by column chromatography, petroleum ether / ethyl acetate=10:1, Rf=0.3, to obtain quinolinone compounds 2a (18% yield, 74% ee).

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Abstract

The present invention provides a method for highly enantioselective catalytic synthesis of a chiral quinolinone compound, particularly a method that adopts bromoarylamide compound as a starting raw material and that includes intramolecular asymmetric carbon-hydrogen bond activation of the amide compound under existence of a palladium catalyst and a chiral ligand to synthesize the chiral quinolinone compound. A non-optically active raw material is adopted, a substrate has a wide application range, and the reaction efficiency is high, and the obtained optically active quinolinone compound can beconverted into an alpha-amino amide compound having a quaternary carbon chiral center. The obtained chiral quinolinone compound can be used as a chiral fragment of quinolinone type drugs, or as an amide small molecule catalyst for catalyzing asymmetric reactions; the quinolinone structure can be further converted to obtain alpha-amino acids; and the chiral quinolinone compound can also be used asa food additive.

Description

technical field [0001] The invention relates to a method for synthesizing a chiral quinolinone compound by activating an intramolecular asymmetric carbon-hydrogen bond of a bromoaryl amide compound. Background technique [0002] Quinolinone and its derivatives are a class of heterocyclic compounds containing a quinoline ring structure, which are widely used in the fields of medicine, pesticides and industrial dyes. In the field of medicine, this type of compound has been proved to have a wide range of pharmacological activities such as antibacterial and anti-inflammatory, anti-malarial, anti-depressant, anti-hypertensive and anti-tumor, and many drugs containing this type of structure have been used in clinical treatment (see B.D.Bertolet , Drug Safety, 2004, 27, 11. and A.A. Lemieux, J.D. Goldman-Levine, J.L. Goren, Journal of Pharmacy Technology, 2003, 19, 365. and D. End, P. Angibaud, M. Venet, Current Topics in Medicinal Chemistry, 2003, 3, 1095.). The first thing to o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/38
CPCC07D215/38C07B2200/07Y02P20/584
Inventor 段伟良孔维炘
Owner YANGZHOU UNIV
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