Synthetic method for high-enantioselectivity N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds

An enantioselective, quinolinone-based technology, applied in the direction of heterocyclic compound active ingredients, organic active ingredients, organic chemistry, etc., can solve problems such as unpreparable, unobtainable, inconsistent steps and atom economy requirements, etc. , to achieve the effect of simple preparation and high enantioselectivity

Active Publication Date: 2014-02-26
南京方生和医药科技有限公司
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Problems solved by technology

The first type of method can only prepare 2-aryl-2,3-dihydro-4-quinolinone compounds, but cannot produce 2-alkyl-2,3-dihydro-4-quinolinone compounds; The second type of method must introduce an ester group into the substrate and remove it after the product is obtained, which does not meet the current steps and atom economy requirements
Recently, Rueping et al. reported a Brensted acid-catalyzed intramolecular asymmetric aza-Michael addition of aminochalcone derivatives (Rueping, M.; Moreth, S.A.; Bolte, M.Z. Naturforsch. (B) 2012 ,67,1021), 2-aryl-2,3-dihydro-4-quinolinone can be synthesized, but the ee value is only 49-63%, and 2-alkyl-2,3-dihydro -4-Quinolinones

Method used

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  • Synthetic method for high-enantioselectivity N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds
  • Synthetic method for high-enantioselectivity N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds
  • Synthetic method for high-enantioselectivity N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds

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Experimental program
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Effect test

Embodiment 1

[0021] Embodiment 1: the synthesis of N-acetyl-2-phenyl-2,3-dihydro-4-quinolinone (Va)

[0022] Add 1-(2-N-acetylaminophenyl)-3-phenyl-2,3-unsaturated acetone 0.1mmol in the reaction flask, quinine-derived thiourea 0.02mmol (catalyst shown in the technical scheme part Structural formula), benzoic acid 0.06mmol and toluene 1mL, stirred at 90°C for 48 hours, purified by column chromatography after reaction to obtain N-acetyl-2-phenyl-2,3-dihydro-4-quinolinone (Va) , the yield was 84%, 1 H NMR (400MHz, CDCl 3 )δ7.94-7.91(m,1H),7.48–7.44(m,1H),7.22–7.13(m,7H),6.47(s,1H),3.37(dd,J=18.0,1.6Hz,1H) ,3.25(dd,J=18.0,5.6Hz,1H),2.43(s,3H). The substance has strong anti-cancer activity (Y.Xia, Z.-Y.Yang, P.Xia, K.F.Bastow, Y.Tachibana, S.-C.Kuo, E.Hamel, T.Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155).

Embodiment 2

[0023] Embodiment 2: Synthesis of N-acetyl-2-(4-methylphenyl)-2,3-dihydro-4-quinolinone (Vb)

[0024] Reaction conditions and purification steps are as N-acetyl-2-phenyl-2,3-dihydro-4-quinolinone (Va) in embodiment 1, by raw material 1-(2-N-acetyl-aminobenzene base)-3-(4-methylphenyl)-2,3-unsaturated acetone (Ⅲb) to synthesize the target product Ⅴb with a yield of 77%. 1 H NMR (400MHz, CDCl 3)δ7.92(d,J=6.8Hz,1H),7.48–7.44(m,1H),7.29(br,1H),7.187.14(m,1H),7.06(d,J=8.0Hz,1H ),6.99(d,J=8.1Hz,1H),6.42(s,1H),3.34(dd,J=18,1.7Hz,1H),3.22(dd,J=18,5.8Hz,1H),2.42 (s,1H),2.21(s,1H).

Embodiment 3

[0025] Embodiment 3: Synthesis of N-acetyl-2-biphenyl-2,3-dihydro-4-quinolinone (Vc)

[0026] Reaction conditions and purification steps are as N-acetyl-2-phenyl-2,3-dihydro-4-quinolinone (Va) in embodiment 1, by raw material 1-(2-N-acetyl-aminobenzene base)-3-biphenyl-2,3-unsaturated acetone (Ⅲc) to synthesize the target product (Ⅴc) with a yield of 77%. 1 H NMR (400MHz, CDCl 3 )δ7.95(dd,J=7.6,1.2Hz,1H),7.50–7.16(m,12H),6.51(s,1H),3.40(dd,J=18.0,1.6Hz,1H),3.27(dd ,J=18.0,6.0Hz,1H),2.45(s,3H).

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Abstract

A synthetic method for high-enantioselectivity N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds is disclosed. A raw material 1-aryl-3-aryl (or alkyl)-2, 3-unsaturated ketone is subjected to an intramolecular 6-endo-trig aza-Michael addition reaction for 4 days under the effect of 0. 2 equivalent of a quinine-derived thiourea compound organic micromolecule catalyst, then separation purification is carried out for obtaining of the N-acetyl-2-substitued-2, 3-dihydro-4-quinolinone compounds. The quinine-derived thiourea compound organic micromolecule catalyst has a structure shown in the specification, wherein R1 represents a bromine atom or a hydrogen atom, R2 represents aryl or alkyl, and R3 represents tosyl (Ts) or acetyl (Ac). Compared with conventional preparation methods, the preparation method provided by the invention employs the simply prepared raw material, the obtained products are substantially high in enantioselectivity, and the products have extremely good application to antitumor drugs and antibacterial medicaments.

Description

technical field [0001] The invention relates to a synthesis method of N-acetyl-2-substituted-2,3-dihydro-4-quinolinone compounds. Background technique [0002] 2-substituted-2,3-dihydro-4-quinolinones (dihydroquinolinones, also known as Azaflavanones) are a class of nitrogen-containing benzoquinolinones with antitumor activity (Zhang, S.-X et al.J.Med.Chem.2000,43,167) and antimalarial activity (Patti,A.et al.J.Organomet.Chem.2012,716,216), can be used as cross-species microRNA inhibitors (Srivari Chandrasekhar et al. Bioorg.Med.Chem.Lett.22,2012,645–648), and is also a key intermediate in the synthesis of many natural products with important biological activities (Ma,D.et al.J.Org.Chem.2003,68,442). [0003] [0004] Due to the important biological activity of this kind of structural skeleton, it has attracted the research interest of the majority of medicinal chemistry and synthetic chemistry workers, trying to develop a reasonable chemical synthesis route, on the one ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/233C07D409/04A61K31/47A61K31/4709A61P35/00A61P31/04
CPCC07D215/233C07D409/04
Inventor 俞寿云程双华
Owner 南京方生和医药科技有限公司
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