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2, 3-dihydroquinoline-4-ketone bioactive skeleton as well as synthesis method and application thereof

A synthetic method and technology of dihydroquinoline, applied in drug combination, non-central analgesics, organic chemistry, etc., can solve the problems of long reaction time of metal catalysts, poor substrate universality, and high price of chiral phosphoric acid, etc. Achieve good practical significance and application value, good substrate universality, green and efficient synthesis

Pending Publication Date: 2022-05-27
山东瀚华工程设计有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In 2015, the research group of Takahiko Akiyama of Gakushuin University reported the method of asymmetric synthesis of 2,3-dihydroquinolin-4-one skeleton catalyzed by chiral phosphoric acid (Org.Lett.2015,17,3202-3205), Chiral phosphoric acid is expensive and takes a long time to react
[0010] Although the above reactions can efficiently synthesize 2,3-dihydroquinolin-4-one skeletons, expensive metal catalysts or long reaction times, long routes, and poor substrate universality greatly limit the application of these reactions, especially Its application in the industrialization of pharmaceutical production

Method used

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  • 2, 3-dihydroquinoline-4-ketone bioactive skeleton as well as synthesis method and application thereof
  • 2, 3-dihydroquinoline-4-ketone bioactive skeleton as well as synthesis method and application thereof
  • 2, 3-dihydroquinoline-4-ketone bioactive skeleton as well as synthesis method and application thereof

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Experimental program
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Embodiment 1

[0047] 1. The present embodiment provides a method for synthesizing a 2,3-dihydroquinolin-4-one biologically active skeleton, comprising the following steps:

[0048]Take 0.1 mmol of methyl 2-aminobenzoylacetate compound in a reaction flask, and add 1 mL of solvent, 0.15 mmol of formaldehyde compound and catalyst in sequence. The reaction temperature of the system was controlled, stirring was continued, and the reaction was followed by spotting on a thin-layer chromatographic plate until the reaction of the raw materials was complete. After the reaction is completed, the silica gel column is used for separation and purification, and the purified product is rotary evaporated to obtain the target product. The reaction formula is as follows:

[0049]

[0050] 2. According to the above method, 9 groups of parallel test groups were set up, respectively using different catalysts and solvents. The catalysts are acetic acid / ammonium acetate Ac(OH) / NH respectively 4 OAc, Piperidi...

Embodiment 2

[0061] Raw materials: methyl 2-tetrahydropyrrole benzoylacetate, benzaldehyde

[0062] Product: chemical formula C 21 H 21 NO 3

[0063] Molecular weight: 335.4030

[0064] Structural formula:

[0065] Yield: 79%

[0066] 1 H NMR (500MHz, CDCl 3 )δ7.69(d,J=7.9Hz,1H),7.38(t,J=7.7Hz,1H),7.09–7.02(m,3H),6.94(d,J=4.3Hz,2H),6.67( dd,J=18.1,10.7Hz,1H),6.57(d,J=8.4Hz,1H),4.17(dd,J=9.5,5.6Hz,1H),3.81(s,3H),3.48(ddd,J =17.8,15.6,8.9Hz,2H),3.32(d,J=13.7Hz,1H),2.90(d,J=13.7Hz,1H),2.20–2.12(m,1H),2.09–1.91(m, 3H). 13 C NMR (126MHz, CDCl 3 )δ190.86(s), 171.96(s), 148.38(s), 136.30(s), 135.54(s), 130.71(s), 129.17(s), 127.47(s), 126.46(s), 118.29( s), 116.59(s), 112.73(s), 77.34(d, J=6.5Hz), 77.11(s), 76.86(s), 63.44(s), 61.74(s), 52.60(s), 46.83( s), 31.74(s), 26.23(s), 22.95(s).HRMS(ESI): calcd for C 21 H 21 NO 3 Na[M+Na] + :358.3922,found:358.3924.

Embodiment 3

[0068] Raw materials: methyl 2-tetrahydropyrrole benzoylacetate, p-nitrobenzaldehyde

[0069] Product: chemical formula C 21 H 20 N 2 O 5

[0070] Molecular weight: 380.1372

[0071] Structural formula:

[0072] Yield: 72%

[0073] 1 H NMR (500MHz, CDCl 3 )δ7.91(d,J=8.6Hz,1H),7.67(d,J=7.9Hz,1H),7.43(t,J=7.7Hz,1H),7.10(d,J=8.6Hz,1H) ,6.72(t,J=7.5Hz,1H),6.63(d,J=8.4Hz,1H),4.20(t,J=7.4Hz,1H),3.83(d,J=9.0Hz,2H),3.53 (ddd, J=17.4, 11.8, 7.5Hz, 1H), 3.43 (d, J=13.5Hz, 1H), 2.99–2.88 (m, 1H), 2.22 (dd, J=11.5, 7.6Hz, 1H), 2.09–1.95(m,2H). 13 C NMR (126MHz, CDCl 3 )δ190.10(s), 171.62(s), 148.39(s), 146.63(s), 144.50(s), 136.08(s), 131.64(s), 129.07(s), 122.58(s), 118.01( s), 117.10(s), 112.97(s), 77.33(s), 77.08(s), 76.83(s), 63.42(s), 61.98(s), 52.84(s), 46.88(s), 31.13( s), 26.21(s), 22.89(s).HRMS(ESI): calcd for C 21 H 20 N 2 O 5 Na[M+Na] + :403.3892,found:403.3896.

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Abstract

The invention discloses a 2, 3-dihydroquinoline-4-ketone bioactive skeleton as well as a synthesis method and application thereof, and belongs to the technical field of chemical synthesis. The technical scheme is as follows: the structural formula of a bioactive skeleton of the 2, 3-dihydroquinoline-4-ketone is as follows: in the formula, R1 is any one of nitrogen heterocyclic ring and ethyl; r2 is any one of nitrogen heterocyclic ring and methyl; r3 is any one of a hydrogen atom and a methoxy group; and R4 is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-benzyne. The method has the advantages of mild reaction conditions, good substrate universality, step economy, atom economy, high chemical selectivity, few byproducts, high yield, cheap raw materials and the like, and is convenient for industrial application in the future.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a 2,3-dihydroquinolin-4-one biologically active skeleton and a synthesis method and application thereof. Background technique [0002] 2,3-Dihydroquinolin-4-one biologically active skeleton compounds are an important class of heterocyclic compounds, which are widely used in anti-malarial, anti-cancer, analgesic and other fields. For example, in 2012, Angela Patti's group at the CNR Institute of Biomolecular Chemistry in Italy found that 2-ferrocene-2,3-dihydroquinolin-4-one has good antimalarial activity. In 2011, the research group of Chul Min Park of the Korea Institute of Chemical Technology discovered that 1-(arylsulfonyl)-2,3-dihydroquinolin-4-one derivatives were very important to 5-HT. 6 exhibit high binding affinity (IC 50 =8nM) has good selectivity for serotonin and dopamine, showing its excellent anticancer activity. In 1965, Atwal's group at the Universit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D215/56A61P35/00A61P29/00A61P33/06
CPCC07D471/04C07D215/56A61P35/00A61P29/00A61P33/06Y02A50/30
Inventor 李爱国王亮解容浩尹相莹陈宁梁国磊
Owner 山东瀚华工程设计有限公司
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