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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, antipyretics, etc., can solve the problems of long reaction time of metal catalysts, expensive chiral phosphoric acid, and poor universality of substrates , to achieve good practical significance and application value, green and efficient synthesis, and good substrate universality

Inactive Publication Date: 2021-11-16
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. This 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. Control the reaction temperature of the system, keep stirring, trace the reaction by spotting samples on the thin-layer chromatographic plate until the reaction of the raw materials is complete. After the reaction is completed, a 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, set up 9 parallel test groups, using different catalysts and solvents respectively. Catalysts are acetic acid / ammonium acetate Ac(OH) / NH 4 OAc, Piperidine, Sc(OTf) 3 , copper trifluoromethanesulfonate Cu(OTf) ...

Embodiment 2

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

[0062] Product: 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 benzoyl acetate, p-nitrobenzaldehyde

[0069] Product: 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 the 2, 3-dihydroquinoline-4-ketone bioactive skeleton is shown in the specification, wherein 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 bioactive skeleton and its synthesis method and application. Background technique [0002] 2,3-Dihydroquinolin-4-one biologically active backbone compounds are an important class of heterocyclic compounds, which are widely used in antimalarial, anticancer, analgesic and other fields. For example, in 2012, Angela Patti's research group at CNR Institute of Biomolecular Chemistry in Italy found that 2-ferrocene-2,3-dihydroquinolin-4-one has good antimalarial activity. In 2011, the Chul Min Park research group of the Korea Institute of Chemical Technology discovered that 1-(arylsulfonyl)-2,3-dihydroquinolin-4-one derivatives have the effect on 5-HT 6 exhibited high binding affinity (IC 50 =8nM) has good selectivity to serotonin and dopamine, showing its excellent anticancer activity. In 1965, the Atwal research group of the University of Illi...

Claims

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Application Information

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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