Isoquinoline compound as well as preparation method and application thereof

A technology of ketone compounds and compounds, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of drug effect decline, kinase mutation, etc., and achieve the effect of simple and safe reaction system, easy operation, and mild reaction conditions

Active Publication Date: 2021-11-26
ZHEJIANG PROVINCIAL PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, with the continuous use of drugs, problems such as kinase mutations and decreased drug effects have also been exposed (Bums T.F., Personalized treatment of EGFR mutant and ALK-positive patients in NSCLC, Expert Opin. Pharmacother., 2014, 15( 18):2693-2708; Zhang A., Discovery of novel 2,4-diarylaminopyrimidine analogues(DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALKkinases, J.Med.Chem.,2015,58(1): 197-211)

Method used

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  • Isoquinoline compound as well as preparation method and application thereof
  • Isoquinoline compound as well as preparation method and application thereof
  • Isoquinoline compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation method of 5-methyl-12-phenyl-5-((benzenesulfonyl)methyl)indole[2,1-α]isoquinolin-6(5H)-one (1), the steps are as follows:

[0042] 1-(2,3-diphenyl-1H-indol-1-yl)-2-methylpropenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (tert-butyl peroxybenzoate) (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE (ethylene dichloride), heated and stirred at 100°C for 10 hours, after the reaction was completed, the Quenching, extraction, drying, and distillation under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to obtain an oily substance.

[0043] The specific results are as follows:

[0044]

[0045] Yield: 85%. 1 H NMR (500MHz, CDCl 3 )δ8.49(d,J=8.2Hz,1H),7.53–7.41(m,6H),7.37(dd,J=8.1,1.1Hz,1H),7.34–7.28(m,2H),7.22–7.18 (m,4H),7.13(dd,J=7.9,0.8Hz,1H),6.99(td,J=7.7,1.3Hz,1H),6.95–6.85(m,1H),4.52(d,J=14.5 Hz,1H),3.90(d,J=16.3Hz,1H),1.61(s,3H). 13 C NMR (126MHz, CDC...

Embodiment 2

[0047] The preparation method of 5-butyl-12-phenyl-5-((benzenesulfonyl)methyl)indole[2,1-α]isoquinolin-6(5H)-one (2), the steps are as follows:

[0048] 1-(2,3-diphenyl-1H-indol-1-yl)-2-butylpropenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and heated and stirred at 100°C for 10 hours. After the reaction was completed, the solvent was removed by quenching, extraction, drying, and vacuum distillation, and the residue Separation by silica gel column chromatography to obtain an oil.

[0049] The specific results are as follows:

[0050]

[0051] Yield: 35%. 1 H NMR (400MHz, CDCl 3 )δ8.58(d,J=8.2Hz,1H),7.63–7.48(m,7H),7.45(dd,J=8.0,1.0Hz,1H),7.43–7.37(m,1H),7.35–7.27 (m,3H),7.23(t,J=7.7Hz,2H),7.17–7.12(m,1H),7.05(td,J=7.6,1.3Hz,1H),7.01–6.96(m,1H), 4.57(d,J=14.6Hz,1H),3.92(d,J=14.6Hz,1H),2.34–2.11(m,1H),1.89–1.72(m,1H),1.19–1.00(m,2H) ,0.97–0.79(m,2H),0.67(t,J=7.3Hz,3H). 13 C NMR (101...

Embodiment 3

[0053] The preparation method of 5-benzyl-12-phenyl-5-((benzenesulfonyl)methyl)indole[2,1-α]isoquinolin-6(5H)-one (3), the steps are as follows:

[0054] 1-(2,3-diphenyl-1H-indol-1-yl)-2-benzylpropenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and heated and stirred at 100°C for 10 hours. After the reaction was completed, the solvent was removed by quenching, extraction, drying, and vacuum distillation, and the residue Separation by silica gel column chromatography to obtain an oil.

[0055] The specific results are as follows:

[0056]

[0057] Yield: 46%. 1 H NMR (500MHz, CDCl 3 )δ8.53(d,J=8.2Hz,1H),7.58–7.52(m,2H),7.44–7.34(m,4H),7.33–7.29(m,1H),7.25(dd,J=14.9, 7.5Hz, 3H), 7.17–7.13(m, 1H), 7.14–7.08(m, 1H), 7.08–7.01(m, 2H), 6.88(ddd, J=11.2, 9.1, 4.2Hz, 2H), 6.69 (t, J=7.7Hz, 2H), 6.69(t, J=7.7Hz, 2H), 6.37(d, J=7.1Hz, 2H), 4.78(d, J=14.6Hz, 1H), 4.12(d ,J=14.6Hz,1H),3.33(d,J=1...

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Abstract

The invention discloses an isoquinoline compound as well as a preparation method and application thereof, and relates to the technical field of chemical synthesis. The isoquinoline compound is an indolo [2, 1-a] isoquinoline compound or a benzimidazo [2, 1-a] isoquinoline-6 (5H) ketone compound, and the preparation method comprises the following steps: dissolving a 1-(2, 3-diphenyl-1H-indole-1-yl)-2-methyl propenyl-1-ketone compound or a 1-methyl acryloyl-2-aryl-benzimidazole compound and an S-phenyl phenyl thiosulfonate compound in an organic solvent, adding tert-butyl benzoate oxide and a catalytic amount of copper bromide, and reacting at 110 DEG C to obtain the isoquinoline compound. The synthesis process does not need diazo compounds, has the characteristics of cheap and easily available raw materials, mild reaction conditions, simplicity and convenience in operation, high regioselectivity and high yield, and is beneficial to industrial production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to an isoquinoline compound and its preparation method and application. Background technique [0002] Indolo[2,1-a]isoquinoline and benzimidazolo[2,1-a]isoquinolin-6(5H)one compounds have a variety of biological activities, and have achieved satisfactory multi-faceted effects in recent years , and more and more attention has been paid by chemical researchers all over the world. At present, most of the available preparation methods of isoquinoline compounds use 2-phenylindole or benzimidazole compounds and diazo compounds as raw materials to react under the condition of metal catalyst heating. However, in the above-mentioned preparation process, the synthesis steps are cumbersome, and the diazo compounds and metal catalysts used are expensive and unsafe, and the reaction needs to be heated, and even needs to be reacted under the protection of an inert gas. Therefore, the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04A61P35/00
Inventor 王震郝荣荣张威郝珂
Owner ZHEJIANG PROVINCIAL PEOPLES HOSPITAL
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