A kind of isoquinoline compound and its preparation method and application

A ketone compound and compound technology, which can be used in organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of kinase mutation and drug effect decline, and achieve the effects of simple operation, simple and safe reaction system, and low reaction cost.

Active Publication Date: 2022-05-27
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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  • A kind of isoquinoline compound and its preparation method and application
  • A kind of isoquinoline compound and its preparation method and application
  • A kind of isoquinoline compound and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0041] The preparation method of 5-methyl-12-phenyl-5-((phenylsulfo)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 (0.1 mmol), S-phenylbenzenesulfonate (0.1 mmol), TBPB (tert-butyl peroxybenzoate) (0.3 mmol) and copper bromide (0.01 mmol) were dissolved in 3 mL of DCE (dichloroethylene), and the reaction was heated and stirred at 100 ° C for 10 hours. 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, CDCl...

Embodiment 2

[0047] The preparation method of 5-butyl-12-phenyl-5-((phenylsulfo)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 (0.1 mmol), S-phenylbenzenesulfonate (0.1 mmol), TBPB (0.3 mmol) and copper bromide (0.01 mmol) were dissolved in 3 mL of DCE, and the reaction was heated and stirred at 100 ° C for 10 hours. After the reaction was completed, the solvent was quenched, extracted, dried, and distilled under reduced pressure to remove the solvent. Separation by silica gel column chromatography gave an oily substance.

[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=7.7 Hz, 2H), 7.17–7.12 (m, 1H), 7.05 (td, J=7.6, 1.3 Hz, 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....

Embodiment 3

[0053] The preparation method of 5-benzyl-12-phenyl-5-((phenylsulfo)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 (0.1 mmol), S-phenylbenzenesulfonate (0.1 mmol), TBPB (0.3 mmol) and copper bromide (0.01 mmol) were dissolved in 3 mL of DCE, and the reaction was heated and stirred at 100 ° C for 10 hours. After the reaction was completed, the solvent was quenched, extracted, dried, and distilled under reduced pressure to remove the solvent. Separation by silica gel column chromatography gave an oily substance.

[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,...

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Abstract

The invention discloses an isoquinoline compound, 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 benzimidazolo[2,1-a]isoquinolin-6(5H)ketone compound, and the preparation method is as follows: 1‑(2,3‑diphenyl‑1H‑indol‑1‑yl)‑2‑methacryl‑1‑ketone compound or 1‑methacryl‑2‑aryl‑benzimidazole The compounds and S-phenylbenzenethiosulfonate compounds are dissolved in an organic solvent, tert-butyl benzoate and a catalytic amount of copper bromide are added to react at 110°C to obtain isoquinoline compounds. The synthesis process of the invention does not require the participation of diazonium compounds, has the characteristics of cheap and easy-to-obtain raw materials, mild reaction conditions, simple 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 a preparation method and application thereof. Background technique [0002] Indolo[2,1-a]isoquinoline and benzimidazo[2,1-a]isoquinoline-6(5H)one compounds have a variety of biological activities and have achieved satisfactory results in recent years , and has been paid more and more attention by chemical researchers all over the world. At present, the existing methods for preparing isoquinoline compounds that can be used mostly use 2-phenylindoles or benzimidazoles and diazo compounds as raw materials to carry out the reaction under the heating condition of a metal catalyst. However, in the above-mentioned preparation process, the synthetic steps are relatively complicated, and the used diazonium compounds and metal catalysts are expensive and unsafe, and the reaction needs to be heated, and even needs to be reacted under the protection o...

Claims

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Application Information

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Patent Type & Authority Patents(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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