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Polyhalogenated isoquinoline class derivate and synthetic method thereof

A technology for isoquinolines and a synthesis method, which is applied in the field of polyhalogenated isoquinoline derivatives and the synthesis thereof, can solve the problems of long route, low total yield, large limitation of substrate range, etc. The synthesis process is simple, the route is simple, and the effect of molecular diversity is achieved

Inactive Publication Date: 2009-09-30
YUNNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Synthetic methods of isoquinoline derivatives usually have long routes and low overall yields, limited scope of substrates or use of expensive and toxic heavy metal catalysts, etc. It is of great significance to develop and research highly efficient and low-toxic antitumor drugs

Method used

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  • Polyhalogenated isoquinoline class derivate and synthetic method thereof
  • Polyhalogenated isoquinoline class derivate and synthetic method thereof
  • Polyhalogenated isoquinoline class derivate and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: 10-benzoyl-6,8,9-trichloro-7-cyano-5-imino-1,2,3,5-tetrahydroimidazo[1,2-b]isoquine Synthesis of phenoline (I-A): Add 0.53 g (2 mmol) 2,4,5,6-tetrachloro-1,3-phthalonitrile and 0.38 g (2 mmol) 2-benzoyl to a mortar Methyleneimidazolinidine, after being fully ground, was heated to 140°C for 30 minutes while grinding on a heating mantle, and the reaction mixture changed from colorless to dark yellow. After TLC showed that the raw materials disappeared completely, 25 ml of 1, 4-Dioxane was transferred to a 50 ml round bottom flask, and 0.22 g (2 mmol) of potassium tert-butoxide was added to react at room temperature for 30 minutes. TLC showed that the reaction of the intermediate was complete, and the reaction was stopped. Column chromatography (ethyl acetate / petroleum ether=2:1) ​​yielded the product 10-benzoyl-6,8,9-trichloro-7-cyano-5-imino-1,2,3,5 - Tetrahydroimidazo[1,2-b]isoquinoline. Yellow solid, 80% yield. Its melting point is: 216-219°C.

[0027] P...

Embodiment 2

[0029] Example 2: 10-benzoyl-6,8-difluoro-9-chloro-7-cyano-5-imino-1,2,3,5-tetrahydroimidazo[1,2-b] Synthesis of isoquinoline (I-B): 0.43 g (2 mmol) 2,4,6-trifluoro-5-chloro-1,3-phthalonitrile and 0.38 g (2 mmol) 2 - Benzoylmethyleneimidazolinidine, after fully pulverized, heated to 120°C for 15 minutes while grinding on the heating mantle, the reaction mixture changed from colorless to dark yellow, TLC showed that the raw materials disappeared completely, and then used 25 ml of 1,4-dioxane was transferred to a 50 ml round bottom flask, and 0.22 g (2 mmol) of potassium tert-butoxide was added to react at room temperature for 30 minutes. TLC showed that the reaction of the intermediate was complete, and the reaction was stopped. Column chromatography (ethyl acetate / petroleum ether=2:1) ​​gave a yellow solid with a yield of 87%. Its melting point is: 260-262°C.

[0030] Proton NMR spectrum (deuterated dimethyl sulfoxide as solvent, Bruker AM 500 instrument): δ=8.64 (br, 2H, NH...

Embodiment 3

[0034]Example 3: 10-Benzoyl-6,8,9-trifluoro-7-cyano-5-imino-1,2,3,5-tetrahydroimidazo[1,2-b]isoquine Synthesis of phenoline (I-C): Add 0.40 g (2 mmol) 2,4,5,6-tetrafluoro-1,3-phthalonitrile and 0.38 g (2 mmol) 2-benzoyl to a mortar Methyleneimidazolinidine, after being fully ground, was heated to 90°C for 10 minutes while grinding on a heating mantle, and the reaction mixture changed from colorless to dark yellow. After TLC showed that the raw materials disappeared completely, 25 ml of 1, 4-Dioxane was transferred to a 50 ml round bottom flask, and 0.22 g (2 mmol) of potassium tert-butoxide was added to react at room temperature for 30 minutes. TLC showed that the reaction of the intermediate was complete, and the reaction was stopped. Column chromatography (ethyl acetate / petroleum ether=2:1) ​​gave a yellow solid with a yield of 94%. Its melting point is: 257-259°C.

[0035] Fluorine nuclear magnetic resonance spectrum (deuterated dimethyl sulfoxide as solvent, Bruker AM 50...

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Abstract

The invention discloses a novel polyhalogenated isoquinoline class derivate and a synthetic method thereof. The structure of the polyhalogenated isoquinoline class derivate is as a formula I, wherein Z=NH, NR', O, S; n=1,2,3; the R' is alkyl and aryl; R is the alkyl, the aryl, heteroaryl, condensed aryl, alkoxyl and alkylthio group; R1 is a halogen atom, a hydrogen atom, the alkyl, the aryl, alkylamino radical, arylamine, alkylthio group and arylthio; R2 is cyano-group, nitryl, ester group, the halogen atom, the hydrogen atom, the alkyl, the aryl, the alkylamino radical, the arylamine, the alkylthio group and the arylthio; X1 is the halogen atom; and the X2 is also the halogen atom. The synthetic method of the polyhalogenated isoquinoline class derivate including the steps of porphyrizing and heating polyhalogenated cyanobenzene and heterocyclic ketene aminals derivates in a mortar. When raw materials are basically completely disappeared, and the polyhalogenated cyanobenzene and the heterocyclic ketene aminals derivates are all transferred to a round bottom flask by menstruum and then reacted to synthesize the polyhalogenated isoquinoline class derivate with potential medicine activity in the formula I after a catalyst is added into the round bottom flask. The invention has simple synthesis technology, high productive rate, stable products, simple routes, rapidness, and the like, realizes a parallel high-efficiency heterocyclic compound library and really realizes the molecular diversity.

Description

technical field [0001] The invention relates to polyhalogenated isoquinoline derivatives with potential drug activity and a synthesis method thereof. Background technique [0002] Isoquinoline alkaloids have a wide range of physiological activities such as anti-tumor, anti-HIV, anti-leukemia, anti-bacterial, anti-oxidation, anti-malarial, analgesic, anti-arrhythmic, anti-platelet aggregation, antihypertensive, immune regulation, etc. The content in plants is very low, and it is difficult to separate and extract from plants to meet the needs of modern drug development. In recent years, the synthesis of isoquinoline derivatives with novel structures has become one of the hotspots in drug research. [0003] Synthetic methods of isoquinoline derivatives usually have long routes and low overall yields, limited substrate scope or use expensive and toxic heavy metal catalysts, etc. Therefore, establishing a simple and efficient method for constructing isoquinoline skeletons is It...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D498/04
Inventor 严胜骄林军黄超苏寸香董莹黄荣
Owner YUNNAN UNIV
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