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3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound and preparation method thereof

A technology of ketone compounds and dihydroquinolines, applied in the direction of organic chemistry, can solve the problems of inability to introduce, lack of step economy and atom economy, lack of substrate universality, etc., to achieve mild conditions and great practical value and socio-economic benefits, environmental friendliness

Pending Publication Date: 2020-05-05
ZUNYI MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are certain limitations in these two methods: (1) the use of highly toxic or flammable and explosive reagents or gases
For example, method one requires the use of highly corrosive and toxic F 2 , method two, need to use NaH (a kind of strong base, easy to produce flammable gas H in contact with water 2 ) and flammable and explosive H 2 ; (2) lack of step economy and atom economy; (3) lack of substrate universality, method 1 has only 1 example, method 2 has only 4 examples; (4) only C-F bonds can be introduced, CF cannot be introduced 2 group

Method used

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  • 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound and preparation method thereof
  • 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound and preparation method thereof
  • 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Synthesis of 4-(3,3-difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)benzonitrile (1a)

[0056]

[0057] 2-(Methyl(phenyl)amino)-2-glyoxylic acid (134mg, 0.75mmol), 4-(2,2-difluorovinyl)benzonitrile (82mg, 0.50mmol), K 2 S 2 o 8 (270mg, 1.0mmol), and AgNO 3 (8.5mg, 0.050mmol) was placed in a Schlenk tube with a magnetic stir bar. Evacuating the reaction tube and filling it with argon was repeated three times. Acetone (1.5 mL) and distilled water (1.5 mL) were successively added to the reaction. The resulting reaction mixture was stirred at 50°C for 9 hours. The resulting mixture was extracted with ethyl acetate (10 mL x 2), anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The resulting crude product was purified on a silica gel column with ethyl acetate and petroleum ether as eluents to obtain 4-(3,3-difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro Quinolin-4-yl)benzonitrile, white solid (117mg, yield 79%), mp 203.3-204.4°C; 1 H NMR (40...

Embodiment 2

[0058] Example 2: Synthesis of 3,3-difluoro-1-methyl-4-(p-tolyl)-3,4-dihydroquinolin-2(1H)-one (1b)

[0059]

[0060] 2-(Methyl(phenyl)amino)-2-glyoxylic acid (134mg, 0.75mmol), 1-(2,2-difluorovinyl)-4-toluene (77mg, 0.50mmol), K 2 S 2 o 8 (270mg, 1.0mmol), and AgNO 3 (8.5mg, 0.050mmol) was placed in a Schlenk tube with a magnetic stir bar. Evacuating the reaction tube and filling it with argon was repeated three times. Acetone (1.5 mL) and distilled water (1.5 mL) were successively added to the reaction. The resulting reaction mixture was stirred at 50°C for 9 hours. The resulting mixture was extracted with ethyl acetate (10 mL x 2), anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The resulting crude product was purified on a silica gel column with ethyl acetate and petroleum ether as eluents to give 3,3-difluoro-1-methyl-4-(p-tolyl)-3,4-dihydroquinoline -2(1H)-one, white solid (68mg, yield 47%), mp 157.2-157.3°C; 1 H NMR (400MHz, Chloroform-d) δ7.40 (t...

Embodiment 3

[0061] Example 3: N-(4-(3,3-difluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)phenyl)acetamide (1c )Synthesis

[0062]

[0063] 2-(Methyl(phenyl)amino)-2-glyoxylic acid (134mg, 0.75mmol), N-(4-(2,2-difluorovinyl)phenyl)acetamide (98mg, 0.50 mmol) ,K 2 S 2 o 8 (270mg, 1.0mmol), and AgNO 3 (8.5mg, 0.050mmol) was placed in a Schlenk tube with a magnetic stir bar. Evacuating the reaction tube and filling it with argon was repeated three times. Acetone (1.5 mL) and distilled water (1.5 mL) were successively added to the reaction. The resulting reaction mixture was stirred at 50°C for 9 hours. The resulting mixture was extracted with ethyl acetate (10 mL x 2), anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The resulting crude product was purified on a silica gel column with ethyl acetate and petroleum ether as eluents to obtain N-(4-(3,3-difluoro-1-methyl-2-oxo-1,2,3,4 -tetrahydroquinolin-4-yl)phenyl)acetamide, white solid (102mg, 62% yield), mp 180.9-...

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Abstract

The invention relates to a 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound and a preparation method thereof. AN oxamic acid derivative and gem-difluoroolefin are used as raw materials; in thepresence of a catalyst AgNO3 and an oxidizing agent (NH4)2S2O8, the raw materials are heated to react in acetone / water (v acetone / v water = 1: 1) to synthesize a series of 3, 3-difluoro-3, 4-dihydroquinoline-2(1H)-one compounds. In the reaction formula, the oxamic acid derivative is selected from R1 which is methyl or benzyl and R2 which is methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl; the gem-difluoroolefin compound is selected from R3 which is a cyano group, a methyl group, a trifluoromethyl group, a methoxy group, a tert-butyl group, bromine, chlorine, an acetamido group, an ester group, a phenyl group and a pyridyl group; and R4 is methyl or hydrogen. According to the method for synthesizing the 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound, a CF2 group isintroduced into a 3, 4-dihydroquinoline-2 (1H)-one structure, the synthesis method of the 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H)-one compound is provided, and the method has the advantages of good substrate universality, high atom economy, simple steps, mild condition, easily-available raw materials, environmental protection, wide application and high practical value.

Description

technical field [0001] The invention relates to a 3,3-difluoro-3,4-dihydroquinolin-2(1H)-one compound and a preparation method thereof, belonging to the field of organic synthetic chemistry. Background technique [0002] 3,4-Dihydroquinolin-2(1H)-one is an important class of nitrogen-containing heterocyclic compounds, and as a core structure ubiquitously exists in natural products and drug molecules, such as the antipsychotic drug aripiprazole (aripiprazole ) [1] , carteolol (carteolol) eye drops [2] , acetylcholinesterase inhibitor trigolutesin A [3] and the insecticide yaequinolone E [4] Wait. Moreover, 3,4-dihydroquinolin-2(1H)-one is also used as an important synthetic building block in the synthesis of drugs [5] . The introduction of fluorine atoms or fluorine-containing groups into small organic molecules can produce unique biological and physical properties, such as effectively improving the molecule's lipid solubility, metabolic stability, and binding character...

Claims

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Application Information

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IPC IPC(8): C07D215/227C07D401/06
CPCC07D215/227C07D401/06
Inventor 刘培均刘小卒陈国均
Owner ZUNYI MEDICAL UNIVERSITY
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