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Preparation method of 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative

A technology of tetrahydrofuran and methylquinoline, which is applied in the field of preparation of 2-methyl-4-quinoline derivatives, can solve the problems of low universality and achieve strong controllability, high reaction yield and wide applicability Effect

Active Publication Date: 2019-05-21
UNIV OF JINAN
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AI Technical Summary

Problems solved by technology

[0004] Due to the use of alkyl carboxylic acid in the reaction, the universality of the reaction is not high

Method used

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  • Preparation method of 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 2-Methylquinoline (1 mmol, 143 mg), Selectfluor (4 mmol, 1.4 g) and AgNO 3 (0.2mmol, 34mg) was added to an aqueous solution of tetrahydrofuran (10ml, THF:H 2 O=3:1) and reacted at 50°C for 3h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), combined organic layers, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate , filtered and concentrated. Column chromatography (eluent: ethyl acetate / n-hexane = 1:4) yielded 143 mg of the product 2-methyl-4-(tetrahydrofuran-2-yl)quinoline with a yield of 67%.

[0027] 1H NMR (600MHz, CDCl3) δ ppm 8.08 (d, J = 8.4 Hz, 1H), 7.85 (d, J =9.0 Hz, 1H), 7.67 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.51 – 7.47 (m, 1H), 7.46(s, 1H), 5.58 (t, J = 7.2 Hz, 1H), 4.26 – 4.20 (m, 1H), 4.05 (dd, J = 15.4,7.2 Hz, 1H), 2.76 (s, 3H), 2.62 (dtd, J = 12.5, 7.8, 6.6 Hz, 1H), 2.13 – 2.05(m, 1H), 2.01 (tt, J = 13.8, 7.0 Hz, 1H), 1.84 (ddt, J = 13.1, 8.1, 6.7 Hz, 1H). 13C NMR (151 MHz, CDCl3...

Embodiment 2

[0029] 2-Methyl-6-fluoroquinoline (1 mmol, 161 mg), Selectfluor (4 mmol, 1.4 g) and AgNO 3 (0.2mmol, 34mg) was added to an aqueous solution of tetrahydrofuran (10ml, THF:H 2 O=3:1) and reacted at 50°C for 3h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), combined organic layers, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate , filtered and concentrated. Column chromatography (eluent: ethyl acetate / n-hexane = 1:4) yielded 222 mg of the product 2-methyl-6-fluoro-4-(tetrahydrofuran-2-yl)quinoline with a yield of 90%.

[0030] 1 H NMR (600MHz, CDCl 3 ) δ ppm 8.04 (dd, J = 9.2, 5.6 Hz, 1H), 7.58(dd, J = 10.0, 2.7 Hz, 1H), 7.49 (s, 1H), 7.44 (ddd, J = 9.2, 8.1, 2.8 Hz ,1H), 5.20 (dd, J = 9.9, 2.4 Hz, 1H), 4.05 (tdd, J = 14.6, 11.9, 2.6 Hz, 3H),3.92 – 3.86 (m, 1H), 3.80 (ddd, J = 11.8 , 10.2, 4.2 Hz, 1H), 3.48 (dd, J =11.9, 9.9 Hz, 1H), 2.73 (s, 3H).; 13 C NMR (151 MHz, CDCl 3 ) δ ppm 160.92,159.28, 15...

Embodiment 3

[0032] 2-Methyl-6-chloroquinoline (1 mmol, 177 mg), Selectfluor (4 mmol, 1.4 g) and AgNO 3 (0.2mmol, 34mg) was added to an aqueous solution of tetrahydrofuran (10ml, THF:H 2 O=3:1) and reacted at 50°C for 3h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), combined organic layers, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate , filtered and concentrated. Column chromatography (eluent: ethyl acetate / n-hexane = 1:4) yielded 210 mg of the product 2-methyl-6-chloro-4-(tetrahydrofuran-2-yl)quinoline with a yield of 80%.

[0033] 1 H NMR (600MHz, CDCl 3 ) δ ppm 7.97 (d, J = 9.0 Hz, 1H), 7.93 (d, J =2.2 Hz, 1H), 7.61 (dd, J = 9.0, 2.3 Hz, 1H), 7.50 (s, 1H), 5.24 ( dd, J = 9.9,2.3 Hz, 1H), 4.13 – 3.99 (m, 3H), 3.94 – 3.87 (m, 1H), 3.80 (ddd, J = 11.8,9.8, 4.5 Hz, 1H), 3.46 (dd, J = 11.9, 9.9 Hz, 1H), 2.73 (s, 3H).; 13 C NMR (151MHz, CDCl 3) δ ppm 159.38, 146.21, 142.77, 131.83, 131.16, 130.05, 124.27, 12...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative. The method comprises the following steps: reacting 2-methyl quinoline and its derivatives with tetrahydrofuran in water phase catalyzed by Selectfluor / AgNO3 to obtain a 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative, a product of dehydrogenation coupling of the 4-position of the 2-methyl quinoline derivative and the 2-psition of the tetrahydrofuran of the 2-methyl quinoline derivative through column chromatography. Carried out ina mixture of water and tetrahydrofuran under the catalysis of Selectfluor / AgNO3, the preparation method of the 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative has the advantages of good solubility, wide applicability, high yield of reaction and strong controllability. The preparation method of the 2-methyl-4-(tetrahydrofuran-2-base) quinoline derivative is green and environmental protection, less by-reaction products, green and high efficiency.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of 2-methyl-4-(tetrahydrofuran-2-yl)quinoline derivatives. Background technique [0002] N-heteroaromatic hydrocarbons are important and ubiquitous building blocks in the frameworks of drugs, natural products and ligands. The functional modification of its C-H bond has very important pharmaceutical and economic value in the synthesis of drug molecules. In the prior art, the method adopted by this type of compound is that in the presence of a catalyst, a carbon free radical is formed by combining an alkyl carboxylic acid and a single-electron oxidant, and then the carbon free radical is nucleophilicly added to the electron-deficient hybrid to generate an aromatic The substitution reaction of the family, the reaction is as follows: [0003] [0004] Due to the use of alkyl carboxylic acid in the reaction, the universality of the reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
Inventor 王守锋范亚飞邢姝雅
Owner UNIV OF JINAN
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