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Preparation method of 4-(1,4-dioxan-2-yl) quinoline-2-methyl formate derivatives

A technology of methyl formate and dioxane, which is applied in the field of preparation of 4-quinoline-2-carboxylic acid methyl ester derivatives, can solve the problems of complex synthesis process, low yield of quinoline compounds and the like, and achieves the reaction yield. The effect of high rate, wide applicability and strong controllability

Active Publication Date: 2019-08-23
UNIV OF JINAN
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Problems solved by technology

In the existing preparation method, the yield of the prepared quinoline compound is low, and the synthesis process is complicated

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Methyl quinoline-2-carboxylate (1 mmol, 187 mg), Selectfluor (4 mmol, 1.4 g) and FeSO 4 ·7H 2 O (4mmol, 1112mg) was added to 1,4-dioxane solution (20ml) and reacted at 80°C for 24h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), combined the organic layers, Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Column chromatography (eluent: ethyl acetate / n-hexane = 1:4) yielded 247mg of the product 4-(1,4-dioxane-2-yl)quinoline-2-carboxylic acid methyl ester, the yield was 90%.

[0022] 1 H NMR (600 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.07(d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 5.41(dd, J = 9.9, 2.2 Hz, 1H), 4.16 – 4.03 (m, 6H), 3.91 (dd, J = 11.7, 2.0 Hz,1H), 3.84 (dd, J = 11.3, 3.3 Hz, 1H), 3.51 (dd, J = 11.4, 10.4 Hz, 1H).

Embodiment 2

[0024] Methyl 6-fluoroquinoline-2-carboxylate (1 mmol, 205 mg), Selectfluor (4 mmol, 1.4 g) and FeSO 4 ·7H 2 O (4 mmol, 1112mg) was added to 1,4-dioxane solution (20ml) and reacted at 80°C for 24h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), and combined the 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 203 g of the product 6-fluoro-4-(1,4-dioxane-2-yl)quinoline-2-carboxylic acid methyl ester , and the yield was 70%.

[0025] 1 H NMR (600 MHz, CDCl 3 ) δ 8.34 (s, 1H), 8.10 (dd, J = 9.3, 5.8 Hz,1H), 7.97 (dd, J = 9.7, 2.5 Hz, 1H), 7.51 – 7.46 (m, 1H), 5.36 (dd, J = 9.9,2.4 Hz, 1H), 4.15 – 4.01 (m, 7H), 3.91 (dd, J = 11.8, 2.3 Hz, 1H), 3.83 (td, J = 11.5, 3.2 Hz, 1H), 3.52 (dd, J = 11.7, 10.1 Hz, 1H).

Embodiment 3

[0027] 7-fluoro-quinoline-2-carboxylic acid methyl ester (1 mmol, 205 mg), Selectfluor (4 mmol, 1.4 g) and FeSO 4 ·7H 2 O (4 mmol, 1112mg) was added to 1,4-dioxane solution (20ml) and reacted at 80°C for 24h, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (3*10 mL), and combined the 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 227 mg of the product 7-fluoro-4-(1,4-dioxane-2-yl)quinoline-2-carboxylic acid methyl ester , and the yield was 78%.

[0028] 1 H NMR (600 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.35 (dd, J = 9.3, 5.6 Hz,1H), 7.70 (dd, J = 9.8, 2.6 Hz, 1H), 7.60 – 7.55 (m, 1H), 5.27 (dd, J = 9.9,2.1 Hz, 1H), 4.14 – 4.01 (m, 7H), 3.91 (dd, J = 11.7, 1.9 Hz, 1H), 3.84 (td, J = 11.4, 3.2 Hz, 1H), 3.53 (dd, J = 11.6, 10.2 Hz, 1H).

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Abstract

The invention belongs to the technical field of chemical synthesis, in particular to a preparation method of 4-(1,4-dioxan-2-yl) quinoline-2-methyl formate derivatives. The method is realized by the following steps: under the catalysis of Selectfluor / FeSO4.7H2O, allowing quinoline-2-methyl formate and its derivatives to react with 1, 4-dioxane, performing column chromatography to obtain 4-(1,4-dioxan-2-yl) quinoline-2-methyl formate derivatives. The method provided by the invention is that Selectfluor / FeSO4.7H2O is used for catalyzing, 1,4-dioxan reacts, the substrate solubility is good and the applicability is wide; and the yield of the reaction is high and the controllability is strong. The method provided by the invention has the advantages of environmental protection, less by-reactionproducts, 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 4-(1,4-dioxane-2-yl)quinoline-2-carboxylic acid methyl ester derivatives. Background technique [0002] Quinoline compounds have a wide range of pharmaceutical activities, such as anti-HIV, anti-inflammatory and anti-tumor. In organic synthesis reactions, by C(sp 3 )-H bond activation to construct C—C bond is a convenient and atom-economics method. However, the C(sp 3 )-H bond activation is a big challenge, and there are few reports so far. and C(sp 3 )-H bond activation compared to the C(sp on the quinoline ring 2 )-H bond activation is more challenging. Various researchers are conducting continuous efforts to try to discover new, potentially effective, highly active drugs. In the existing preparation method, the yield of the prepared quinoline compound is low, and the synthesis process is complicated. Contents of the inven...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 蔡延博常龙凤李航蕾王文贵王守锋
Owner UNIV OF JINAN
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