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Synthesis of 1-R-2,3-dihydrogen-1H-quinoline-4-ketone

A synthesis method and 1-R-2 technology, applied in organic chemistry and other directions, can solve the problems of inconvenient reaction operation, difficult amplification of raw materials, long route, etc., and achieve the effects of simple raw materials, easy amplification and high yield

Active Publication Date: 2009-05-13
上海药明康德新药开发有限公司
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Problems solved by technology

It mainly solves the technical problems in the current synthesis method that the raw materials are not easy to enlarge, the route is long, and the reaction operation is inconvenient.

Method used

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  • Synthesis of 1-R-2,3-dihydrogen-1H-quinoline-4-ketone
  • Synthesis of 1-R-2,3-dihydrogen-1H-quinoline-4-ketone
  • Synthesis of 1-R-2,3-dihydrogen-1H-quinoline-4-ketone

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Experimental program
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Embodiment 1

[0012]

[0013] 1. Synthesis of 1-methyl-1H-quinolin-4-one

[0014] At room temperature, iodomethane (11.8g, 82.8mmol) was slowly added dropwise to 4-hydroxyquinoline (4g, 27.6mmol) and K 2 CO 3 (7.6g, 55.2mmol) in acetonitrile solution. After dropping, heat to reflux overnight. Then the reaction solution was spin-dried, and 200 mL of ethyl acetate was added to the residue, stirred for 0.5 hours and filtered, and the filtrate was spin-dried to obtain 1-methyl-1H-quinolin-4-one (2.8 g, yield 64%).

[0015] 1 H-NMR (400MHz, DMSO): δ 8.14(d, J=7.6Hz, 1H), 7.94(d, J=7.6Hz, 1H), 7.72(t, J=13.2Hz, 1H), 7.63(d, J=8.4Hz, 1H), 7.37(t, J=14.4Hz, 1H), 6.01(d, J=11.6Hz, 2H), 3.78(s, 3H).

[0016] 2. Synthesis of 1-methyl-4-hydroxy-1,2,3,4-tetrahydroquinoline

[0017] Dissolve 1-methyl-1H-quinolin-4-one (1g, 6.3mmol) in methanol, add NaBH under ice-bath cooling 4 (1.9 g, 50.3 mmol), then stirred overnight at room temperature. After the reaction solution was quenched with ice wat...

Embodiment 2

[0023]

[0024] 1. Synthesis of 1-ethyl-1H-quinolin-4-one

[0025] At room temperature, iodoethane (12.9g, 82.8mmol) was slowly added dropwise to 4-hydroxyquinoline (4g, 27.6mmol) and K 2 CO 3 (7.6g, 55.2mmol) in ethanol solution. After dropping, heat to reflux overnight. Then the reaction solution was spin-dried, and 200 mL of ethyl acetate was added to the residue, stirred for 0.5 hours and filtered, and the filtrate was spin-dried to obtain 1-ethyl-1H-quinolin-4-one (2.86 g, yield 60%).

[0026] 1 H-NMR (400MHz, DMSO): δ 8.17 (d, J = 8Hz, 1H), 7.99 (d, J = 7.6Hz, 1H), 7.72 (m, J = 3.6Hz, 2H), 7.36 (m, J =15.6Hz, 1H), 6.04(d, J=7.6Hz, 1H), 4.26(q, J=21.2Hz, 2H), 1.32(t, 3H).2.1-ethyl-4-hydroxyl-1,2 , the synthesis of 3,4-tetrahydroquinoline

[0027] Dissolve 1-ethyl-1H-quinolin-4-one (1g, 5.8mmol) in ethanol, add KBH under ice-bath cooling 4 (2.49g, 46.2mmol), then stirred overnight at room temperature. After the reaction solution was quenched with ice water, the ...

Embodiment 3

[0033]

[0034] 1. Synthesis of 1-benzyl-1H-quinolin-4-one

[0035] At room temperature, benzyl bromide (7g, 41.3mmol) was slowly added dropwise to 4-hydroxyquinoline (2g, 13.8mmol) and K 2 CO 3(3.8g, 27.6mmol) in tetrahydrofuran solution. After dropping, heat to reflux overnight. Then the reaction solution was spin-dried, and 200 mL of ethyl acetate was added to the residue, stirred for 0.5 hours and filtered, and the filtrate was spin-dried to obtain 1-benzyl-1H-quinolin-4-one (1.0 g, yield 31%).

[0036] 1 H-NMR (400MHz, DMSO): δ 8.21(q, J=41.6Hz, 2H), 7.59(m, J=31.2Hz, 2H), 7.35-7.20(m, 6H), 6.14(d, J=7.6 Hz, 1H), 5.52(s, 2H).

[0037] 2. Synthesis of 1-benzyl-4-hydroxy-1,2,3,4-tetrahydroquinoline

[0038] 1-Benzyl-1H-quinolin-4-one (1 g, 4.3 mmol) was dissolved in anhydrous THF, and lithium aluminum hydride (0.65 g, 17 mmol) was added under ice-cooling, followed by stirring overnight at room temperature. After the reaction solution was quenched with ice water, t...

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Abstract

The invention relates to a method for synthesizing 1-R-2, 3-dihydrogen-1H-quinoline-4-ketone, which mainly solves the technical problems that the prior synthesis method is difficult to amplify raw material, long in route, inconvenient in reaction operation, and the like. The method for synthesizing 1-R-2, 3-dihydrogen-1H-quinoline-4-ketone is characterized by comprising the following steps: a. 4-hydroxyquinoline is taken as a raw material and reacts with alkyl halogenated matter, benzyl halogenated matter or alkyl sulphonic acid ester in solvent to form ketene; b. the ketene dissolves in the solvent, and a reducing agent is added to the solvent so as to obtain corresponding alcohol; and c. oxidant is added to the corresponding alcohol dissolved in the solvent, so as to obtain the 1-R-2, 3-dihydrogen-1H-quinoline-4-ketone through oxidation.

Description

Technical field: [0001] The invention relates to a synthesis method of 1-R-2,3-dihydro-1H-quinolin-4-one. Background technique: [0002] 1-R-2,3-dihydro-1H-quinolin-4-one has been widely used in medicinal chemistry and organic synthesis. At present, the synthesis of such compounds is mainly obtained through the intramolecular Friedel-Crafts reaction after the addition of the corresponding monosubstituted alkylaniline and acrylate or nitrile, as shown in the following documents: J.Chem.Soc., 1954, 403-406 ; FR806715, 1936; Chem.Abstr., 1961, 3600; The route is synthesized as follows: [0003] [0004] In the above-mentioned existing methods, the first step of intramolecular Friedel-Crafts reaction cyclization is mainly carried out by polyphosphoric acid, which requires a large amount of polyphosphoric acid, high reaction temperature, difficult post-treatment, and difficult to scale up. At the same time, some of these ketones are highly water-soluble and difficult to ext...

Claims

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Application Information

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IPC IPC(8): C07D215/233
Inventor 蒋剑峰楼良马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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