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Synthesis of 1-R-4-amino-1,2,3,4-tetrahydroquinoline

A tetrahydroquinoline and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of inconvenient reaction operation, difficult amplification of raw materials, long route, etc., and achieve the effect of simple and easy-to-obtain raw materials, high yield, and reasonable process selection

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-4-amino-1,2,3,4-tetrahydroquinoline
  • Synthesis of 1-R-4-amino-1,2,3,4-tetrahydroquinoline
  • Synthesis of 1-R-4-amino-1,2,3,4-tetrahydroquinoline

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Experimental program
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Effect test

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

[0026]

[0027] 1. Synthesis of 1-ethyl-1H-quinolin-4-one

[0028] 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%).

[0029] 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).

[0030] 2. Synthesis of 1-ethyl-4-hydroxy-1,2,3,4-tetrahydroquinoline

[0031] 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, ...

Embodiment 3

[0040]

[0041] 1. Synthesis of 1-benzyl-1H-quinolin-4-one

[0042] 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 g, yield 31%).

[0043] 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).

[0044] 2. Synthesis of 1-benzyl-4-hydroxy-1,2,3,4-tetrahydroquinoline

[0045] 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, te...

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Abstract

The invention relates to a method for synthesizing 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline, which mainly solves the technical problems that the prior synthesis method is difficult to amplify, long in route, inconvenient in reaction operation, and the like. The invention adopts a technical proposal that the method for synthesizing 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline 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; c. corresponding alcohol of anhydrous tetrahydrofuran dissolved in the solvent is added to diphenoxyphosphinyl azide so as to be transformed into corresponding azide; and d. the obtained azide is dissolved in the solvent, and the 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline is obtained by a hydrogenation or chemical reduction method.

Description

Technical field: [0001] The invention relates to a synthesis method of 1-R-4-amino-1,2,3,4-tetrahydroquinoline. Background technique: [0002] 1-Alkyl-4-amino-1,2,3,4-tetrahydroquinolines are widely used in medicinal chemistry and organic synthesis. The synthesis of such compounds such as WO2005 / 42533A2 (2005 / 05 / 12), J.Chem.Soc., 1954,403-406 at present; FR806715,1936; Chem.Abstr., 1961,3600; J.Med.Chem. , 8, 1965, 566-569 et al. Mainly through the addition of the corresponding monosubstituted alkylaniline and propylene ester or nitrile, the corresponding ketone is obtained through the intramolecular Friedel-Crafts reaction, which is converted into an oxime, and after hydrogenation and reduction, 1-alkyl-4-amino- 1,2,3,4-tetrahydroquinoline, 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 lar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/42
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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