Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation

A tetrahydroquinoline, asymmetric technology, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalysts, organic chemistry, etc., to achieve the effect of easy-to-obtain raw materials, mild reaction conditions, and convenient separation

Active Publication Date: 2015-06-17
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Abstract
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  • Application Information

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Problems solved by technology

However, they all mainly synthesize tetrahydroquinolines containing one or two chiral centers, while synthesizing tetrahyd

Method used

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  • Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation
  • Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation
  • Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation

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Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1: optimization of conditions

[0039] Under nitrogen protection, add 4-methyl-1,2,3,4-tetrahydroacridine (1a), 1,4-dihydropyridine (4,2.4eq.) and chiral phosphoric acid (CPA-3 , 5mol%), add 3-5 ml of 1,4-dioxane into the Schlenk tube. After stirring and reacting at 25°C for 15-24 hours, direct column chromatography (volume ratio of eluent petroleum ether and ethyl acetate is 30:1) to obtain pure product, the reaction formula is as follows:

[0040]

[0041] The yield is the separation yield. The enantiomeric excess of the product is determined by chiral liquid chromatography, and the diastereomeric excess is determined by crude nuclear magnetic spectrum. See Table 1.

[0042] Table 1. Optimization of asymmetric transfer hydrogenation conditions

[0043]

[0044] a 25°C

Embodiment 2

[0045] Example 2: Synthesis of tetrahydroquinoline compound 2 with three consecutive chiral centers by asymmetric transfer hydrogenation

[0046] Under nitrogen protection, 4-substituted-1,2,3,4-tetrahydroacridine (1), 1,4-dihydropyridine (4d, 2.4eq.) and chiral phosphoric acid ((S)- 3f, 5mol%) into a Schlenk tube with 3 ml of 1,4-dioxane. After stirring and reacting at 25°C for 15-24 hours, direct column chromatography (volume ratio of eluent petroleum ether and ethyl acetate is 30:1) to obtain pure product, the reaction formula is as follows:

[0047]

[0048] The productive rate is the separation yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, and the diastereomeric excess is determined by rough NMR spectrum, see figure 1 .

[0049] (4S,4aS,9aR)-4-Methyl-1,2,3,4,4a,9,9a,10-octahydroacridine(2a):Pale solid,mp=51-53℃,99%yield,R f =0.82(petroleum ether / EtOAc=30:1),83%ee,[α] 21 D =-45.8(c0.90, CHCl 3 ); 1 H NMR (400...

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Abstract

The invention relates to a method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation, wherein chiral phosphoric acid is adopted as a catalyst and substituted 1,4-dihydropyridine is adopted as a hydrogen source in the used catalysis system. The reaction can be performed under the following conditions that: the temperature is 0-70 DEG C, the solvent is 1,4-dioxane, and a ratio of the substrate to the catalyst is 20/1. According to the present invention, simple and easily-available 4-substituted-1,2,3,4-tetrahydroacridine is subjected to transfer hydrogenation to obtain the corresponding tetrahydroquinoline compound containing three continuous chiral centers, wherein the diastereoselectivity can be more than 20:1, and the enantiomeric excess can achieve 89%; and the method of the present invention has characteristics of simple and practical operation, high diastereoselectivity/enantioselectivity and high yield, and the reaction has characteristics of green atom economy and environment-protection.

Description

technical field [0001] The invention relates to a method for synthesizing a tetrahydroquinoline compound containing three continuous chiral centers through asymmetric transfer hydrogenation of 4-substituted-1,2,3,4-tetrahydroacridine. technical background [0002] Chiral tetrahydroquinolines are key intermediates of many natural products and drug molecules, and are widely used in the synthesis of materials chemistry, pesticides and pharmaceutical intermediates [1] . Therefore, it has attracted the attention of many scientists. So far, a series of methods have been developed to synthesize chiral tetrahydroquinolines. However, they all mainly synthesize tetrahydroquinolines containing one or two chiral centers, while synthesizing tetrahydroquinolines containing three consecutive chiral centers [2] , is still a challenging topic in organic chemistry synthesis. [0003] Dynamic dynamic resolution has been widely used in organic synthesis, it can convert 100% of racemic substr...

Claims

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Application Information

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IPC IPC(8): C07D219/02C07D219/06C07D219/04B01J31/02
Inventor 周永贵陈木旺
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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