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Synthesizing method of tetrahydroquinoline derivative

A technology of tetrahydroquinoline and synthetic method, which is applied in the field of synthesis of tetrahydroquinoline derivatives, can solve the problems of highly corrosive production equipment, unfavorable mass production and application, and large consumption of accelerators, etc., and achieves low corrosiveness, The effect of low price and short reaction time

Active Publication Date: 2013-03-27
CHINA UNIV OF PETROLEUM (BEIJING)
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Problems solved by technology

However BF 3 .OEt 2 It can be hydrolyzed immediately when it encounters moisture in the air, producing highly toxic fluoride fumes. In addition, it is highly corrosive and unfavorable to production equipment.
Beaton et al. used 1.2eq Sc(OTf) 3 To prepare tetrahydroquinoline derivatives as accelerators and aliphatic aldehydes as raw materials, the consumption of accelerators is large [Cheng, D,; Zhou, J.; Saiah, E.; Beaton, G.Org.Lett.2002, 4 , 4411-4414.]; David et al. also used the catalytic amount of Dy(OTf) 3 Catalyze the reaction of p-bromoaniline, aliphatic aldehyde, and cyclopentadiene, and obtain the target product [David, A.Tetrahedron Lett.2003, 44, 7569-7573.] with a good yield. It is also highly corrosive, expensive, and the production cost is very high, which is not conducive to mass production and application in industry

Method used

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  • Synthesizing method of tetrahydroquinoline derivative
  • Synthesizing method of tetrahydroquinoline derivative
  • Synthesizing method of tetrahydroquinoline derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: prepare 4-methyl-2-propyl group-4-neopentyl-1,2,3,4-tetrahydroquinoline (cis-D 1 +trans-D 1 )

[0061] SnCl 2 0.3792g (2mmol) and FeCl 3 Dissolve 0.6488g (4mmol) in 13mL of dichloromethane, stir at 40°C for 4 hours (h), add n-butyraldehyde 0.150mL (1.667mmol), aniline 0.152mL (1.667mmol), diisobutylene (ie: 2 , 4,4-trimethylpentene) 0.260mL (1.667mmol) and internal standard dodecane 0.095mL (0.4168mmol), the reaction progress was monitored by gas chromatography, and the reaction time was 5h. After the reaction was finished, the reaction was quenched with 3mol / L ammonia water, extracted with diethyl ether, the obtained organic layer was concentrated, and separated with a chromatographic silica gel column (300-400 mesh coarse-pore silica gel), and the eluent was diethyl ether:petroleum ether =1:50, finally obtained light yellow liquid, the total yield of chromatogram was 71%, diastereomer ratio cis-D 1 :trans-D 1 =1.2:1 (chromatographic integration rat...

Embodiment 2

[0065] Embodiment 2: 4-methyl-2-propyl group-4-neopentyl-6-chloro-1,2,3,4-tetrahydroquinoline (cis-D 2 +trans-D 2 )

[0066] SnCl 2 0.3204g (1.6899mmol) and KMnO 4 Dissolve 0.1068g (0.676mmol) in 13mL of chloroform, add a small amount of hydrochloric acid dropwise, stir at room temperature for 5h, add n-butyraldehyde 0.152mL (1.6899mmol), p-chloroaniline 0.1078g (0.8450mmol), diisobutene 0.263 mL (1.6899mmol) and internal standard dodecane 0.096mL (0.4225mmol), the reaction progress was monitored by gas chromatography, and the reaction time was 36h. After the reaction was finished, the reaction was quenched with 3mol / L ammonia water, extracted with diethyl ether, the obtained organic layer was concentrated, and separated using a chromatographic silica gel column. The eluent was diethyl ether:petroleum ether=1:20, and finally a light yellow Liquid, target product chromatographic overall yield 45%, diastereomer ratio cis-D 2 :trans-D 2 =1:1.

[0067] Product Characterizat...

Embodiment 3

[0071] Embodiment 3: Preparation of 4-methyl-2-propyl-4-neopentyl-6-methoxy-1,2,3,4-tetrahydroquinoline (cis-D 3 +trans-D 3 )

[0072] SnCl 2 0.4394g (2.3175mmol) and FeCl 3 Dissolve 0.7518g (4.635mmol) in 15mL of 1,2-dichloroethane, stir at 0°C for 1h, raise the temperature to room temperature (30°C), add 0.209mL (2.3175mmol) of n-butyraldehyde, p-formaldehyde Oxyaniline 0.4335g (3.476mmol), diisobutylene 0.361mL (2.3175mmol) and internal standard dodecane 0.132mL (0.5794mmol), the reaction progress was monitored by gas chromatography, and the reaction time was 8h. After the reaction was finished, the reaction was quenched with 3mol / L ammonia water, extracted with ether, and the obtained organic layer was concentrated and separated with a chromatographic silica gel column, and the eluent was ethyl acetate:petroleum ether=1:20 to obtain light Yellow viscous liquid, the total yield of chromatography is 85%, the total yield of separation is 73%, the ratio of diastereoisomers...

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Abstract

The invention relates to a synthesizing method of a tetrahydroquinoline derivative. Specifically, a Lewis acid SnCl2 and an oxidant are subjected to an oxidation reduction reaction; a produced oxidation product SnCl4 assists in in-situ promotion of an aza-Diels-Alder cycloaddition reaction of aniline, aldehyde and olefin, such that a 1,2,3,4-tetrahydroquinoline derivative is obtained. With the method, aliphatic aldehyde successfully participates in the reaction, and a range of aldehyde substrates in Povarov reactions is expanded. An accelerant is the combination of SnCl2 and the oxidant. Compared with a method for directly using SnCl4 or other Lewis acid accelerant, with the method provided by the invention, the synthesis of the 1,2,3,4-tetrahydroquinoline derivative has the advantages of cheap price, simple operation, mild reaction conditions, low corrosion, and high yield of prepared 1,2,3,4-tetrahydroquinoline derivative.

Description

technical field [0001] The present invention relates to the synthetic method of tetrahydroquinoline derivatives, specifically use Lewis acid SnCl 2 After the oxidation-reduction reaction with the oxidant, the oxidation product SnCl is generated 4 In situ promoted aza-Diels-Alder cycloaddition reaction of aniline, aldehyde and alkenes to obtain 1,2,3,4-tetrahydroquinoline derivatives. technical background [0002] Tetrahydroquinoline derivatives are an important class of nitrogen-containing heterocyclic compounds, which widely exist in natural products. Among them, 1,2,3,4-tetrahydroquinoline compounds have attracted much attention due to their unique biological activities. attention, it can be used as analgesic [Liu, Y.F.; Wu, L.Y.; Liu, X.J.; Wang, Y.L.; Song, H.R. Chinese Journal of Medicinal Chemistry.2007, 17, 144-147], anticancer agent [Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.J.Am.Chem.Soc.1990, 112, 3715-3716], antiparasitic agents [Pagliero, R.J.; Lusvarghi, S.; ...

Claims

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Application Information

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IPC IPC(8): C07D215/06C07D215/18C07D215/20
Inventor 郭巧霞滕卫灵申宝剑王延卿陈利维饶莎莎
Owner CHINA UNIV OF PETROLEUM (BEIJING)
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