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2-substituted tetrahydroquinoline compound and derivative, preparation method and application thereof

A technology of tetrahydroquinoline and compounds, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problem of damage sustainability and achieve the green effect of the preparation method

Active Publication Date: 2020-06-05
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the methods mentioned above often require homogeneous catalysts based on rare, expensive, or even toxic noble metals, thus compromising sustainability (S.A.Girard, T.Knauber, C.Li, Angew.Chem.Int.Ed, 2014, 53, 74-100)

Method used

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  • 2-substituted tetrahydroquinoline compound and derivative, preparation method and application thereof
  • 2-substituted tetrahydroquinoline compound and derivative, preparation method and application thereof
  • 2-substituted tetrahydroquinoline compound and derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Preparation of compound I-1 (N-benzyl-2-nitromethyl-1,2,3,4-tetrahydroquinoline)

[0081] R 1 is benzyl; R 2 is hydrogen; R 3 for hydrogen

[0082] Take compound 1-1 (0.25mmol) in a 15ml thick-walled pressure bottle, weigh the metal catalyst ZnBr 2 (0.025mmol, 5.7mg) was added to a thick-walled pressure bottle, and nitromethane (500 μl) was added to the pressure bottle, N 2 Protection, stirring reaction at 100 ° C for 24h. After the reaction, the reaction solution was transferred to a 25ml eggplant-shaped bottle using dichloromethane, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography, and the eluent was petroleum ether:ethyl acetate=30:1 (v / v) , separation and purification to obtain pure product, light yellow solid, yield: 65% (45.8mg); 1 H-NMR (400MHz, CDCl 3 ): δ7.30(t, J=7.3Hz, 2H), 7.23(dd, J=14.1, 7.1Hz, 3H), 7.04(d, J=7.4Hz, 1H), 6.99(t, J=7.8Hz ,1H),6.67(t,J=7.3Hz,1H), 6.55(d,J=8.3Hz,1H),4.62(ABq,...

Embodiment 2

[0084] Preparation of compound I-2 (N-phenyl-2-nitromethyl-1,2,3,4-tetrahydroquinoline)

[0085] R 1 is phenyl; R 2 is hydrogen; R 3 for hydrogen

[0086] Get compound 1-2 (0.25mmol) in 15ml thick-walled pressure bottle, weigh metal catalyst ZnBr 2 (0.025mmol, 5.7 mg) into a thick-walled pressure bottle, measure nitromethane (500μl) into the pressure bottle, N 2 Protection, stirring reaction at 100 ° C for 24h. After the reaction, the reaction solution was transferred to a 25ml eggplant-shaped bottle using dichloromethane, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography, and the eluent was petroleum ether:ethyl acetate=30:1 (v / v) , separation and purification to obtain pure product, yellow oily liquid; yield: 61% (40.8mg); 1 H-NMR (400MHz, CDCl 3 ): δ7.36(t, J=7.8Hz, 2H), 7.20-7.14(m, 3H), 7.09(d, J=7.5Hz, 1H), 6.96(t, J=7.7Hz, 1H), 6.79 (t, J=7.4Hz, 1H), 6.62(d, J=8.2Hz, 1H), 4.63-4.44(m, 3H), 2.93-2.84(m, 2...

Embodiment 3

[0088] Preparation of compound I-3 (N-allyl-2-nitromethyl-1,2,3,4-tetrahydroquinoline)

[0089] R 1 is allyl; R 2 is hydrogen; R 3 for hydrogen

[0090] Take compound 1-3 (0.25mmol) in a 15ml thick-walled pressure bottle, weigh the metal catalyst ZnBr 2 (0.025mmol, 5.7 mg) into a thick-walled pressure bottle, measure nitromethane (500μl) into the pressure bottle, N 2 Protection, stirring reaction at 100 ° C for 24h. After the reaction, the reaction solution was transferred to a 25ml eggplant-shaped bottle using dichloromethane, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography, and the eluent was petroleum ether:ethyl acetate=30:1 (v / v) , separation and purification to obtain pure product, yellow oily liquid, yield: 55% (31.9mg); 1 H-NMR (400MHz, CDCl 3 ): δ7.08(t, J=7.8Hz, 1H), 7.03(d, J=7.3Hz, 1H), 6.69(t, J=7.3Hz, 1H), 6.63(d, J=8.3Hz, 1H ),5.85(ddt,J=15.6,10.0,4.9Hz,1H), 5.24-5.16(m,2H),4.53(dd,J=11.5,5.6Hz...

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Abstract

The invention belongs to the technical field of medicines and chemical engineering, and relates to a 2-substituted tetrahydroquinoline compound and a derivative, a preparation method and application thereof. The 2-substituted tetrahydroquinoline compound and the derivative thereof prepared by the invention have antimalarial activity, can be used as various medicinal key intermediates and can be applied to preparation of antitumor drugs and HIF-1 inhibitors. The preparation method is green, simplified and efficient.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and more specifically relates to a class of 2-substituted tetrahydroquinoline compounds and their derivatives, preparation methods and applications. Background technique [0002] Hypoxia-inducible factor HIF-1 is a basic helix-loop-helix (bHLH-PAS) family protein that forms a heterodimer from its α and β subunits and functions as a transcription factor. HIF-1βis expressed in any state, and HIF-1αis regulated by oxygen status. Under oxygen-enriched conditions, the production and degradation of HIF-1α are in balance. During this process, two proline sites (Pro402 and Pro564) in the oxygen-dependent degradation (ODD) domain are hydroxylated by prolyl hydroxylase. Of the three prolyl hydroxylases (PHD1, PHD2 and PHD3) in mammalian cells, PHD2 is known to play a major role. Under normoxia, PHD2 uses molecular oxygen and 2-oxoglutarate (α-ketoglutarate) as co-substrates for th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/12C07D471/04C07D215/20C07D215/06C07D215/14C07D215/18C07D405/06C07D401/04A61P35/00
CPCC07D215/12C07D471/04C07D215/20C07D215/06C07D215/14C07D215/18C07D405/06C07D401/04A61P35/00
Inventor 李广哲王成栋邵堃李悦青王世盛赵伟杰郭修晗
Owner DALIAN UNIV OF TECH
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