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A kind of preparation method and application of multi-substituted pyridine derivatives

A derivative and multi-substitution technology, which is applied in the field of preparation of multi-substituted pyridine derivatives, can solve the problems of harsh reaction conditions, complicated experimental operations, and difficult availability of starting materials, and achieve high reactivity, simple experimental operations, and excellent reaction conditions. mild effect

Active Publication Date: 2021-01-19
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of method has the disadvantages of harsh reaction conditions (high temperature, microwave, use of a strong oxidant 2-iodoxybenzoic acid (IBX) with a risk of explosion, etc.), difficult to obtain starting materials, and complicated experimental operations.

Method used

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  • A kind of preparation method and application of multi-substituted pyridine derivatives
  • A kind of preparation method and application of multi-substituted pyridine derivatives
  • A kind of preparation method and application of multi-substituted pyridine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Preparation of 6-(4-bromophenyl)-2-phenylnicotinic acid ethyl ester (Ia)

[0033] Ethyl 3-amino-3-phenylacrylate (0.96g, 5mmol), p-bromopropiophenone (1.28g, 6mmol), copper acetate (0.18g, 1mmol), bpy (0.31g, 2mmol) and 4-OH -TEMPO (0.86g, 5mmol) in toluene (10mL) was stirred at 120°C for 24 hours. After the reaction, it was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and washed with petroleum ether / acetic acid Ethyl ester = 50 / 1 (V / V) mixed solvent as eluent, separated by silica gel column chromatography to obtain 1.59g of white solid 6-(4-bromophenyl)-2-phenylnicotinic acid ethyl ester (Ia) , yield: 83%, melting point: 59-60°C.

[0034] The structural formula of Ia is:

[0035]

[0036] 1 H NMR (600MHz, CDCl 3 ,ppm)δ8.18(d,J=7.8Hz,1H),8.01(d,J=8.4Hz,2H),7.75(d,J=7.8Hz,1H),7.63-7.60(m,4H), 7.46(m,3H),4.17(q,J=7.2Hz,2H),1.07(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl 3 ,ppm)δ168.2,15...

Embodiment 2

[0037] Example 2: Preparation of ethyl 6-(4-bromophenyl)-2-(2-thienyl)nicotinate (Ib)

[0038] 3-Amino-3-(2-thienyl)enoic acid ethyl ester (0.91g, 5mmol), p-bromopropiophenone (1.07g, 5mmol), copper acetate (0.18g, 1mmol), bpy (0.16g, 1mmol) ) and 4-OH-TEMPO (1.29g, 7.5mmol) in toluene (10mL) were stirred at 110°C for 30 hours. After the reaction, extracted with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated , using petroleum ether / ethyl acetate=50 / 1 (V / V) mixed solvent as eluent, separated by silica gel column chromatography to obtain white solid 6-(4-bromophenyl)-2-(2-thienyl ) ethyl nicotinate (Ib) 1.30 g, yield: 70%. Melting point: 65.5-66.2°C.

[0039] Ib structural formula is:

[0040]

[0041] 1 H NMR (600MHz, CDCl 3 ,ppm)δ8.03-8.01(m,3H),7.66-7.63(m,3H),7.50-7.48(m,2H),7.13-7.11(m,1H),4.40(q,J=7.2Hz, 2H), 1.34(t, J=7.2Hz, 3H). 13 C NMR (150MHz, CDCl 3 , ppm) δ168.3, 156.7, 150.5, 143.2, 138.7, 136.7, 132.0, ...

Embodiment 3

[0042] Example 3: Preparation of tert-butyl 6-(4-bromophenyl)-2-benzyl nicotinate (Ic)

[0043] tert-butyl 3-amino-3-phenylacrylate (1.10g, 5mmol), p-bromopropiophenone (3.20g, 15mmol), copper acetate (0.18g, 1mmol), 1,10-Phen (0.20g, 1mmol ) and TEMPO (5mmol, 0.78g) in toluene (10mL) were stirred and reacted at 130°C for 20 hours. After the reaction, extracted with water and ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated, and washed with petroleum ether / Ethyl acetate=50 / 1 (V / V) mixed solvent was used as eluent, separated by silica gel column chromatography to obtain white solid 6-(4-bromophenyl)-2-benzyl nicotinic acid tert-butyl ester (Ic ) 1.01g, yield: 49%.

[0044] The structural formula of Ic is:

[0045]

[0046] 1 H NMR (600MHz, CDCl 3 ,ppm)δ8.19(d,J=7.8Hz,1H),8.02(d,J=9.0Hz,2H),7.75(d,J=8.4Hz,1H),7.53(dd,J=7.8,1.8 Hz,2H)7.63(d,J=9.0Hz,2H),7.51-7.46(m,3H),1.35(s,9H). 13 C NMR (150MHz, CDCl 3 , ppm) δ167.3, 158.7, 156.8...

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Abstract

The invention discloses a preparation method of a polysubstituted pyridine derivative and application thereof. The method comprises the following steps of dissolving an enamine ester compound, a ketone compound, a catalyst and an oxidant in an organic solvent, and under the action of the catalyst and the oxidant, enabling the enamine ester compound and the ketone compound to generate the polysubstituted pyridine derivative through oxidative cyclization. Reactive raw materials in the preparation method provided by the invention are simple and easily obtained; the experimental operation is simple; the reaction condition is relatively mild; the reaction activity is high; the polysubstituted pyridine derivative with different substituent groups is constructed through high chemoselectivity andregioselectivity; the performing of next derivatization research is facilitated. Further, the obtained polysubstituted pyridine derivative has potential inhibitory activity to a human lung cancer cellA-549 and a human liver cancer cell HepG-2, and pyridine derivatives (I) and (II) prepared by the preparation method have potential in-vitro anti-tumor cell activity, and have prospects of being developed into anti-tumor drugs.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, and in particular relates to a preparation method and application of multi-substituted pyridine derivatives. Background technique [0002] Multi-substituted pyridine derivatives are an important class of heterocyclic compounds, which are used in medicine, agriculture, chemical industry, spinning and dyeing and other fields. In particular, one class of pyridine derivatives - nicotinic acid ester, the hydrolyzed product of nicotinic acid belongs to the vitamin B group compound, which has the effect of expanding peripheral blood vessels. Such multi-substituted pyridine derivatives can be modified to prepare a variety of drugs. For example, MK-1064, currently developed by Merck, is mainly used for insomnia and is currently in the first phase of clinical trials. MK-1064 can be obtained by aminolysis of nicotinic acid ester substituted with pyridyl group ...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803C07D409/04C07D491/052A61P35/00
CPCC07D213/80C07D213/803C07D409/04C07D491/052
Inventor 凌飞肖莲钟为慧
Owner ZHEJIANG UNIV OF TECH
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