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Preparation method of imidazo-[1,2-a] pyridine compound

A compound, 2-a technology, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome steps, expensive raw materials, harsh substrate preparation conditions, etc., and achieve the effects of wide sources, accelerated fracture, and simple operation

Active Publication Date: 2013-12-11
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above methods have disadvantages such as expensive raw materials, harsh substrate preparation conditions, and cumbersome steps, and are not suitable for large-scale synthesis of such compounds.

Method used

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  • Preparation method of imidazo-[1,2-a] pyridine compound
  • Preparation method of imidazo-[1,2-a] pyridine compound
  • Preparation method of imidazo-[1,2-a] pyridine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～9

[0040] The preparation process of the imidazo[1,2-a]pyridine compounds in Examples 1-9 is as follows:

[0041] (1) Synthesis of imine IV: Add 2-aminopyridine compound II (20mmol), propiophenone compound III (20mmol), p-toluenesulfonic acid (2mmol), toluene 100mL, N 2Protected, using a Dean-Stark apparatus to reflux the reaction overnight. The progress of the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, evaporate toluene under reduced pressure, extract with ethyl acetate (2×30mL), wash with saturated brine (20mL), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure and recrystallize with absolute ethanol Or separated by flash column chromatography to obtain a series of products of imine intermediate IV.

[0042] (2) Synthesis of imidazo[1,2-a]pyridine compound I: add imine intermediate IV (0.5mmol), copper acetate (0.1mmol), silver carbonate (0.5mmol), carbonic acid Potassium (1mmol) and toluene (2mL) we...

Embodiment 1

[0048] The imine intermediate prepared in Example 1 (IV-1, CAS No.: 893600-90-3):

[0049]

[0050] White solid, yield: 68%.m.p118-119℃; 1 H NMR (400MHz, CDCl 3 ):δ8.07(d,1H,J=8.0Hz),7.49(d,2H,J=8.0Hz),7.24-7.32(m,4H),6.71(br s,1H),6.59(t,1H ,J=6.4Hz),6.13(d,1H,J=8.4Hz),5.78(q,1H,J=6.8Hz),1.82(d,3H,J=7.2Hz). 13 C NMR (CDCl 3 ,100MHz)δ157.0,148.1,138.6,137.4,137.0,128.4,127.7,126.0,117.4,113.8,107.7,13.6.MS(EI):m / z(%):210(M + ,7), 195(100), 149(8), 105(74), 91(15), 77(41).

[0051] The imidazo[1,2-a]pyridine compound prepared in Example 1 (I-1, CAS No.: 34658-68-9)

[0052]

[0053] Pale yellow solid, yield: 80%.m.p152-153℃; 1 H NMR (400MHz, CDCl 3 ):δ7.90(d,1H,J=6.4Hz),7.80(d,2H,J=7.2Hz),7.64(d,1H,J=8.4Hz),6.47(t,2H,J=7.2Hz ),7.36(t,1H,J=7.6Hz),7.18(t,1H,J=7.6Hz),6.85(t,1H,J=6.4Hz),2.65(s,3H). 13 C NMR (CDCl 3 ,100MHz)δ144.3,142.4,134.8,128.4,128.3,127.3,123.4,122.8,117.4,115.8,111.9,9.6.MS(EI):m / z(%):208(M + ,100),136(11),103(28),94(41),78(46).

Embodiment 2

[0054] The imine intermediate (IV-2) prepared in Example 2:

[0055]

[0056] Pale white solid, yield: 65%.m.p102-104℃; 1 H NMR (400MHz, CDCl 3 ):δ7.80(d,2H,J=8.0Hz),7.62(d,2H,J=6.8Hz),7.38-7.46(m,1H),7.28(d,1H,J=5.6Hz),7.20 (d,2H,J=8.4Hz),7.10(d,1H,J=9.2Hz),6.63(t,1H,J=5.6Hz),2.37(s,3H). 13 C NMR (CDCl 3 ,100MHz)δ155.0,142.7,141.4,140.6,135.5,129.0,128.7,127.1,125.8,114.2,112.0,21.3.MS(EI):m / z(%):244(M + ,11), 229(100), 194(9), 115(13), 94(78).

[0057] The imidazo[1,2-a]pyridine compound prepared in Example 2 (I-2, CAS No.: 1404292-73-4)

[0058]

[0059] Pale yellow solid, yield: 63%.m.p109-110℃; 1 H NMR (400MHz, CDCl 3 ):δ7.89(d,1H,J=6.8Hz),7.74(d,2H,J=8.4Hz),7.63(d,1H,J=8.8Hz),7.43(d,2H,J=8.4Hz ),7.19(t,1H,J=8.0Hz),6.86(t,1H,J=6.4Hz),2.62(s,3H). 13 C NMR (CDCl 3 ,100MHz)δ145.5,144.8,134.9,134.2,131.3,129.3,128.9,126.5,124.8,117.3,114.6,10.3.MS(EI):m / z(%):242(M + ,100),205(29),149(9),103(50),78(72).

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Abstract

The invention discloses a preparation method of an imidazo-[1,2-a] pyridine compound. The preparation method comprises the following steps of: (1) adding 2-aminopyridine compound, a propiophenone compound and a condensation catalyst to an organic solvent, and heating for condensation reaction, wherein an imine intermediate is obtained after complete reaction; (2) adding a copper catalyst, an oxidizing agent, alkali the imine intermediate obtained from the step (1) to the organic solvent, heating for ring closing reaction, and carrying out post processing to obtain the imidazo-[1,2-a] pyridine compound after the complete reaction. The preparation method disclosed by the invention has the advantages of wide source, cheapness and easiness for obtaining of used raw materials, namely the 2-aminopyridine compound and the propiophenone compound, is easy to operate without a complex post processing process and is suitable for the large-scale preparation of the compound.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of imidazo[1,2-a]pyridine compounds. Background technique [0002] Imidazo[1,2-a]pyridine compounds are an important class of drug intermediates (Hanson, S.M.; Morlock, E.V.; ​​Satyshur, K.A.; Czajkowski, C.J.Med.Chem.2008, 51, 7243), including Drugs used for anxiolytics such as alpitant (Jain, A.N.J.Med.Chem. 2004, 47, 947), necopitant (Depoortere, H.; George, P. US5064836, 1991.) and salipitant (Sanger, D.J. Behav.Pharmacol.1995,6,116); and Zolpidem (Hsua, N.; Jha, S.K.; Coleman, T.; Frank, M.G.Behav.Brain Res.2009, 201, 233), etc. In addition, this type of compound is also an important synthetic intermediate, such as this type of compound can be used as a ligand in the field of luminescent materials for the preparation of phosphorescent iridium complexes (S.Takizawa et.al.; Mol.Cryst.Liq.Cryst. 2006, 455, 381-385). [0003] In recent years ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 张玉红陈铮凯
Owner ZHEJIANG UNIV
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