Method for preparing indolyl spirocyclic compound through iodine catalyzed multi-component reaction

A multi-component reaction, indole spiro ring technology, applied in the direction of organic chemistry, can solve the problems of polluted environment, corroded equipment, many side reactions, etc., to achieve the effects of simple reaction operation, high catalytic efficiency, and easy availability of raw materials

Inactive Publication Date: 2017-11-17
JIANGSU UNIV
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Problems solved by technology

[0003] Most of the catalytic methods used in the current synthesis of indole spirocyclic compounds are protonic acid catalysis, organic catalysis and metal catalysis, etc., which are often accompanied by obvious disadvantages such as poor applicability, many side reactions, complicated post-treatment process, corrosion of equipment, and pollution of the environment.

Method used

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  • Method for preparing indolyl spirocyclic compound through iodine catalyzed multi-component reaction
  • Method for preparing indolyl spirocyclic compound through iodine catalyzed multi-component reaction
  • Method for preparing indolyl spirocyclic compound through iodine catalyzed multi-component reaction

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018]

[0019] Accurately weigh 0.1611g N-methylisatin, 0.1121g 1,3-cyclohexanedione, 0.1621g 4-hydroxycoumarin and 0.0254gI 2 Dissolve in 4mL ClCH 2 CH 2 After magnetic stirring at 60° C. for 24 h in Cl, the reaction was determined to be complete by TLC detection, the solvent was removed by rotary evaporation, and a white solid Ia was obtained by column chromatography. Yield 82%, m.p.320.5~321.2℃; 1 HNMR (400MHz, CDCl 3 )δ: 7.88(d, J=7.9Hz, 1H), 7.61~7.56(m, 1H), 7.36(t, J=7.6Hz, 1H), 7.28(d, J=8.1Hz, 2H), 6.96~ 6.92(m,2H),6.88(d,J=7.7Hz,1H),3.38(s,3H),2.86~2.83(m,2H),2.46~2.31(m,2H),2.18~2.02(m, 2H); 13 C NMR (100MHz, CDCl 3 )δ: 195.1, 176.7, 164.9, 158.5, 154.8, 152.6, 145.6, 132.9, 132.1, 129.1, 124.4, 122.7, 122.6, 122.1, 116.8, 114.6, 113.1, 107.9, 106.5, 40.1, 20.0, 397.2 .Anal.Calcd for C 24 h 17 NO 5 : C 72.17, H 4.29, N 3.51; Found: C 72.37, H 4.51, N 3.40.

Embodiment 2

[0021]

[0022] Accurately weigh 0.2373g N-benzyl isatin, 0.1121g 1,3-cyclohexanedione, 0.1621g 4-hydroxycoumarin and 0.0254gI 2 Dissolved in 4 mL of DMF, stirred magnetically at 70°C for 36 hours, detected by TLC, confirmed that the reaction had ended, removed the solvent by rotary evaporation, and obtained white solid Ib by column chromatography, with a yield of 83%, m.p.306.9-307.1°C; 1 H NMR (400MHz, DMSO-d 6 )δ: 8.04(d, J=7.8, Hz, 1H), 7.76(t, J=7.8Hz, 1H), 7.63(d, J=7.5Hz, 2H), 7.52(t, J=7.7Hz, 1H ),7.47(d,J=8.2Hz,1H),7.36(t,J=7.5Hz,2H),7.28(t,J=7.3Hz,1H),7.12(t,J=8.1Hz,1H), 6.88(t, J=7.4Hz, 1H), 6.64(d, J=7.8Hz, 1H), 4.97(ABd, J=16.4Hz, 1H), 4.92(ABd, J=16.4Hz, 1H), 2.96~ 2.93(m,2H),2.42~2.26(m,2H),2.05~1.95(m,2H); 13 C NMR (100MHz, DMSO-d 6 )δ: 195.8, 176.8, 166.2, 158.6, 155.1, 152.3, 145.2, 137.0, 134.1, 132.6, 128.9, 128.8, 127.8, 127.5, 125.5, 123.9, 123.6, 122.4, 117.0, 113.9, 419.5, 18012 ,44.7,37.3,27.4,20.1.Anal.Calcd forC 30 h 21 NO 5 : C 75.78, H 4...

Embodiment 3

[0024]

[0025] Accurately weigh 0.2401g 5-bromo-N-methylisatin, 0.0981g 1,3-cyclopentanedione, 0.1621g 4-hydroxycoumarin and 0.0508g I 2 Dissolve in 4mL CH 2 Cl 2 In the process, after magnetic stirring at 60°C for 24 hours, TLC detection confirmed that the reaction had ended, the solvent was removed by rotary evaporation, and a white solid Ic was obtained by column chromatography with a yield of 79%, m.p.315.1-315.4°C; 1 HNMR (400MHz, DMSO-d 6 )δ:8.07(dd,J=7.9,1.3Hz,1H),7.82~7.77(m,1H),7.57~7.52(m,2H),7.50~7.47(m,2H),7.05(d,J= 8.8Hz, 1H), 3.21(s, 3H), 3.03~3.00(m, 2H), 2.50~2.47(m, 2H); 13 C NMR (100MHz, DMSO-d 6 )δ: 200.5, 177.6, 174.7, 159.2, 157.6, 152.5, 144.5, 134.3, 133.6, 132.1, 127.3, 125.6, 123.6, 117.1, 116.5, 114.5, 113.3, 110.4, 105.3, 46.1, 27.1, 33.1 .Calcd for C 23 h 14 BrNO 5 : C 59.50, H 3.04, N 3.02; Found: C 59.56, H 3.03, N 2.81.

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Abstract

The invention belongs to the technical field of preparation of pharmaceutical intermediates, and concretely relates to a new method for preparing an indolyl spirocyclic compound through an iodine catalyzed multi-component reaction. An isatin derivative, a 1,3-dicarbonyl compound, and 4-hydroxycoumarin and a derivative thereof are used as raw materials, and iodine is used as a catalyst, so the method has the advantages of easiness in obtaining of the raw materials, and simple reaction operation, and the generated compound product can be used as a candidate drug, and has potential application values.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a new method for preparing indole spiro compounds through multi-component reaction catalyzed by iodine. Background technique [0002] Indole spiro compounds are the core structures of many drugs and natural alkaloids with a wide range of biological and pharmacological activities. For example, drugs such as strychnine, cyclopamine and NITD 609 all contain indole spiral structures, among which strychnine can be used as a central nervous system stimulant; cyclopamine is a Hedgehog signaling pathway inhibitor, which can inhibit protein activity; and NITD 609 is a good antimalarial drug candidate. [0003] Most of the catalytic methods used in the current synthesis of indole spirocyclic compounds are protonic acid catalysis, organic catalysis and metal catalysis, etc., which are often accompanied by obvious disadvantages such as poor ap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20
CPCC07D491/20
Inventor 张敏杨文博钱敏刘莉赵婷仰榴青吴向阳
Owner JIANGSU UNIV
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