CN107226816A - A kind of preparation method of indoline spiro-compound - Google Patents
A kind of preparation method of indoline spiro-compound Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of indoline spiro-compound.Based on Ugi reacts, with carboxylic acid, aldehyde, 3 amino 1HIndoles and different cyanides are raw material, using microwave radiation, prepare new indole quinoline spiro-compound.The synthetic method simple and fast, raw materials used simple and easy to get, experimental implementation is easy, suitable popularization and application.
Description
Technical field
The application is related to pharmaceutical synthesis field, especially a kind of fast preparation method of indoline spiro-compound.
Background technology
The structure of indoline spiro-compound can be made up of indoline and piperidines and form, and the structural compounds have a lot
Pharmaceutical activity, such as growth hormone secretagogues, AKT kinase inhibitors, NK1 receptor antagonists, cathepsin inhibitors
Deng.Can all have obvious therapeutic action in treatment angiocardiopathy and tumor disease.
The prior synthesizing method of indoline spiro-compound is：With 4- piperidine carboxylic acids and phenylhydrazine, 2- fluorophenyl acetonitriles, -2 hydroxyls
Indoles, halo aniline, piperidine carboxylic acid, tetrahydropyridine methanol and trifluoro picolinamide are that raw material is synthesized.But close above
Longer into step, last handling process is complicated, is unfavorable for Fast back-projection algorithm.However, reactions steps can be reduced using multi-component reaction,
Post processing is simple, attracts wide attention and payes attention to.The present invention relates to new indole quinoline spiro-compound structure do not have also
Report, be badly in need of people concern and study.
The content of the invention
It is an object of the invention to provide the preparation method of indoline spiro-compound.The present invention is multigroup using Ugi
Divide reaction to obtain Ugi products, then in acid condition, pass through microwave radiation technology reaction and synthesize a series of indoline spiro compounds
Thing.The intermediate product of synthesis is without separation, it is only necessary to which the separating-purifying of final product just can obtain target compound, simplify conjunction
Into step, yield is higher.The indoline spiro-compound has potential antitumor activity, can be used as preparing antineoplastic.
The purpose of the present invention is achieved through the following technical solutions：
A kind of indoline spiro-compound, it is characterised in that：The general structure of derivative is as follows：
Wherein described R1For aryl and heteroaryl, R2For hydrogen atom, alkyl, aryl and heteroaryl, R3For alkyl, aryl and miscellaneous
Aryl.
Moreover, the compound is（±）- 1- benzyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2] pyrrolo- [3,
2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyls -3-（3,4- dichlorophenyls）- 6- phenyl -1H- imidazo [1', 2'：
1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyls -3-（4- methoxyphenyls）- 6- phenyl -1H- imidazo [1', 2'：
1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyls -3-（4- chlorphenyls）- 6- phenyl -1H- imidazo [1', 2'：1,2]
Pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyl -3- phenethyl -6- phenyl -1H- imidazo [1', 2'：1,2] pyrroles
And [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyl -6- phenyl -3-（P-methylphenyl）-1H- imidazo [1', 2'：1,2]
Pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyl -3- butyl -6- phenyl -1H- imidazo [1', 2'：1,2] pyrrolo-
[3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- benzyls -3-（4- nitrobenzophenones）- 6- phenyl -1H- imidazo [1', 2'：1,
2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Moreover, the compound is（±）- 1- cyclohexyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2] pyrrolo-
[3,2-b] indoles -2,5（3H, 7H）- diketone.
Described indoline spiro-compound, it is characterised in that：Synthetic route is as follows
Wherein described R1For aryl and heteroaryl, R2For hydrogen atom, alkyl, aryl and heteroaryl, R3For alkyl, aryl and miscellaneous
Aryl.
Moreover, indoline spiro-compound has potential antitumor action, it can be used as antineoplastic.
Advantages and positive effects of the present invention：
（1）The present invention is with 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters are one of which raw material, are reacted by Ugi, obtained production
Thing is without separating-purifying, then in acid condition（10% TFA/DCE）, pass through microwave radiation technology one pot process indoline loop coil
Compound.The synthetic method has the advantages that step is brief, separating-purifying is convenient, atom utilization is high.The indoline spiral shell of synthesis
Cycle compound has potential antitumor activity, can be used as preparing antineoplastic.
（2）Synthetic route of the present invention has that operating procedure is simple, synthetic route is short, low cost and other advantages.
Brief description of the drawings
Fig. 1 is general structure, wherein described R1For aryl and heteroaryl, R2For hydrogen atom, alkyl, aryl and heteroaryl,
R3For alkyl, aryl and heteroaryl.
Fig. 2 is（±）- 1- benzyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5
（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Fig. 3 is（±）- 1- benzyls -3-（3,4- dichlorophenyls）- 6- phenyl -1H- imidazo [1', 2'：1,2] pyrrolo-
[3,2-b] indoles -2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Fig. 4 is（±）- 1- benzyls -3-（4- methoxyphenyls）- 6- phenyl -1H- imidazo [1', 2'：1,2] pyrrolo-
[3,2-b] indoles -2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Fig. 5 is（±）- 1- benzyls -3-（4- chlorphenyls）- 6- phenyl -1H- imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone.
Fig. 6 is（±）- 1- benzyl -3- phenethyl -6- phenyl -1H- imidazos [1', 2'：1,2] pyrrolo- [3,2-b] Yin
Diindyl -2,5（3H, 7H）- diketone.
Fig. 7 is（±）- 1- benzyl -6- phenyl -3-（P-methylphenyl）-1H- imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Fig. 8 is（±）- 1- benzyl -3- butyl -6- phenyl -1H- imidazos [1', 2'：1,2] pyrrolo- [3,2-b] indoles-
2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Fig. 9 is（±）- 1- benzyls -3-（4- nitrobenzophenones）- 6- phenyl -1H- imidazo [1', 2'：1,2] pyrrolo- [3,
2-b] indoles -2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Figure 10 is（±）- 1- cyclohexyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles-
2,5（3H, 7H）The nuclear magnetic spectrogram of-diketone.
Embodiment
In order to understand the present invention, with reference to examples of implementation, the invention will be further described：Following examples of implementation are to say
Bright property, be not limited, it is impossible to limit protection scope of the present invention with following embodiments.
The general structure of indoline spiro-compound of the present invention is as follows：
Wherein described R1For aryl and heteroaryl, R2For hydrogen atom, alkyl, aryl and heteroaryl, R3For alkyl, aryl and miscellaneous
Aryl.
Described indoline spiro-compound, it is characterised in that：Synthetic route is as follows
Wherein described R1For aryl and heteroaryl, R2For hydrogen atom, alkyl, aryl and heteroaryl, R3For alkyl, aryl and miscellaneous
Aryl.
Building-up process is illustrated below by examples of implementation.
Embodiment 1
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- benzyl -3,6- diphenyl -1H- imidazo [1', 2'：1,
2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
And benzaldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 mM）With
Benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin-layer chromatography
Isocyanide compound is detected, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10% TFA/
DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）After dilution,
Washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate, adopt
Separated with silicagel column, obtain target compound（±）- 1- benzyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2] pyrrole
Cough up simultaneously [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 92%.
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.2 Hz, 2H), 7.47 – 7.37 (m,
3H), 7.33 (d, J = 5.6 Hz, 2H), 7.23 (d, J = 6.5 Hz, 7H), 7.10 (d, J = 3.8 Hz,
2H), 7.01 (s, 1H), 6.85 – 6.75 (m, 2H), 6.52 (d, J = 6.3 Hz, 1H), 5.88 (s,
1H), 4.87 (d, J = 15.5 Hz, 1H), 3.31 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 180.03, 171.16, 163.38, 148.59, 136.79, 136.12, 131.70, 129.87,
128.90, 128.58, 128.25,128.13, 127.91, 127.50, 126.65,126.49, 125.50, 123.06,
111.76, 109.00, 87.81, 60.79, 43.88. HRMS (ESI) m/z calcd for C31H24N3O2 +(M+H)+
470.18630, found 470.18628。
Embodiment 2
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- benzyls -3-（3,4- dichlorophenyls）- 6- phenyl -1H- miaow
Azoles simultaneously [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
With 3,4- dichlorobenzaldehydes（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0
MM）With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stir a whole night, then use under reaction solution normal temperature
Thin-layer chromatography detects isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in
10% TFA/DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）
After dilution, washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.Organic phase is dry using magnesium sulfate
After dry, separated using silicagel column, obtain target compound（±）- 1- benzyls -3-（3,4- dichlorophenyls）- 6- phenyl -1H-
Imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 85%.
1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.53
(d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 6.6 Hz, 2H), 7.23
(d, J = 7.2 Hz, 4H), 7.09 (d, J = 6.7 Hz, 2H), 6.90 (d, J = 3.7 Hz, 1H), 6.86
(dd, J = 7.7, 3.9 Hz, 2H), 6.56 (d, J = 7.5 Hz, 1H), 5.79 (s, 1H), 4.87 (d, J
= 15.5 Hz, 1H), 3.31 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 179.84,
170.34, 163.34, 148.51, 136.51, 132.92, 132.42, 131.99, 130.57, 129.61,
129.00, 128.67, 128.34, 128.07,127.92, 127.66, 127.43, 126.15,126.02, 125.24,
123.38, 111.96, 109.08, 87.80, 59.81, 44.04. HRMS (ESI) m/z calcd for
C31H22Cl2N3O2 +(M+H)+ 538.10836, found 538.10815。
Embodiment 3
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- benzyls -3-（4- methoxyphenyls）- 6- phenyl -1H- miaow
Azoles simultaneously [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
And 4-methoxybenzaldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0
MM）With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stir a whole night, then use under reaction solution normal temperature
Thin-layer chromatography detects isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in
10% TFA/DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）
After dilution, washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.Organic phase is dry using magnesium sulfate
After dry, separated using silicagel column, obtain target compound（±）- 1- benzyls -3-（4- methoxyphenyls）- 6- phenyl -1H-
Imidazo [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 82%.
1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.65 (d, J = 8.7 Hz, 2H),
7.41 – 7.37 (m, 2H), 7.32 (dd, J = 17.4, 7.6 Hz, 4H), 7.26 – 7.22 (m, 3H),
7.09 – 7.05 (m, 4H), 6.98 (d, J = 7.9 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.40
(d, J = 7.5 Hz, 1H), 5.62 (s, 1H), 4.67 (d, J = 15.7 Hz, 1H), 3.82 (s, 3H),
3.26 (d, J = 15.7 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 180.92, 170.96,
164.90, 159.63, 149.77, 137.31, 132.43, 130.46, 128.92, 128.64, 128.27,
128.02, 127.79, 127.63, 125.65, 125.13, 122.62, 114.56, 112.70, 105.10,
88.42, 60.34, 55.69, 43.50. HRMS (ESI) m/z calcd for C32H26N3O3 +(M+H)+
500.19687, found 500.19672。
Embodiment 4
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- benzyls -3-（4- chlorphenyls）- 6- phenyl -1H- imidazo
[1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
With 4- chlorobenzaldehydes（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 mmoles
You）With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin layer
Chromatogram detects isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10%
TFA/DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）Dilution
Afterwards, washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate,
Separated using silicagel column, obtain target compound（±）- 1- benzyls -3-（4- chlorphenyls）- 6- phenyl -1H- imidazo
[1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 86%.
1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H),
7.59 (d, J = 8.5 Hz, 2H), 7.42 – 7.37 (m, 2H), 7.35 – 7.27 (m, 4H), 7.24 (dd,J = 4.9, 1.6 Hz, 3H), 7.06 (dd, J = 6.4, 2.6 Hz, 2H), 6.99 (d, J = 7.9 Hz,
1H), 6.85 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.71 (s, 1H), 4.67
(d, J = 15.7 Hz, 1H), 3.25 (d, J = 15.7 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ
180.82, 170.46, 164.87, 149.75, 137.16, 135.60, 133.40, 132.54, 130.37,
129.20, 128.95, 128.67, 127.80, 125.52, 124.96, 122.76, 112.79, 105.07,
88.44, 60.25, 43.59. HRMS (ESI) m/z calcd for C31H23ClN3O2 +(M+H)+ 504.14733,
found 504.14713。
Embodiment 5
Wherein R1For aryl, R2For alkyl, R3For alkyl, i.e.,（±）- 1- benzyl -3- phenethyl -6- phenyl -1H- imidazo [1',
2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
With phenethyl aldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 mM）
With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin layer color
Spectrum detection isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10% TFA/
DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）After dilution,
Washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate, adopt
Separated with silicagel column, obtain target compound（±）- 1- benzyl -3- phenethyl -6- phenyl -1H- imidazo [1', 2'：1,
2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 76%.
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.29 (m, 8H), 7.26 – 7.19 (m, 7H),
7.09 – 7.04 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.90 – 6.84 (m, 2H), 4.86 (d,J = 15.6 Hz, 1H), 4.70 (dd, J = 11.0, 4.1 Hz, 1H), 3.36 (d, J = 15.6 Hz, 1H),
3.16 – 3.00 (m, 2H), 2.61 – 2.52 (m, 1H), 2.08 – 2.00 (m, 1H). 13C NMR
(100MHz, CDCl3) δ 180.39, 173.13, 163.29, 148.81, 141.30, 136.88, 131.83,
129.86, 128.91, 128.68,128.52, 128.24, 127.89, 127.45, 126.11, 125.55,
123.25, 112.10, 109.46, 87.86, 59.37, 43.70, 35.52, 32.88. HRMS (ESI) m/z
calcd for C33H28N3O2 +(M+H)+ 498.21760, found 498.21725。
Embodiment 6
Wherein R1For aryl, R2For alkyl, R3For alkyl, i.e.,（±）- 1- benzyl -6- phenyl -3-（P-methylphenyl）-1H- imidazo
[1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
And p-tolyl aldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 milli
Mole）With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin
Layer chromatography detects isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10%
TFA/DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）Dilution
Afterwards, washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate,
Separated using silicagel column, obtain target compound（±）- 1- benzyl -6- phenyl -3-（P-methylphenyl）-1H- imidazo
[1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 89%.
1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H),
7.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 8.2 Hz, 6H), 7.26 – 7.21 (m, 3H), 7.06
(dd, J = 6.2, 2.6 Hz, 2H), 6.98 (d, J = 7.9 Hz, 1H), 6.81 (t, J = 7.5 Hz,
1H), 6.41 (d, J = 7.5 Hz, 1H), 5.65 (s, 1H), 4.66 (d, J = 15.7 Hz, 1H), 3.26
(d, J = 15.7 Hz, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 180.94,
170.84, 164.91, 149.77, 137.88, 137.30, 133.54, 132.44, 130.45, 129.69,
128.93, 128.64, 127.79, 127.64, 126.69, 125.64, 125.13, 122.59, 112.71,
105.11, 88.43, 60.63, 43.52, 21.24. HRMS (ESI) m/z calcd for C32H26N3O2 +(M+H)+
484.20195, found 484.20190。
Embodiment 7
Wherein R1For aryl, R2For alkyl, R3For alkyl, i.e.,（±）- 1- benzyl -3- butyl -6- phenyl -1H- imidazo [1',
2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
With butyl aldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 mM）With
Benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin-layer chromatography
Isocyanide compound is detected, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10% TFA/
DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）After dilution,
Washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate, adopt
Separated with silicagel column, obtain target compound（±）- 1- benzyl -3- butyl -6- phenyl -1H- imidazo [1', 2'：1,2]
Pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 72%.
1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.43 – 7.34 (m, 4H), 7.25
(dt, J = 6.4, 4.8 Hz, 6H), 7.07 – 6.97 (m, 4H), 4.64 (d, J = 15.7 Hz, 1H),
4.39 (dd, J = 11.0, 4.4 Hz, 1H), 3.24 (d, J = 15.7 Hz, 1H), 2.16 – 2.05 (m,
1H), 1.83 – 1.73 (m, 1H), 1.62 (dt, J = 15.9, 8.4 Hz, 2H), 1.57 – 1.40 (m,
2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 181.30, 173.03,
164.99, 149.89, 137.49, 132.44, 130.52, 128.88, 128.62, 127.67,127.54,
125.57, 125.37, 122.87, 112.70, 105.32, 88.41, 59.30, 43.24, 32.39, 28.80,
21.91, 14.37. HRMS (ESI) m/z calcd for C29H28N3O2 +(M+H)+ 450.21760, found
450.21753。
Embodiment 8
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- benzyls -3-（4- nitrobenzophenones）- 6- phenyl -1H- imidazoles
And [1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
With 4- nitrobenzaldehydes（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 milli
Mole）With benzyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin
Layer chromatography detects isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10%
TFA/DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）Dilution
Afterwards, washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate,
Separated using silicagel column, obtain target compound（±）- 1- benzyls -3-（4- nitrobenzophenones）- 6- phenyl -1H- imidazo
[1', 2'：1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 83%.
1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.40 (d, J = 8.7 Hz, 2H),
8.05 (d, J = 8.7 Hz, 2H), 7.39 (dd, J = 17.4, 10.0 Hz, 3H), 7.30 (d, J = 7.0
Hz, 3H), 7.27 – 7.21 (m, 3H), 7.07 (dd, J = 6.3, 2.7 Hz, 2H), 7.00 (d, J =
7.9 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.89 (s,
1H), 4.68 (d, J = 15.7 Hz, 1H), 3.25 (d, J = 15.7 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 179.67, 168.82, 163.82, 148.65, 146.91, 142.98, 135.97, 131.54,
129.22, 127.90, 127.63, 126.98,126.80,126.66, 124.50, 123.77, 123.30, 121.83,
111.75, 103.98, 87.39, 59.54, 42.63.HRMS (ESI) m/z calcd for C31H23N4O4 +(M+H)+
515.17138, found 515.17065.
Embodiment 9
Wherein R1For aryl, R2For aryl, R3For alkyl, i.e.,（±）- 1- cyclohexyl -3,6- diphenyl -1H- imidazo [1', 2'：
1,2] pyrrolo- [3,2-b] indoles -2,5（3H, 7H）The synthesis of-diketone, is comprised the following steps that：
In the micro-wave oven reaction tube of 10 milliliters of sizes, first by 3- amino -1H- indoles -1- carboxylic acid tert-butyl esters（1.0 mM）
And benzaldehyde（1.0 mM）In the methanol solution for being dissolved in 2.0 milliliters, then again by benzoyl formic acid（1.0 mM）With
Cyclohexyl isocyanide（1.0 mM）Sequentially add in the solution, stirred a whole night under reaction solution normal temperature, then using thin layer color
Spectrum detection isocyanide compound, if without remaining isocyanide raw material, solution is dried up using nitrogen, is then re-dissolved in 10% TFA/
DCE (5 milliliters).In microwave 100oAfter C reacts 10 minutes, the reactant mixture uses ethyl acetate（15 milliliters）After dilution,
Washed 3 times, every time 20 milliliters with saturated sodium carbonate solution and sodium chloride solution.After organic phase is dried using magnesium sulfate, adopt
Separated with silicagel column, obtain target compound（±）- 1- cyclohexyl -3,6- diphenyl -1H- imidazo [1', 2'：1,2]
Pyrrolo- [3,2-b] indoles -2,5（3H, 7H）- diketone, yield 75%.
1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 14.0, 7.6 Hz, 3H), 7.81 (d, J
= 7.7 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.47 (dd, J = 7.3, 3.5 Hz, 4H), 6.89
(d, J = 7.9 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 5.71
(s, 1H), 3.00 – 2.93 (m, 1H), 2.15 (dd, J = 12.5, 3.5 Hz, 1H), 1.92 – 1.81
(m, 2H), 1.72 (d, J = 10.7 Hz, 3H), 1.12 (d, J = 10.7 Hz, 2H), 0.98 (d, J =
10.0 Hz, 1H), 0.84 (dd, J = 13.3, 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
190.88, 179.84, 170.12, 163.80, 148.55, 136.64, 133.59, 131.54, 130.17,
129.96, 129.09, 128.54, 127.51, 126.70, 123.05, 112.04, 109.66, 88.10, 61.45,
54.40, 30.55, 29.14, 26.36,26.16, 24.98. HRMS (ESI) m/z calcd for C30H28N3O2 +(M
+H)+ 462.21760, found 462.21744。
Claims (6)
1. a kind of indoline spiro-compound, it is characterised in that：The general structure of derivative is as follows：
。
2. indoline spiro-compound according to claim 1, it is characterised in that：Described R1For aryl and heteroaryl.
3. indoline spiro-compound according to claim 1, it is characterised in that：Described R2For hydrogen atom, alkyl, virtue
Base and heteroaryl.
4. indoline spiro-compound according to claim 1, it is characterised in that：Described R3For alkyl, aryl and heteroaryl
Base.
5. indoline spiro-compound according to claim 1, it is characterised in that：Synthetic route is as follows：
。
6. indoline spiro-compound according to claim 1, it is characterised in that：With carboxylic acid, aldehyde, 3- amino -1H- indoles
It is raw material with different cyanides, is reacted using Ugi, using microwave radiation, one kettle way obtains indoline spiro-compound.
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| CN112480129A (en) * | 2020-11-26 | 2021-03-12 | 广州大学 | Polycyclic spiroindoline compound containing guanidyl structural unit and preparation method and application thereof |
| WO2024083164A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Solvate of indoline spiro compound, and crystal form thereof, preparation method therefor and use thereof |
| WO2024083160A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Crystal form and amorphous substance of indoline spiro compound, and preparation method therefor and use thereof |
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| CN102180828A (en) * | 2011-03-31 | 2011-09-14 | 四川大学 | Chiral indolinone spiropentacyclic skeleton compounds and asymmetric synthesis thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112480129A (en) * | 2020-11-26 | 2021-03-12 | 广州大学 | Polycyclic spiroindoline compound containing guanidyl structural unit and preparation method and application thereof |
| WO2024083164A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Solvate of indoline spiro compound, and crystal form thereof, preparation method therefor and use thereof |
| WO2024083160A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Crystal form and amorphous substance of indoline spiro compound, and preparation method therefor and use thereof |
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