CN108017637A - A kind of indoles and pyrroloquinoline compounds and its synthetic method - Google Patents

A kind of indoles and pyrroloquinoline compounds and its synthetic method Download PDF

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CN108017637A
CN108017637A CN201711390154.6A CN201711390154A CN108017637A CN 108017637 A CN108017637 A CN 108017637A CN 201711390154 A CN201711390154 A CN 201711390154A CN 108017637 A CN108017637 A CN 108017637A
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malononitrile
arh
quinoline
isatin
reaction
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孙晶
张瑜
颜朝国
韩莹
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Yangzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

A kind of indoles and pyrroloquinoline compounds and its synthetic method, belong to technical field of organic synthesis.By quinoline quaternary ammonium salt and 2（2 oxindole, 3 subunit）Malononitrile derivative mixing stirring at normal temperature reaction, carries out silica gel column chromatography with the mixed solvent of ethyl acetate and petroleum ether after reaction, obtains spiral shell [indoline 3,2' pyrrolo-es [1,2 a] quinoline] class compound.Present invention offer is a kind of with gentle reaction condition, and wieldy raw material, substrate expansion scope is big, easy to operate, and yield is high, and cis-selectivity is high, the method for synthesizing spiral shell [indoline 3,2' pyrrolo-es [1,2 a] quinoline] class compound.There is no literature reported on it has important application value to the target molecule structure of the invention in the every field such as medicine, pesticide and life science at present.

Description

A kind of indoles and pyrroloquinoline compounds and its synthetic method
Technical field
The invention belongs to technical field of organic synthesis.
Background technology
Many quinolines are all important medicine intermediates and medicine, recent studies suggest that quinolines With preferable antihypertensive function（Muruganantham, N., Sivakumar, R., Anbalagan, N., et al. Synthesis, anticonvu-lsant and antihypertensive activities of 8- substituted quinoline derivatives. [J]. Biol Pharm Bull, 2004, 27(10), 1683- 1687）, newly designing the quinoline with labyrinth of synthesis can directly act on tumour cell and with antitumor Activity（Bekhit, A. A., El-Sayed, O. A., Al-Allaf, T. A., et al. Synthesis, characterizati-on and cytotoxicity evaluation of some new platinum(II) complexes of tetraz-olo [l, 5-a]quinolines. [J]. Eur J Med Chem, 2004, 39 (6)., 499-505）, quinoline medicine that Li et al. people synthesizes can suppress new vessels intra-tumor growth so as to compared with Good antitumor cell effect（J. D., Xiao, Z. L., Ihnat, M. A., et al. Strueture- activity relationships stud-of the anti-angiogenic activities of linomide. [J]. Bioorg Med Chem Lett, 2003, 13(6), 1187-1189）.
Many has and the derivative of cyclopyrrole structure has significant bioactivity.Such as：Lukianol A are to mankind's table The derived cell system of skin cancer shows activity.(Furstner, A.; weintritt, H.; Hupperts, A. A new, titanium-mediated approach to pyrroles: first synthesis of Lukiaaol A and Lamellarra O dimethyl ether [J]. J. Org. Chem, 1995, 60, 6637-6641).And cyclopyrrole The research of structure obtains the concern of researcher, such as：Quiroga in 2010 et al. is in ethanol as solvent, vinegar acid as catalyst Under conditions of, by 5,5- dimethyl -1, hydroresorcinol, aryl second diketone, three component reaction of aminopyrimidine obtain pyrrolo- [2,3-d] pyrimidine compound (Quiroga, J.; Cruz, S; et al. Generation of pyrrolo[2,3-d] pyrimidmes. Unexpected products in the multicomponent reaction of 6- aminopyrimidines, dimedone, and arylglyoxal. [J]. Tetrahedron Lett., 2010, 51, 5443-5447).It can be seen from the above that the research for simultaneously cyclopyrrole structural compounds all has in terms of synthesis and medicine Important meaning.
The study on the synthesis of indoles and pyrroloquinoline compounds is there is not yet document report, has been reported the portion of only relating at present Divide the synthesis of simultaneously ring structure, and come with some shortcomings, scope is small, and raw material is not easy to obtain, and reaction condition is more severe as substrate is expanded Carve, yield is excessively low, therefore simultaneously pyrroloquinoline compounds have preferable application prospect to synthesis of indole.
The content of the invention
In order to overcome the above problem, the present invention proposes a kind of indoles and pyrroloquinoline compounds, extensively should to it For in field of medicaments.
Indoles of the present invention and pyrroloquinoline compounds, structural formula are as follows：
Wherein R1For alkyl, alkoxy or halogen；R2For alkyl or alkyl-substituted phenyl；R3For formyl ester group or aryl.
The present invention is another object is that propose the synthetic method of above compound.
Synthetic method of the present invention is：Using acetonitrile as solvent, under the catalytic action of triethylamine, by quinoline quaternary ammonium salt and 2- （2- oxindole -3- subunits）Malononitrile derivative hybrid reaction, after reaction with the mixing of ethyl acetate and petroleum ether Solvent carries out silica gel column chromatography, obtains spiral shell [indoline -3,2'- pyrrolo- [1,2-a] quinoline] class compound.
Reaction expression of the present invention is as follows：
Reaction mechanism of the present invention is as follows, and in the presence of basic catalyst, quinoline quaternary ammonium salt forms ring nitrogen by deprotonation Ylide（A）.Ring nitrogen ylide（A）Nucleophilic addition occurs with different alkylidene malononitrile again and obtains adduct（B）.Finally, adduction Thing（B）Generation intramolecular cyclization, obtains target compound 1 --- spiral shell [indoline-3,2'- coughs up simultaneously [1,2-a] quinoline].
Isoquinoline quaternary ammonium salt, 2- of the present invention to be easy to get（2- oxindole -3- subunits）Malononitrile derivative is original Material, in the presence of no transition-metal catalyst, is not required to anhydrous and oxygen-free reaction condition, it is not necessary to strong acid or highly basic are added, it is used Raw material, solvent and catalyst need not anticipate.The synthetic method is easy to operate, and mild condition, raw material is simple and easy to get, Without the participation of metallic catalyst, substrate expansion scope is big, easy to operate, and yield is high, and cis-selectivity is high, can reach 68%~89% higher yield.
Further, 2- of the present invention（2- oxindole -3- subunits）Malononitrile derivative for isatin malononitrile, 5- chlorisatides malononitrile, 5- methylisatins malononitrile, N- benzyl isatin malononitrile, the chloro- N- benzyls isatin malononitrile of 5-, 5- first Appointing in base-N- benzyl isatin malononitrile, the fluoro- N- normal-butyls isatin malononitrile of 5- or 5- methyl-N- normal-butyl isatin malononitrile Meaning is a kind of.
The quinoline quaternary ammonium salt and 2-（2- oxindole -3- subunits）The molar ratio of malononitrile derivative is 1: 1.Using the amount ratio isatin malononitrile is fully reacted, obtain the higher product of purity.
The reaction condition is that reaction temperature is room temperature, when the reaction time 12 is small.Experimental research find that：In cryogenic conditions Under do not react；And temperature is excessive, then accessory substance is produced, reduce yield.
Embodiment
First, prepared by raw material：
1st, using acetonitrile as solvent, quinoline is reacted with monobromo-acetic acid ester type compound with equimolar than mixing, reaction terminates After filter, obtain quinoline quaternary ammonium salt.
Or using acetonitrile as solvent, quinoline is reacted with p-nitrobenzyl bromide with equimolar than mixing, after reaction Filter, equally also can obtain quinoline quaternary ammonium salt.
2nd, using ethanol as solvent, in basic catalyst triethylamine（Et3N）In the presence of, by the isatin of different substituents and third Dintrile mixing carries out aldol condensation/aldol condensation（Aldol）Reaction, obtains 2-（2- oxindole -3- subunits）Malononitrile class Compound, such as isatin malononitrile, 5- chlorisatides malononitrile, 5- methylisatins malononitrile, N- benzyl isatin malononitrile, the chloro- N- benzyls of 5- Base isatin malononitrile, 5- methyl-N-benzyl isatin malononitrile, the fluoro- N- normal-butyls isatin malononitrile of 5- or 5- methyl-N- normal-butyls Isatin malononitrile.
2nd, compound is synthesized：
Embodiment 1, preparation structure formula following 3', 3'- dicyano -2- oxos -3', 3a'- dihydro -1'H- spiral shells [indoline - 3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters, reaction equation is as follows：
Preparation method is as follows：
0.2950g (1.0mmol) quinoline quaternary ammonium salt, 0.1950g (1.0mmol) isatin the third two is added in 50mL round-bottomed flasks Nitrile, 0.1517g (1.5mmol) Et3N, as solvent, it is small to stir 12 at room temperature as basic catalyst and 10mL drying acetonitriles When, detect reaction process by thin-layer chromatographic analysis.
Solvent concentration is evaporated on a rotary evaporator after reaction, is separated using column layer chromatography（With 1:3 volume ratios will Ethyl acetate and petroleum ether are mixed, and column chromatography for separation is carried out as solvent）, up to pure 3', 3'- dicyano -2- oxos - 3', 3a'- dihydro -1'H- spiral shells [indoline -3,2'- pyrrolo- [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters.
Separation yield is 86%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ:major isomer: 11.40 (s, 1H, NH), 7.60 (d, J = 8.0 Hz, 1H, ArH), 7.48-7.43 (m, 1H, ArH), 7.19-7.15 (m, 1H, ArH), 7.12-7.03 (m, 3H, ArH), 6.93-6.87 (m, 1H, ArH), 6.78-6.71 (m, 1H, ArH), 6.51 (d, J = 8.0 Hz, 1H, ArH), 6.05 (m, 1H, ArH), 5.91-5.86 (m, 1H, CH), 5.17 (m, 1H, CH), 4.17-4.10 (m, 1H, CH), 4.00-3.92 (m, 1H, CH), 1.06 (m, 3H, CH3); minor isomer: 1H NMR (400 MHz, DMSO-d 6 ) δ: 11.44 (s, 1H, NH), 6.29 (d, J = 8.0 Hz, 1H, ArH), 6.15 (m, 1H, ArH), 4.74 (m, 1H, CH), 3.76-3.71 (m, 2H, CH), 0.60 (m, 3H, CH3). Ratio of major/minor = 0.62:0.38; 13C NMR (150 MHz, DMSO-d 6 ) δ: 174.4, 171.8, 167.3, 167.0, 142.8, 142.7, 141.2, 131.5, 131.2, 131.0, 130.7, 130.4, 130.2, 127.9, 127.7, 126.1, 125.1, 124.0, 122.7, 122.4, 119.5, 119.0, 118.8, 118.5, 115.4, 114.9, 111.0, 110.9, 110.6, 110.5, 68.6, 68.3, 66.7, 61.5, 61.3, 58.0, 57.5, 49.7, 49.3, 13.3, 13.0; IR (KBr) υ: 3466, 2984, 2314, 1760, 1715, 1650, 1486, 1374, 1312, 1266, 1194, 1151, 750 cm-1; MS (m/z): HRMS (ESI) C24H18N4NaO3 ([M+Na]+) theoretical value 433.1271, measured value 433.1266.
Embodiment 2, the following 5- of preparation structure formula chloro- 3', 3'- dicyano -2- oxos -3', 3a'- dihydro -1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline -1 '-carboxylic acid, ethyl ester：
0.2950g (1.0mmol) quinoline quaternary ammonium salt, 0.1950g (1.0mmol) isatin the third two is added in 50mL round-bottomed flasks Nitrile, 0.1517g (1.5mmol) Et3N, as solvent, it is small to stir 12 at room temperature as basic catalyst and 10mL drying acetonitriles When, detect reaction process by thin-layer chromatographic analysis.
Solvent concentration is evaporated on a rotary evaporator after reaction, is separated using column layer chromatography（With 1:3 volume ratios will Ethyl acetate and petroleum ether are mixed, and column chromatography for separation is carried out as solvent）, in embodiment 1, isatin used the third two The 5- chlorisatides malononitrile of nitrile equimolar amounts is replaced, other steps are identical with example 1, obtain the chloro- 3' of 5-, 3'- dicyanos -2- Oxo -3', 3a'- dihydro -1'H- spiral shell [indoline -3,2'- pyrrolo- [1,2-a] quinoline -1 '-carboxylic acid, ethyl esters.
Separation yield is 89%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: major isomer: 11.56 (s, 1H, NH), 7.74 (m, 1H, ArH), 7.54-7.50 (m, 1H, ArH), 7.17-7.05 (m, 3H, ArH), 6.92-6.87 (m, 1H, ArH), 6.79-6.71 (m, 1H, ArH), 6.47 (d, J = 8.0 Hz, 1H, ArH), 6.05 (m, 1H, ArH), 5.88 (m, 1H, CH), 5.39 (s, 1H, CH), 4.02-3.93 (m, 1H, CH), 3.85-3.77 (m, 1H, CH), 1.06 (t, J = 7.1 Hz, 3H, CH3);minor isomer: 7.62 (m, 1H, ArH), 6.31 (d, J = 8.0 Hz, 1H, ArH), 6.25 (m, 1H, ArH), 4.76 (s, 1H, CH), 4.17-4.11 (m, 1H, CH), 0.67 (t, J = 7.1 Hz, 3H, CH3).ratio of major/minor = 0.57:0.43.13C NMR (150 MHz, DMSO-d 6 ) δ: 174.2, 171.6, 167.3, 167.0, 141.8, 141.6, 141.1, 131.5, 131.1, 131.0, 130.7, 130.3, 130.1, 127.9, 127.6, 126.6, 126.1, 125.8, 125.7, 125.3, 119.5, 119.0, 118.8, 118.5, 115.5, 114.8, 112.3, 112.0, 111.4, 110.6, 68.6, 68.4, 66.7, 66.2, 61.6, 58.0, 49.6, 13.3, 13.0; IR (KBr) υ: 3458, 3032, 2315, 1758, 1716, 1648, 1486, 1369, 1312, 1267, 1199, 1151, 749 cm-1; MS (m/z): HRMS (ESI) C24H17ClN4NaO3 ([M+Na]+) theoretical value 467.0881, measured value 467.0886。
Embodiment 3, preparation structure formula following 3', 3'- dicyano -5- methyl -2- oxos -3', 3a'- dihydro -1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline] -1 '-carboxylic acid, ethyl ester：
In embodiment 1, the 5- methylisatins malononitrile of isatin malononitrile equimolar amounts used is replaced, other steps and reality Example 1 is identical, obtains 3', 3'- dicyano -5- methyl -2- oxos -3', 3a'- dihydro -1'H- spiral shell [indoline -3,2'- pyrroles And [1,2-a] quinoline] -1 '-carboxylic acid, ethyl ester, its separation yield is 87%, and structural characterization data are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: major isomer: 11.34 (s, 1H, NH), 7.44 (m, 1H, ArH), 7.35 (d, J = 8.0 Hz, 1H, ArH), 7.12-7.06 (m, 2H, ArH), 6.96-6.87 (m, 2H, ArH), 6.78-6.71 (m, 1H, ArH), 6.50 (d, J = 8.0 Hz, 1H, ArH), 6.06- 6.05 (m, 1H, ArH), 5.92-5.86 (m, 1H, CH), 5.16 (s, 1H, CH), 4.19-4.13 (m, 1H, CH), 3.98-3.92 (m, 1H, CH), 2.30 (s, 3H, CH3), 1.06 (t, J = 7.2 Hz, 3H, CH3); minor isomer: 11.37 (s, 1H, NH), 7.34 (m, 1H, ArH), 6.29 (d, J = 8.0 Hz, 1H, ArH), 6.19-6.18 (m, 1H, ArH), 4.72 (s, 1H, CH), 3.79-3.73 (m, 2H, CH), 0.60 (t, J = 7.2 Hz, 3H, CH3). ratio of major/minor = 0.57:0.43.13C NMR (150 MHz, DMSO-d 6 ) δ: 174.4, 171.7, 167.3, 167.1, 141.3, 141.2, 140.3, 140.2, 131.8, 131.6, 131.5, 131.4, 131.0, 130.7, 130.3, 130.2, 127.8, 127.7, 126.5, 125.6, 124.0, 123.5, 119.5, 119.0, 118.8, 118.5, 115.4, 114.9, 111.0, 110.6, 110.5, 110.3, 68.5, 68.3, 66.7, 61.5, 61.4, 57.9, 57.6, 49.8, 49.3, 20.7, 20.5, 13.3, 12.9; IR (KBr) υ: 3497, 2977, 2314, 1761, 1716, 1617, 1492, 1456, 1373, 1312, 1265, 1188, 1009, 810, 746 cm-1; MS (m/z): HRMS (ESI) C25H20N4NaO3 ([M+Na ]+) theoretical value 447.1428, measured value 447.1423.
Embodiment 4, with following 1- benzyls -3', 3'- dicyano -2- oxos -3', the 3a'- dihydro -1'H- of preparation structure formula [exemplified by indoline -3,2'- pyrrolo- [1,2-a] quinoline -1 '-carboxylic acid, ethyl ester, its preparation method is as follows for spiral shell：
In embodiment 1, the N- benzyl isatin malononitrile of isatin malononitrile equimolar amounts used is replaced, other steps and reality Example 1 is identical, obtains 1- benzyls -3', 3'- dicyano -2- oxos -3', 3a'- dihydro -1'H- spiral shell [indoline -3,2'- pyrroles And [1,2-a] quinoline -1 '-carboxylic acid, ethyl ester.
Separation yield is 82%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: major isomer: 7.68 (d, J = 8.0 Hz, 1H, ArH), 7.50-7.30 (m, 6H, ArH), 7.24-7.20 (m, 1H, ArH), 7.17-7.08 (m, 3H, ArH), 6.95- 6.90 (m, 1H, ArH), 6.80-6.73 (m, 1H, ArH), 6.53 (d, J = 8.4 Hz, 1H, ArH), 6.14-6.13 (m, 1H, ArH), 5.95-5.88 (m, 1H, CH), 5.27 (s, 1H, CH), 5.22 (d, J = 16.0 Hz, 1H, CH), 5.15 (d, J = 16.0 Hz, 1H, CH), 4.04-3.96 (m, 1H, CH), 3.75- 3.70 (m, 1H, CH), 0.97 (t, J = 7.2 Hz, 3H, CH3); minor isomer: 7.54 (d, J = 8.0 Hz, 1H, ArH), 6.34 (d, J = 8.4 Hz, 1H, ArH), 6.21-6.20 (m, 1H, ArH), 5.03 (d, J = 16.0 Hz, 1H, CH), 4.86-4.85 (m, 1H, CH), 3.64-3.60 (m, 1H, CH), 0.31 (t, J = 7.2 Hz, 3H, CH3). ratio of major /minor = 0.50:0.50. 13C NMR (150 MHz, DMSO-d 6 ) δ: 172.7, 170.7, 167.2, 166.8, 143.1, 143.0, 141.2, 141.1, 135.3, 135.1, 131.5, 131.3, 131.1, 130.8, 130.4, 130.2, 128.6, 128.5, 127.9, 127.8, 127.7, 127.4, 125.9, 125.1, 123.6, 123.2, 123.1, 122.9, 119.6, 119.2, 118.8, 118.6, 115.3, 114.8, 111.1, 110.7, 110.6, 110.4, 68.8, 68.4, 67.1, 67.0, 61.8, 61.4, 57.5, 57.0, 49.8, 49.6, 43.7, 43.6, 13.6, 12.6; IR (KBr) υ: 3044, 2314, 1724, 1649, 1608, 1495, 1462, 1373, 1289, 1193, 1015, 961, 793, 750, 700 cm-1; MS (m/z): HRMS (ESI) C31H24N4NaO3 ([M+Na]+) theoretical value 523.1741, measured value 523.1746。
Embodiment 5, following 1- benzyls -5- chloro- 3', 3'- dicyano -2- oxos -3', the 3a'- dihydro of preparation structure formula - 1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters：
In embodiment 1, the chloro- N- benzyls isatin malononitrile of the 5- of isatin malononitrile equimolar amounts used is replaced, other steps Suddenly it is identical with example 1, obtain 1- benzyls -5- chloro- 3', 3'- dicyano -2- oxos -3', 3a'- dihydro -1'H- spiral shells [dihydro Yin Diindyl -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters.
Separation yield is 85%, and the target product structural characterization data of acquirement are as follows：
1H NMR (600 MHz, DMSO-d 6 ) δ: major isomer: 7.84 (s, 1H, ArH), 7.59-7.57 (m, 1H, ArH), 7.47-7.45 (m, 1H, ArH), 7.40-7.30 (m, 4H, ArH), 7.20 (d, J = 8.4 Hz, 1H, ArH), 7.12-7.08 (m, 2H, ArH), 6.91 (t, J = 10.2 Hz, 1H, ArH), 6.77-6.74 (m, 1H, ArH), 6.49 (d, J = 8.4 Hz, 1H, ArH), 6.13 (s, 1H, ArH), 5.93 (d, J = 10.2 Hz, 1H, CH), 5.50 (s, 1H, CH), 5.15 (d, J = 15.6 Hz, 1H, CH), 4.90-4.88 (m, 1H, CH), 4.06-3.96 (m, 2H, CH), 0.97 (t, J = 7.0 Hz, 3H, CH3); minor isomer: 7.70 (s, 1H, ArH), 7.24 (d, J = 8.4 Hz, 1H, ArH), 6.94 (d, J = 10.2 Hz, 1H, ArH), 6.80-6.78 (m, 2H, ArH), 6.36 (d, J = 8.4 Hz, 1H, ArH), 6.31 (s, 1H, CH), 5.89 (d, J = 10.2 Hz, 1H, CH), 5.24 (d, J = 15.6 Hz, 1H, CH), 5.03 (d, J = 15.6 Hz, 1H, CH), 3.83-3.77 (m, 1H, CH), 3.69-3.63 (m, 1H, CH), 0.36 (t, J = 7.0 Hz, 3H, CH3). ratio of major/minor = 0.58:0.42. 13C NMR (150 MHz, DMSO-d 6 ) δ: 172.4, 170.5, 167.3, 166.8, 142.0, 141.1, 141.0, 135.0, 134.8, 131.4, 131.2, 130.8, 130.4, 130.1, 128.7, 128.6, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 126.0, 125.8, 125.0, 124.7, 119.6, 119.2, 118.8, 118.5, 115.5, 114.7, 112.1, 111.8, 111.5, 110.7, 68.8, 68.5, 67.1, 66.7, 61.9, 61.6, 57.5, 57.1, 49.8, 49.4, 43.9, 43.8, 13.6, 12.6; IR (KBr) υ: 2987, 2108, 1719, 1642, 1506, 1426, 1341, 1190, 1131, 926, 876, 832, 787, 741, 700 cm-1; MS (m/z): HRMS (ESI) C31H24ClN4O3 ([M+H]+) theoretical value 535.1531, measured value 535.1534.
Embodiment 6, following 1- benzyls -3', 3'- dicyano -5- methyl -2- the oxos -3', 3a'- bis- of preparation structure formula Hydrogen -1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters：
In embodiment 1, the 5- methyl-N-benzyl isatin malononitrile of isatin malononitrile equimolar amounts used is replaced, other Step is identical with example 1, obtains 1- benzyls -3', 3'- dicyano -5- methyl -2- oxos -3', 3a'- dihydro -1'H- spiral shell [dihydros Indoles -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid, ethyl esters.
Separation yield is 83%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: major isomer: 7.52 (s, 1H, ArH), 7.47-7.45 (m, 1H, ArH), 7.42-7.26 (m, 5H, ArH), 7.13-7.07 (m, 2H, ArH), 7.03 (d, J = 8.0 Hz, 1H, ArH), 6.95-6.89 (m, 1H, ArH), 6.79-6.73 (m, 1H, ArH), 6.51 (d, J = 8.0 Hz, 1H, ArH), 6.14-6.13 (m, 1H, ArH), 5.94-5.88 (m, 1H, CH), 5.24 (s, 1H, CH), 5.12 (d, J = 15.6 Hz, 1H, CH), 4.84-4.81 (m, 1H, CH), 4.03-3.97 (m, 2H, CH), 2.31 (s, 3H,CH3), 0.97 (t, J = 7.2 Hz, 3H, CH3); minor isomer: 6.33 (d, J = 8.0 Hz, 1H, ArH), 6.23-6.22 (m, 1H, ArH), 5.18 (d, J = 15.6 Hz, 1H, CH), 5.01 (d, J = 15.6 Hz, 1H, CH), 3.78-3.74 (m, 1H, CH), 3.67-3.61 (m, 1H, CH), 2.27 (s, 3H, CH3), 0.33 (t, J = 7.2 Hz, 3H, CH3). ratio of major/minor = 0.53:0.47. 13C NMR (100 MHz, DMSO-d 6 ) δ: 173.0, 171.0, 167.7, 167.3, 141.7, 141.6, 141.2, 141.0, 135.9, 135.6, 133.3, 133.0, 132.0, 131.9, 131.6, 131.2, 130.8, 130.7, 129.0, 128.9, 128.3, 128.2, 128.1, 127.8, 126.9, 126.1, 123.7, 123.3, 120.0, 119.6, 119.2, 119.0, 115.8, 115.3, 111.5, 111.2, 110.8, 110.6, 69.1, 68.8, 67.5, 62.2, 61.9, 58.0, 57.6, 50.4, 50.0, 44.2, 44.1, 21.1, 20.9, 14.1, 13.0; IR (KBr) υ: 2982, 2108, 1752, 1714, 1642, 1505, 1426, 1341, 1195, 1130, 924, 876, 832, 788, 741, 700 cm-1; MS (m/z): HRMS (ESI) C32H27N4O3 ([M+H ]+) theoretical value 515.2078, measured value 515.2083.
Embodiment 7, following 1- benzyls -3', 3'- dicyano -5- methyl -2- the oxos -3', 3a'- bis- of preparation structure formula Hydrogen -1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylate methyl esters：
In embodiment 1, the methyl bromoacetate of bromoacetate equimolar amounts used is replaced, and isatin malononitrile used is used The 5- methyl-N-benzyl isatin malononitrile of equimolar amounts is replaced, other steps are identical with example 1, obtain 1- benzyls -3', 3'- bis- Cyano group -5- methyl -2- oxos -3', 3a'- dihydro -1'H- spiral shells [indoline -3,2'- pyrrolo- [1,2-a] quinoline] -1'- carboxylics Sour methyl esters.
Separation yield is 70%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: major isomer: 7.52 (s, 1H, ArH), 7.43-7.36 (m, 4H, ArH), 7.31-7.25 (m, 2H, ArH), 7.12-7.04 (m, 3H, ArH), 6.95-6.89 (m, 1H, ArH), 6.80-6.73 (m, 1H, ArH), 6.53 (d, J = 7.2 Hz 1H, ArH), 6.09 (s, 1H, ArH), 5.94-5.89 (m, 1H, CH), 5.30 (s, 1H, CH), 5.07 (d, J = 15.6 Hz, 1H, CH), 4.90 (d, J = 15.2 Hz, 1H, CH), 3.43 (s, 3H, OCH3); minor isomer:7.43-7.36 (m, 1H, ArH), 6.36 (d, J = 7.6 Hz, 1H, ArH), 6.24 (s, 1H, ArH), 5.20 (d, J = 15.6 Hz, 1H, CH), 5.01 (d, J = 15.6 Hz, 1H, CH), 4.92 (s, 1H, CH), 3.08 (s, 3H, OCH3).ratio of major/minor = 0.60:0.40 13C NMR (100 MHz, DMSO-d 6 ) δ: 174.5, 172.8, 171.2, 168.5, 152.8, 141.4, 141.1, 140.9, 134.5, 134.4, 134.0, 133.8, 133.6, 131.8, 131.6, 131.5, 131.1, 130.4, 129.0, 128.9, 128.8, 128.7, 128.6, 128.3, 128.1, 128.0, 127.9, 127.7, 127.6, 127.3, 126.5, 126.2, 125.2, 123.6, 122.0, 119.8, 119.2, 118.9, 114.7, 113.8, 111.5, 111.3, 111.1, 110.7, 110.1, 109.9, 109.8, 109.7, 68.5, 67.8, 62.9, 62.4, 58.3, 53.0, 52.3, 50.3, 49.9, 47.2, 44.6, 44.0, 21.1, 21.0; IR (KBr) υ: 2677, 1761 1715, 1608, 1532, 1495, 1450, 1371, 1258, 1198, 1080, 980, 882, 816, 741 cm-1; MS (m/z): HRMS (ESI) C31H24N4O3 ([M+H]+) theoretical value 501.1921, measured value 501.1916.
Embodiment 8, following 1- benzyls -5- chloro- 3', 3'- dicyano -2- oxos -3', the 3a'- dihydro of preparation structure formula - 1'H- spiral shells [indoline -3,2'- pyrrolo-es [1,2-a] quinoline] -1'- carboxylic acid tert-butyl esters：
In embodiment 1, the bromo-acetic acid tert-butyl of bromoacetate equimolar amounts used is replaced, isatin malononitrile used Replaced with the chloro- N- benzyls isatin malononitrile of the 5- of equimolar amounts, other steps are identical with example 1, obtain 2- (4- methoxybenzenes Base) -3- nitros benzo [d] pyrrolo- [2,1-b] thiazole -1- Ethyl formates.
Separation yield is 83%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ:major isomer: 7.43-7.41 (m, 2H, ArH), 7.38- 7.34 (m, 3H, ArH), 7.33-7.30 (m, 2H, ArH), 7.13-7.10 (m, 1H, ArH), 6.85 (d, J = 8.0 Hz 1H, ArH), 6.81-6.76 (m, 2H, ArH), 6.72 (d, J = 8.4 Hz 1H, ArH), 6.24 (d, J = 8.4 Hz, 1H, ArH), 5.93-5.92 (m, 1H, ArH), 5.81-5.74 (m, 1H, ArH), 5.29 (d, J = 15.6 Hz, 1H, CH), 5.11 (d, J = 15.6 Hz, 1H, CH), 4.91 (s, 1H, CH), 1.36 (s, 9H, 3CH3);minor isomer: 7.61 (d, J = 2.0 Hz, 1H, ArH), 7.38- 7.34 (m, 1H, ArH), 7.01-6.99 (m, 2H, ArH), 6.34-6.33 (m, 1H, ArH), 6.17 (d, J = 8.0 Hz, 1H, ArH), 4.95 (d, J = 15.6 Hz, 1H, CH), 4.62 (d, J = 15.6 Hz, 1H, CH), 4.65 (s, 1H, CH), 1.01 (s, 9H, 3CH3). mratio of major/minor = 0.60:0.40.13C NMR (100 MHz, DMSO-d 6 ) δ: 172.4, 166.5, 142.0, 141.6, 133.7, 131.7, 131.0, 130.4, 129.3, 129.1, 129.0, 128.3, 128.2, 127.6, 127.4, 125.7, 124.9, 119.8, 119.1, 114.3, 111.1, 110.6, 109.9, 84.1, 83.8, 69.3, 67.9, 57.9, 49.8, 44.8, 27.7, 27.2; IR (KBr) υ: 2983, 1725, 1648, 1604, 1490, 1447, 1360, 1267, 1227, 1188, 1151, 1033, 965, 875, 815, 749, cm-1; MS (m/z): HRMS (ESI) C33H27ClN4O3 ([M+H]+) theoretical value 563.1844, measured value 563.1834.
Embodiment 9, the following fluoro- 1'- of 1- butyl -5- of preparation structure formula（4- nitrobenzophenones）- 2- oxo -1'H- spiral shells [two Hydrogen indoles -3,2'- pyrrolo- [1,2-a] quinoline] -3', 3'（3a'H）Dintrile：
In embodiment 1, the p-nitrobenzyl bromide of bromoacetate equimolar amounts used is replaced, isatin malononitrile used Replaced with the 5- methyl-N- normal-butyl isatin malononitrile of equimolar amounts, other steps are identical with example 1, obtain 1- butyl -5- Fluoro- 1'-（4- nitrobenzophenones）- 2- oxo -1'H- spiral shells [indoline -3,2'- pyrrolo- [1,2-a] quinoline] -3', 3'（3a'H） Dintrile.
Separation yield is 69%, and the target product structural characterization data of acquirement are as follows：
1H NMR (600 MHz, DMSO-d 6 ) δ: 8.15 (brs, 2H, ArH), 7.86 (s, 1H, ArH), 7.72-7.69 (m, 1H, ArH), 7.40 (d, J = 7.8 Hz, 1H, ArH), 7.12-7.09 (m, 2H, ArH), 6.93-6.92 (m, 2H, ArH), 6.85-6.55 (m, 3H, ArH), 5.99 (dd, J 1 = 10.2 Hz,J 2 = 3.0 Hz, 1H, CH), 5.90 (d, J = 8.4 Hz, 1H, CH), 5.74 (s, 1H, CH), 3.49- 3.44 (m, 1H, CH), 3.40-3.36 (m, 1H, CH), 2.41 (s, 3H, CH3), 1.13-1.06 (m, 1H, CH), 1.00-0.93 (m, 1H, CH), 0.83-0.76 (m, 1H, CH), 0.73-0.66 (m, 1H, CH), 0.58 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, DMSO-d 6 ) δ: 170.3, 147.6, 143.1, 141.6, 141.0, 132.9, 132.1, 130.4, 130.0, 127.8, 126.1, 123.7, 121.0, 119.3, 119.0, 115.5, 111.3, 109.7, 70.0, 66.8, 59.7, 48.6, 39.1, 28.7, 20.8, 19.0, 13.3; IR (KBr) υ: 3071, 2959, 2248, 1709, 1651, 1603, 1505, 1455, 1347, 1271, 1205, 1112, 1051, 1007, 935, 857, 819, 748 cm-1; MS (m/z): HRMS (ESI) C32H27N5NaO3 ([M+Na]+) theoretical value 552.2006, measured value 552.2003.
Embodiment 10, the following fluoro- 1'- of 1- butyl -5- of preparation structure formula（4- nitrobenzophenones）- 2- oxo -1'H- spiral shells [two Hydrogen indoles -3,2'- pyrrolo- [1,2-a] quinoline] -3', 3'（3a'H）Dintrile：
In embodiment 1, the p-nitrobenzyl bromide of bromoacetate equimolar amounts used is replaced, isatin malononitrile used Replaced with the fluoro- N- normal-butyls isatin malononitrile of the 5- of equimolar amounts, other steps are identical with example 1, and it is fluoro- to obtain 1- butyl -5- 1'-（4- nitrobenzophenones）- 2- oxo -1'H- spiral shells [indoline -3,2'- pyrrolo- [1,2-a] quinoline] -3', 3'（3a'H）Two Nitrile.
Separation yield is 70%, and the target product structural characterization data of acquirement are as follows：
1H NMR (400 MHz, DMSO-d 6 ) δ: 8.12 (brs, 2H, ArH), 7.91 (d, J = 8.4 Hz, 1H, ArH), 7.84-7.30 (m, 3H, ArH), 7.24-7.21 (m, 1H, ArH), 7.06 (d, J = 6.4 Hz, 1H, ArH), 6.90-6.88 (m, 2H, ArH), 6.69-6.66 (m, 2H, ArH), 5.96 (dd, J 1 = 10.4 Hz, J 2 = 2.8 Hz, 1H, CH), 5.88-5.86 (m, 2H, CH), 3.47-3.36 (m, 2H, CH), 1.12-1.06 (m, 1H, CH), 0.96-0.87 (m, 1H, CH), 0.82-0.63 (m, 2H, CH), 0.56 (t,J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, DMSO-d 6 ) δ: 170.2, 159.3, 157.7, 147.6, 142.9, 141.4, 139.6, 130.5, 130.0, 127.8, 123.8, 122.5, 122.4, 119.3, 119.0, 118.5, 118.3, 115.3, 114.1, 113.9, 111.5, 111.2, 111.1, 69.5, 66.9, 59.8, 48.5, 28.6, 18.9, 13.3; IR (KBr) υ: 3072, 2952, 2250, 1706, 1654, 1607, 1527, 1493, 1455, 1349, 1273, 1199, 1116, 1051, 935, 872, 825, 745 cm-1; MS (m/z): HRMS (ESI) C31H23FN5O3 ([M-H]+) theoretical value 532.1779, measured value 532.1780.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention and from above-described embodiment Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification, Equivalent substitute mode is should be, is included within protection scope of the present invention.
3rd, product property, purposes：
Having proven to spiral shell [indoline -3,3'- pyrrolidines] -2- ketone has very strong bioactivity, is many natural alkaloids Basic framework.This basic framework the substituted hexahydropyridine structure in 2 ', 3 ' positions can with to nervous system with protection Function.
Such as：Natural alkaloid rhynchophyllin has anti-hypertension and blood pressure lowering characteristic, may be attributed to rhynchophyllin to Ca2+Into Enter the inhibitory action of vascular smooth muscle.And rhynchophyllin also shows neuroprotective function, for example, weakening the induction of hippocampus ischemic Neure damage.Therefore, rhynchophyllin can be the potential clinical medicine for treating hypertension and apoplexy, and rhynchophyllin is also prevented from The cytotoxicity of glutamate induction（Chou, C.-H.; Gong, C.-L.; Chao, C.-C.; Lin, C.-H.; Kwan, C.-Y.; Hsieh, C.-L.; Leung, Y.-M. J. Nat. Prod. 2009, 72, 830–834)。
When spiral shell [indoline -3,3'- pyrrolidines] -2- ketone when there are electron-withdrawing substituent group in 2 ', 4 ' positions equally With certain neuroprotective function.Such as：Spiral shell gibberellin A and B are well-known neuroprotective agent or anticancer respectively （(a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–12666; (b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832–835.)。
Compound of the present invention is respectively provided with spiral shell [indoline -3,3'- pyrrolidines] -2- ketone knots with above-claimed cpd Structure, in the change of the substituted base in 2 ', 4 ', 5 ' positions, therefore visible compound of the present invention also has certain nerve Defencive function, N, O in the compound structure carry lone pair electrons, are probably very much a kind of good ligand greatly, Ke Yizeng The conjugated system of big complex, makes the fat-soluble enhancing of complex, strengthens its neuroprotective ability, in the future may be in nerve is adjusted There is potential medical value in terms of pivot medicine.

Claims (5)

1. a kind of indoles and pyrroloquinoline compounds, it is spiral shell [indoline -3,2'- pyrrolo- [1,2-a] quinoline] class Compound, structural formula are as follows：
Wherein R1For alkyl, alkoxy or halogen；R2For alkyl or alkyl-substituted phenyl；R3For formyl ester group or aryl.
2. the synthetic method of indoles as claimed in claim 1 and pyrroloquinoline compounds, it is characterised in that：Using acetonitrile as Solvent, under the catalytic action of triethylamine, by quinoline quaternary ammonium salt and 2-（2- oxindole -3- subunits）Malononitrile derivative Hybrid reaction, carries out silica gel column chromatography with the mixed solvent of ethyl acetate and petroleum ether after reaction, obtains spiral shell [dihydro Yin Diindyl -3,2'- pyrrolo-es [1,2-a] quinoline] class compound.
3. synthetic method according to claim 2, it is characterised in that：The 2-（2- oxindole -3- subunits）Malononitrile Class compound is isatin malononitrile, 5- chlorisatides malononitrile, 5- methylisatins malononitrile, N- benzyl isatin malononitrile, the chloro- N- of 5- Benzyl isatin malononitrile, 5- methyl-N-benzyl isatin malononitrile, the fluoro- N- normal-butyls isatin malononitrile of 5- or the positive fourths of 5- methyl-N- Any one in base isatin malononitrile.
4. synthetic method according to claim 2, it is characterised in that：The quinoline quaternary ammonium salt and 2-（2- oxindoles- 3- subunits）The molar ratio of malononitrile derivative is 1: 1.
5. the synthetic method according to Claims 2 or 3, it is characterised in that：The reaction condition is that reaction temperature is room temperature, When reaction time 12 is small.
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Publication number Priority date Publication date Assignee Title
CN111848637A (en) * 2020-07-06 2020-10-30 扬州大学 Method for synthesizing cis/trans spiro compound containing oxygen nitrogen heteroatom

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106977524A (en) * 2017-04-12 2017-07-25 扬州大学 A kind of synthetic method of phenanthro- furans and azoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JING SUN 等: "Molecular Diversity of 1,3-Dipolar Cycloaddition of Quinolinium Ylides with Isatylidene Malononitriles", 《CHEMISTRY SELECT》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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