CN107383027A - A kind of synthetic method of tetrahydrochysene snail compound - Google Patents

A kind of synthetic method of tetrahydrochysene snail compound Download PDF

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CN107383027A
CN107383027A CN201710607680.7A CN201710607680A CN107383027A CN 107383027 A CN107383027 A CN 107383027A CN 201710607680 A CN201710607680 A CN 201710607680A CN 107383027 A CN107383027 A CN 107383027A
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ketone
synthetic method
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chloro
indoles
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孙晶
杨仁银
颜朝国
韩莹
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Yangzhou University
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Yangzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

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Abstract

A kind of synthetic method of tetrahydrochysene snail compound, belongs to technical field of organic synthesis.Protected with nitrogen, under the conditions of existing for solvent and acidic catalyst, after indoles is mixed into progress condensation reaction with ketone, add the ketone of 3 alkylidene indoles 2 and carry out ring-closure reaction, obtain tetrahydrochysene spiral shell [carbazole 1,3' indoline] class compound.Raw material of the present invention is simple and easy to get, substrate need not previously prepared, substrate expand that scope is big, high income.

Description

A kind of synthetic method of tetrahydrochysene snail compound
Technical field
The invention belongs to technical field of organic synthesis.
Background technology
Many natural products contain tetrahydro carbazole structural framework, cause people's because some of them have bioactivity Concern.(Dhara, K.; Mandal, T.; Das, J.; Dash, J.Angew. Chem., Int. Ed.2015,54, 15831; Ito, C.; Katsuno, S.; Itoigawa, M.; Ruangrungsi, N.; Mukainaka, T.; Okuda, M.; Kitagawa, Y.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2000, 63, 125.) such as tumor growth inhibitors and inhibitors of protein kinase C.(Rajasekaran, A.; Thampi, P. P. Eur. J. Med. Chem. 2005, 40, 1359. Shaikh, M. S.; Karpoormath, R.; Thapliyal, N.; Rane, R. A.; Palkar, M. B.; Faya, A. M.; Patel, H. M.; Alwan, W. S.; Jain, K.; Hampannavar, G. A. Anti-Cancer Agents Med. Chem.2015,15, 1049. Siripurapu, U.; Kolanos, R.; Dukat, M.; Roth, B. L.; Glennon, R. A.Bioorg. Med. Chem. Lett. 2006, 16, 3793.) spiral shell indoles also appear in many natural products in, wherein Some have bioactivity, such as gelsemium elegan alkaloid known to people, and kounidine has very strong toxicity.Due to the tool of spiral shell indoles There are potential bioactivity and potential medical value, the synthetic method of spiral shell indoles equally causes concern and the interest of people. Research for spiral shell tetrahydro carbazole structure all has great importance in terms of synthesis and medicine.
The study on the synthesis document report of only a small number of polysubstituted tetrahydrochysene spiral shell [carbazole -1,3'- indoline] class compounds at present Road.2011, (2- oxoindolines -3- was sub- with ethyl -2- using 3- vinyl indoles by Carlos F. Barbas, III Base) ethyl acetate synthesized spiral shell indoles tetrahydro carbazole (Bin T., Gloria under the catalytic action of bis-thiourea chiral catalyst H. T. and Carlos F. B. III, J. Am. Chem. Soc.2011, 133, 12354), still, this method is used 20 mol% catalyst, and raw material need it is previously prepared.Xiao Wen essences seminar of Central China Normal University utilizes 2- second within 2009 Diels-Alder reaction tetrahydrobiopterin synthesis carbazole compounds, (Chen, C. occur for the different reaction site of alkenyl indoles itself B., Wang, X. F., Cao, Y. J.,Cheng, H. G., and Xiao, W. J., J. Org. Chem. 2009, 74, 3533) however the raw material of this method need also exist for it is previously prepared.
The content of the invention
Present invention aims to overcome that above mentioned problem, there is provided a kind of raw material is simple and easy to get, substrate need not previously prepared, bottom Thing expands the synthetic method of big, high income tetrahydrochysene spiral shell [carbazole -1,3'- indoline] the class compound of scope.
The technical scheme is that：Protected with nitrogen, under the conditions of existing for solvent and acidic catalyst, by indoles and ketone After mixing carries out condensation reaction, add 3- alkylidenes indol-2-one and carry out ring-closure reaction, obtain tetrahydrochysene spiral shell [carbazole -1,3'- Indoline] class compound.
Its structural formula is as follows：
Wherein, R1For any one in H or methyl；
R2For C3~C4, and R3For methylene CH2；Or R2For phenyl, p-methylphenyl, p-methoxyphenyl, rubigan or right Any one in nitrobenzophenone, and R3For H；
Alkyl, phenyl, p-methylphenyl, p-methoxyphenyl, rubigan or p-nitrophenyl；
R3For H or methylene CH2；
R4For any one in the substitution of H, 5- halogen or the substitution of 6- halogen；
R5For any one in H, normal-butyl or benzyl；
R6For any one in methoxyl group, ethyoxyl, p-methylphenyl, p-methoxyphenyl or rubigan.
The present invention reaction expression be：
Reaction mechanism of the present invention is as follows：Indoles and ketone carry out addition reaction in acid condition, through dehydration, further occurβ-H Eliminate, obtain divinyl macromer, [4+2] cycloaddition occurs with 3- alkylidenes indol-2-one again afterwards, aromatisation further occurs and obtains Tetrahydrochysene spiral shell [carbazole -1,3'- indoline] class compound.
Detailed process formula is as follows：
The raw material of the present invention is simple and easy to get, and reaction condition is simple, and substrate spectrum is wide and need not be previously prepared, without metal catalytic The participation of agent, yield are high.
Further, the molar ratio of indoles of the present invention, ketone and 3- alkylidene indol-2-ones is 1: 3: 1.Such as adopt With indoles and ketone with 1:1 feeds intake, then can not react complete, and the present invention use excessive ketone with for consuming indoles, the ratio Under the conditions of reaction yield it is best.
Described indoles is one kind in indoles or N- methyl indols.The ketone is acetophenone, melilotal, to chlorine One kind in acetophenone, acetanisole, p-nitroacetophenone or cyclohexanone.Reacted, can be carried out with the substrate Expand on a large scale, and yield is excellent, condition is simple, is advantageous to operate.
Described solvent is dry toluene.Using the specific product, synthetic yield is set to reach 62%~92%.
In order to ensure higher synthetic yield, described acidic catalyst is trifluoromethane sulfonic acid.
The molar ratio of trifluoromethane sulfonic acid and 3- the alkylidene indol-2-one is 0.05: 1.The catalyst is this Reaction necessary auxiliary reagent, excessive catalyst waste of resource, very few catalyst can not complete catalytic reaction, this feeds intake Ratio can reach good catalytic effect.
The 3- alkylidenes indol-2-one is 2-（1- benzyl -5- chloro-2-oxo indoline -3- subunits）Carboxylic acid, ethyl ester, 2-（The fluoro- 2- oxoindolines -3- subunits of 1- normal-butyls -5-）Carboxylic acid, ethyl ester, 2-（6- chloro-2-oxo indoline -3- is sub- Base）Carboxylate methyl ester, the chloro- 3- of 1- normal-butyls 5- (2- oxos -2- (p-methoxyphenyl) ethylidene) indole-2-ketone, 1- benzyls The fluoro- 3- of 5- (2- oxos -2- (p-methylphenyl) ethylidene) indole-2-ketone, (2- oxos -2- is (to chlorine by the chloro- 3- of 1- benzyls 5- Phenyl) ethylidene) indole-2-ketone or the chloro- 3- of 1- benzyls 5- (2- oxos -2- (p-methylphenyl) ethylidene) indoline -2- One kind in ketone.Due to the conjugated double bond with electron deficient, its conjugated double bond cycloaddition easily occurs for 3- alkylidenes indol-2-one Reaction, can advantageously build spiral shell Benzazole compounds, and spiral shell benzazolyl compounds have potential bioactivity.The present invention utilizes Three component reactions of indoles, ketone and 3- alkylidene indol-2-ones, a step construct tetrahydrochysene spiral shell [carbazole -1,3'- indoline] class Compound.This method is easy to operate and yield is very high.
In addition, the temperature conditionss of described ring-closure reaction are 0~100 DEG C, react 4~24 hours.It is highly preferred that reaction temperature Spend to react 16 hours at 80 DEG C.Because low temperature the reaction time is long, reaction is not thorough；Temperature is too high, produces accessory substance, shadow Ring yield.Experiment shows that at such a temperature, reaction rate is most fast, yield highest.
Embodiment
Embodiment 1：Prepare the chloro- 9- methyl -2'- oxos -4- phenyl -2,3,4,9- tetrahydrochysenes spiral shell [clicks of ethyl 1'- benzyls -5'- Azoles -1,3'- indoline] exemplified by -2- carboxylate methyl esters, its reaction equation is as follows：
Preparation method is as follows：
Under the protection of nitrogen, added in 10 mL Schlenck pipesN- methyl indol (0.5 mmol, 0.066g), benzene Ethyl ketone (1.5 mmol, 0.180g), 2 mL dry toluene and trifluoromethanesulfonic acid (5 mol%, 0.004g) is in 60 DEG C of stirrings 1.5 hours, then add 2-（1- benzyl -5- chloro-2-oxo indoline -3- subunits）Carboxylic acid, ethyl ester (0.5 mmol, 0.170g) heat up 80 DEG C and stir 12 hours.TLC detects reaction process, after reaction terminates, adds 5mL water to system, uses acetic acid Ethyl ester extracts (5mL × 3), merges organic layer, organic layer anhydrous Na2SO4Dry, decompression filters, by filtrate rotary evaporation, profit By the use of ethyl acetate and light sherwood oil as solvent, by silica gel column layer chromatographic isolation obtain the chloro- 9- methyl of 1'- benzyls -5'- - 2'- oxo -4- phenyl -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2- carboxylate methyl esters, its separation yield are 92%, 0.264 g。
Structural characterization data are as follows：
m.p. 224-226℃; 1H NMR (400 MHz, CDCl3) δ: 7.49-7.44 (m, 4H, ArH), 7.37- 7.30 (m, 5H, ArH), 7.25-7.23 (m, 2H, ArH), 7.10-7.08 (m, 3H, ArH), 6.83-6.80 (m, 2H, ArH), 6.70 (d, J = 8.0 Hz, 1H, ArH), 5.23 (d, J = 15.2 Hz, 1H, CH), 4.77 (d, J = 15.6 Hz, 1H, CH), 4.41 (dd, J 1 = 11.6 Hz, J 2 = 5.6 Hz, 1H, CH), 3.97-3.84 (m, 2H, CH), 3.45 (d, J = 12.8 Hz, 1H, CH), 3.18-3.08 (m, 1H, CH), 2.83 (s, 3H, CH3), 2.44 (dd, J 1 = 13.2 Hz, J 2 = 5.6 Hz, 1H, CH), 1.01 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 175.2, 171.2, 144.8, 142.7, 138.0, 135.7, 132.8, 131.9, 129.0, 128.8, 128.5, 128.4, 128.3, 128.2, 128.0, 126.6, 125.5, 124.0, 122.1, 120.3, 119.1, 116.5, 110.1, 108.7, 60.9, 52.8, 49.8, 45.0, 41.5, 33.1, 29.9, 13.9; IR (KBr) υ: 3029, 2936, 2857, 1720, 1606, 1487, 1468, 1337, 1244, 1168, 1091, 1019, 929, 813, 748, 700 cm-1; MS (m/z): HRMS (ESI) theoretical values C36H32ClN2O3 ([M+H]+):575.2101. measured value 575.2107.
Embodiment 2：The following 1'- butyl -4- of preparation structure formula（4- chlorphenyls）Fluoro- 9- methyl -2'- oxo -2 of -5'-, 3,4,9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2- carboxylic acid, ethyl esters：
Preparation method：In embodiment 1,2- used（1- benzyl -5- chloro-2-oxo indoline -3- subunits）Carboxylic acid, ethyl ester With the 2- of equimolar amounts（The fluoro- 2- oxoindolines -3- subunits of 1- normal-butyls -5-）Carboxylic acid, ethyl ester replace, acetophenone with etc. rub The parachloroacetophenone of your amount is replaced, and other step methods are identical with example 1, obtain ethyl 1'- butyl -4-（4- chlorphenyls）-5'- Fluoro- 9- methyl -2'- oxos -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2- carboxylic acids, its separation yield are 79%, 0.220 g。
Structural characterization data are as follows：
m.p. 239-241℃; 1H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 7.6 Hz, 2H, ArH), 7.27 (d, J = 7.6 Hz, 2H, ArH), 7.11-7.06 (m, 3H, ArH), 6.90-6.86 (m, 2H, ArH), 6.84-6.82 (m, 1H, ArH), 6.70 (d, J = 8.0 Hz, 1H, ArH), 4.38 (dd, J 1 = 11.2 Hz, J 2 = 5.6 Hz, 1H, CH), 3.93-3.83 (m, 3H, CH), 3.76-3.71 (m, 1H, CH), 3.39 (d, J = 12.8 Hz, 1H, CH), 3.10-3.00 (m, 1H, CH), 2.96 (s, 3H, CH3), 2.36 (dd, J 1 = 13.6 Hz, J 2 = 5.6 Hz, 1H, CH), 1.79-1.70 (m, 2H, CH), 1.52-1.43 (m, 2H, CH), 1.03-0.98 (m, 6H, 2CH3); 13C NMR (100 MHz, CDCl3) δ: 174.9, 170.9, 159.2 (d, J = 240.8 Hz), 143.6, 140.3, 140.2, 138.0, 132.6 (d, J = 7.6 Hz), 132.2, 132.1, 129.7, 128.6, 125.3, 122.1, 120.1, 119.1, 115.7, 115.5 (d, J = 23.2 Hz), 111.8 (d, J = 24.7 Hz), 109.0, 108.9, 108.8, 60.8, 52.6, 49.9, 40.7, 40.6, 32.8, 29.7, 29.3, 20.5, 13.9, 13.8; IR (KBr) υ: 3245, 3028, 2966, 2861, 1724, 1609, 1473, 1352, 1288, 1195, 1107, 1018, 875, 812, 748, 699 cm-1; MS (m/z):HRMS (ESI) theoretical values C33H33ClFN2O3 ([M+H]+):559.2164. measured value 559.2186.
Embodiment 3：The following chloro- 4- of 1'- benzyls -5'- of preparation structure formula（4- methoxyphenyls）- 9- methyl -2'- oxygen Generation -2,3,4,9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2- carboxylic acid, ethyl esters：
Preparation method：In embodiment 1, the acetanisole of acetophenone equimolar amounts used is replaced, other steps Method is identical with example 1, obtains the chloro- 4- of 1'- benzyls -5'-（4- methoxyphenyls）- 9- methyl -2'- oxos -2,3,4,9- four Hydrogen spiral shell [carbazole -1,3'- indoline] -2- carboxylic acid, ethyl esters, its separation yield are 88%, 0.266 g.
Structural characterization data are as follows：
m.p. 207-209℃; 1H NMR (400 MHz, CDCl3) δ: 7.47 (d, J = 7.2 Hz, 2H, ArH), 7.37-7.28 (m, 5H, ArH), 7.24 d, J = 8.0 Hz, 1H, ArH), 7.11-7.08 (m, 3H, ArH), 6.86 (d, J = 6.8 Hz, 2H, ArH), 6.84-6.80 (m, 2H, ArH), 6.75 (d, J = 7.6 Hz, 1H, ArH), 5.23 (d, J = 15.2 Hz, 1H, CH), 4.77 (d, J = 14.8 Hz, 1H, CH), 4.36 (dd, J 1 = 11.6 Hz, J 2 = 5.6 Hz, 1H, CH), 3.98-3.83 (m, 2H, CH), 3.81 (s, 3H, OCH3), 3.44 (d, J = 12.8 Hz, 1H, CH), 3.14-3.05 (m, 1H, CH), 2.82 (s, 3H, CH3), 2.43-2.38 (m, 1H, CH), 1.01 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 175.2, 171.2, 158.2, 142.6, 138.0, 137.0, 135.7, 132.8, 131.7, 129.3, 129.0, 128.8, 128.3, 128.2, 128.0, 125.5, 124.0, 122.0, 120.4, 119.0, 116.8, 113.8, 110.1, 108.7, 60.8, 55.2, 52.9, 49.8, 44.9, 40.7, 33.2, 29.9, 13.9; IR (KBr) υ: 3055, 2932, 2843, 1726, 1607, 1477, 1435, 1328, 1301, 1246, 1170, 1110, 1070, 1028, 969, 912, 874, 809, 740 cm-1; MS (m/z):HRMS (ESI) is managed By value C37H34ClN2O4 ([M+H]+):605.2207. measured value 605.2222.
Embodiment 4：The following chloro- 9- methyl -4- of 1'- benzyls -5'- of preparation structure formula（4- nitrobenzophenones）- 2'- oxos- 2,3,4,9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2- carboxylic acid, ethyl esters：
Preparation method：In embodiment 1, the p-nitroacetophenone of acetophenone equimolar amounts used is replaced, other step sides Method is identical with example 1, obtains the chloro- 9- methyl -4- of 1'- benzyls -5'-（4- nitrobenzophenones）- 2'- oxo -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2- carboxylic acid, ethyl esters, its separation yield are 91%, 0.282 g.
Structural characterization data are as follows：
m.p. 269-271℃; 1H NMR (400 MHz, CDCl3) δ: 8.24 (d, J = 8.4 Hz, 2H, ArH), 7.53-7.52 (m, 4H, ArH), 7.41-7.33 (m, 3H, ArH), 7.29 d, J = 8.8 Hz, 1H, ArH), 7.17 (s, 1H, ArH), 7.13-7.12 (m, 2H, ArH), 6.95 (d, J = 8.4 Hz, 1H, ArH), 6.85-6.81 (m, 1H, ArH), 6.53 (d, J = 8.4 Hz, 1H, ArH), 5.13 (d, J = 15.2 Hz, 1H, CH), 4.91 (d, J = 15.2 Hz, 1H, CH), 4.53 (dd, J 1 = 11.6 Hz, J 2 = 5.2 Hz, 1H, CH), 3.83-3.72 (m, 3H, CH), 2.98 (s, 3H, CH3), 2.64-2.60 (m, 1H, CH), 2.33-2.24 (m, 1H, CH), 0.87 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 176.7, 169.9, 152.4, 146.9, 141.6, 138.0, 135.0, 132.2, 130.4, 129.4, 128.9, 128.6, 128.4, 128.3, 125.6, 124.5, 124.1, 122.5, 120.0, 119.3, 114.1, 110.3, 109.0, 61.0, 51.4, 50.6, 45.3, 40.4, 33.8, 29.3, 13.8; IR (KBr) υ: 3059, 2940, 2858, 1729, 1601, 1519, 1475, 1435, 1341, 1237, 1168, 1114, 1071, 1015, 945, 860, 845, 818, 742, 700 cm-1; MS (m/z):HRMS (ESI) theoretical value C36H31ClN3O5 ([M+H]+):620.1952. measured value 620.1949.
Embodiment 5：The chloro- 9- methyl -2'- oxos -4- phenyl -2,3,4,9- tetrahydrochysenes spiral shell [clicks of the following 6'- of preparation structure formula Azoles -1,3'- indoline] -2- carboxylate methyl esters：
Preparation method：In embodiment 1,2- used（The fluoro- 2- oxoindolines -3- subunits of 1- normal-butyls -5-）Carboxylic acid second The 2- of ester equimolar amounts（6- chloro-2-oxo indoline -3- subunits）Methyl acetate is replaced, other step methods and example 1 It is identical, obtain the chloro- 9- methyl -2'- oxos -4- phenyl -2,3 of 6'-, 4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2- carboxylics Sour methyl esters, its separation yield are 89%, 0.209 g.
Structural characterization data are as follows：
m.p. 278-280℃; 1H NMR (400 MHz, CDCl3) δ: 8.97 (s, 1H, NH), 7.43 (d, J = 7.2 Hz, 2H, ArH), 7.33 (t, J = 7.2 Hz, 2H, ArH), 7.28 (d, J = 6.8 Hz, 1H, ArH), 7.13-7.07 (m, 2H, ArH), 7.04-6.99 (m, 3H, ArH), 6.81 (t, J = 7.2 Hz, 1H, ArH), 6.70 (d, J = 8.0 Hz, 1H, ArH), 4.40 (dd, J 1 = 11.2 Hz, J 2 = 5.6 Hz, 1H, CH), 3.52-3.47 (m, 4H, CH, CH3), 3.12-3.03 (m, 4H, CH, CH3), 2.46-2.41 (m, 1H, CH); 13C NMR (100 MHz, CDCl3) δ: 178.0, 172.0, 144.7, 143.1, 138.1, 134.8, 131.8, 129.8, 128.5, 128.4, 126.7, 125.4, 124.5, 122.9, 122.1, 120.3, 119.0, 116.2, 111.1, 108.8, 52.8, 52.2, 49.9, 41.5, 33.3, 29.8; IR (KBr) υ: 3311, 3059, 2942, 2851, 1739, 1611, 1476, 1362, 1291, 1241, 1201, 1169, 1116, 1065, 1021, 973, 922, 853, 819, 747, 702 cm-1; MS (m/z):HRMS (ESI) theoretical value C28H24ClN2O3 ([M+H]+):471.1475. measured value 471.1493.
Embodiment 6：The following chloro- 2- of 1'- butyl -5'- of preparation structure formula（4- methoxybenzoyl bases）- 4- phenyl -2, 3,4,9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2'- ketone：
Preparation method：In embodiment 1, the indoles of N- methyl indol equimolar amounts used is replaced, 2-（1- benzyls -5- is chloro- 2- oxoindoline -3- subunits）(2- oxos -2- is (to methoxyl group by the chloro- 3- of 1- normal-butyls 5- of carboxylic acid, ethyl ester equimolar amounts Phenyl) ethylidene) to replace other step methods identical with example 1 for indole-2-ketone, obtain the chloro- 2- of 1'- butyl -5'-（4- first Epoxide benzoyl）- 4- phenyl -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2'- ketone, its separation yield are 80%, 0.235 g。
Structural characterization data are as follows：
m.p. 204-206℃; 1H NMR (600 MHz, CDCl3) δ: 7.83 (d, J = 9.0 Hz, 2H, ArH), 7.47-7.46 (m, 2H, ArH), 7.30-7.27 (m, 3H, ArH), 7.23-7.20 (m, 2H, ArH), 7.13 (d, J = 7.8 Hz, 1H, ArH), 7.08 (brs, 1H, NH), 7.04 (t, J = 7.8 Hz, 1H, ArH), 6.91-6.90 (m, 3H, ArH), 6.83 (t, J = 7.2 Hz, 1H, ArH), 6.77-6.76 (m, 1H, ArH), 4.53-4.50 (m, 1H, CH), 4.48 (d, J = 12.0 Hz, 1H, CH), 3.87-3.82 (m, 5H, CH, CH3), 3.37-3.30 (m, 1H, CH), 2.51-2.48 (m, 1H, CH), 1.90-1.79 (m, 2H, CH), 1.54-1.47 (m, 2H, CH), 1.02 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3) δ: 196.7, 176.4, 163.7, 144.6, 143.5, 136.4, 132.3, 132.2, 130.6, 129.1, 128.5, 128.4, 128.3, 127.4, 126.7, 126.6, 123.6, 122.2, 120.0, 119.5, 115.5, 114.0, 110.8, 109.5, 55.5, 53.7, 49.1, 41.5, 40.6, 33.9, 29.1, 20.4, 13.9; IR (KBr) υ: 3353, 3060, 2959, 2866, 1878, 1717, 1681, 1602, 1483, 1452, 1347, 1243, 1176, 1113, 1024, 969, 915, 880, 834, 744 cm-1; MS (m/z): HRMS (ESI) theoretical value C37H34ClN2O3 ([M+H]+):589.2258. measured value 589.2268.
Embodiment 7：The following fluoro- 2- of 1'- benzyls -5'- of preparation structure formula（4- methyl benzoyls）- 4- phenyl -2,3, 4,9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2'- ketone：
Preparation method：In embodiment 1, N- methyl indols used are replaced with equimolar indoles, 2-（The chloro- 2- of 1- benzyls -5- Oxoindoline -3- subunits）(2- oxos -2- (p-methylphenyl) is sub- by the fluoro- 3- of 1- benzyls 5- of carboxylic acid, ethyl ester equimolar amounts Ethyl) indole-2-ketone replacement, other step methods are identical with example 1, obtain the fluoro- 2- of 1'- benzyls -5'-（4- methylbenzene first Acyl group）- 4- phenyl -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2'- ketone, its separation yield are 73%, 0.215 g。
Structural characterization data are as follows：
m.p. 260-262℃; 1H NMR (600 MHz, CDCl3) δ: 7.77 (d, J = 7.8 Hz, 2H, ArH), 7.52 (d, J = 7.2 Hz, 2H, ArH), 7.50 (d, J = 7.2 Hz, 2H, ArH), 7.39-7.37 (m, 2H, ArH), 7.32-7.29 (m, 3H, ArH), 7.24-7.21 (m, 3H, ArH), 7.17 (brs, 1H, NH), 7.14 (d, J = 7.8 Hz, 1H, ArH), 7.07-7.04 (m, 1H, ArH), 6.91-6.87 (m, 1H, ArH), 6.86-6.83 (m, 2H, ArH), 6.78 (d, J = 7.8 Hz, 1H, ArH), 6.75-6.73 (m, 1H, ArH), 5.26 (d, J = 15.6 Hz, 1H, CH), 4.92 (d, J = 15.6 Hz, 1H, CH), 4.57- 4.54 (m, 2H, CH), 3.42-3.36 (m, 1H, CH), 2.56-2.53 (m, 1H, CH), 2.39 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3) δ: 197.9, 176.8, 159.1 (J = 240.2 Hz), 144.4, 140.3, 136.5, 136.2, 132.9, 132.3, 131.9 (J = 7.8 Hz), 129.5, 128.9, 128.9, 128.5, 128.4, 128.4, 127.7, 126.7, 126.7, 122.3, 120.1, 119.6, 115.6, 115.5 (J = 23.4 Hz), 111.1, 111.0, 110.8, 110.2, 110.1, 53.7, 49.5, 44.6, 41.6, 33.9, 21.6; IR (KBr) υ: 3398, 3058, 2928, 2854, 1713, 1674, 1608, 1491, 1447, 1337, 1277, 1237, 1172, 1123, 1078, 1020, 975, 928, 804, 746 cm-1; MS (m/z): HRMS (ESI) theoretical values C40H32FN2O2 ([M+H]+):591.2248. measured value 591.2456.
Embodiment 8：The following chloro- 2- of 1'- benzyls -5'- of preparation structure formula（4- chlorobenzene formacyls）- 4- phenyl -2,3,4, 9- tetrahydrochysenes spiral shell [carbazole -1,3'- indoline] -2'- ketone：
Preparation method：In embodiment 1, the indoles of N- methyl indol equimolar amounts used is replaced, 2-（1- benzyls -5- is chloro- 2- oxoindoline -3- subunits）(2- oxos -2- (rubigan) is sub- by the chloro- 3- of 1- benzyls 5- of carboxylic acid, ethyl ester equimolar amounts Ethyl) indole-2-ketone replacement, other step methods are identical with example 1, obtain the chloro- 2- of 1'- benzyls -5'-（4- chlorobenzoyls Base）- 4- phenyl -2,3,4,9- tetrahydrochysene spiral shells [carbazole -1,3'- indoline] -2'- ketone, its separation yield are 78%, 0.244 g。
Structural characterization data are as follows：
m.p. 297-299℃; 1H NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 8.4 Hz, 2H, ArH), 7.51-7.48 (m, 4H, ArH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 7.40-7.37 (m, 2H, ArH), 7.34-7.29 (m, 3H, ArH), 7.24-7.22 (m, 1H, ArH), 7.19-7.15 (m, 3H, ArH, NH), 7.09-7.05 (m, 2H, ArH), 6.87-6.84 (m, 1H, ArH), 6.79-6.75 (m, 2H, ArH), 5.23 (d, J = 15.6 Hz, 1H, CH), 4.94 (d, J = 15.6 Hz, 1H, CH), 4.57-4.50 (m, 2H, CH), 3.43-3.33 (m, 1H, CH), 2.54-2.49 (m, 1H, CH); 13C NMR (100 MHz, CDCl3) δ: 197.2, 176.3, 144.2, 142.8, 140.0, 136.4, 135.8, 133.5, 131.8, 131.8, 129.7, 129.2, 129.1, 128.9, 128.5, 128.3, 128.0, 127.8, 127.6, 126.8, 126.6, 123.3, 122.4, 120.1, 119.7, 115.5, 110.8, 110.6, 53.7, 49.1, 44.5, 41.4, 33.7; IR (KBr) υ: 3390, 3060, 3027, 2934, 2847, 1723, 1687, 1604, 1484, 1430, 1358, 1332, 1272, 1242, 1192, 1168, 1126, 1075, 1026, 975, 912, 875, 815, 744, 701 cm-1; MS (m/z):HRMS (ESI) theoretical values C39H29Cl2N2O2 ([M+H]+): 627.1606. Measured value 627.1593.
Embodiment 9：The following chloro- 5- of 1'- benzyls -5'- of preparation structure formula（4- methyl benzoyls）- 1,2,3,4,4a, 5,7,11c octahydros spiral shell [benzo [c] carbazole -6,3'- indoline] -2'- ketone：
Preparation method：In embodiment 1, the indoles of N- methyl indol equimolar amounts used is replaced, 2-（1- benzyls -5- is chloro- 2- oxoindoline -3- subunits）The chloro- 3- of the 1- benzyls 5- (2- oxos -2- (p-methylphenyl) of carboxylic acid, ethyl ester equimolar amounts Ethylidene) indole-2-ketone replacement, the cyclohexanone replacement of acetophenone equimolar amounts, other step methods are identical with example 1, Obtain the chloro- 5- of 1'- benzyls -5'-（4- methyl benzoyls）- 1,2,3,4,4a, 5,7,11c octahydro spiral shells [benzo [c] carbazole -6, 3'- indoline] -2'- ketone, its separation yield is 62%, 0.181 g.
Structural characterization data are as follows：
m.p. 259-261℃; 1H NMR (600 MHz, CDCl3) δ: 7.79-7.64 (m, 3H, NH, ArH), 7.58 (d, J = 7.8 Hz, 2H, ArH), 7.40 (t, J = 7.2 Hz, 2H, ArH), 7.35-7.33 (m, 1H, ArH), 7.28 (d, J = 7.8 Hz, 2H, ArH), 7.13-7.06 (m, 5H, ArH), 6.91 (d, J = 1.8 Hz, 1H, ArH), 6.73 (d, J = 8.4 Hz, 1H, ArH), 5.31 (d, J = 15.0 Hz, 1H, CH), 4.89 (d, J = 15.0 Hz, 1H, CH), 4.48 (d, J = 1.8 Hz, 1H, CH), 3.74 (brs, 1H, CH), 3.04 (d, J = 13.8 Hz, 1H, CH), 2.68-2.64 (m, 2H, CH), 2.43 (s, 3H, CH3), 1.66 (d, J = 12.0 Hz, 1H, CH), 1.51 (d, J = 12.0 Hz, 1H, CH), 1.29 (m, 3H, CH), 1.11-1.05 (m, 1H, CH); 13C NMR (150 MHz, CDCl3) δ: 198.2, 176.8, 144.1, 141.6, 137.0, 136.5, 135.1, 133.4, 131.9, 129.5, 128.9, 128.7, 128.4, 128.0, 127.9, 127.7, 126.5, 123.5, 122.1, 120.4, 119.6, 112.8, 111.0, 110.2, 60.5, 50.1, 44.7, 41.8, 36.8, 30.0, 26.3, 23.9, 21.6, 21.2; IR (KBr) υ: 3356, 3033, 2923, 2855, 1719, 1604, 1480, 1440, 1391, 1328, 1255, 1163, 1112, 1075, 1026, 954, 820, 742, 700 cm-1; MS (m/z):HRMS (ESI) theoretical values C38H33ClN2NaO2 ([M+ Na]+):607.2128. measured value 607.2114.

Claims (10)

  1. A kind of 1. synthetic method of tetrahydrochysene snail compound, it is characterised in that：Protected with nitrogen, deposited in solvent and acidic catalyst Under the conditions, indoles is mixed with ketone after carrying out condensation reaction, adds 3- alkylidenes indol-2-one and carry out ring-closure reaction, Tetrahydrochysene spiral shell [carbazole -1,3'- indoline] class compound is obtained, its structural formula is as follows：
    Wherein, R1For any one in H or methyl；
    R2For C3~C4, and R3For methylene CH2；Or R2For phenyl, p-methylphenyl, p-methoxyphenyl, rubigan or right Any one in nitrobenzophenone, and R3For H；
    R4For any one in the substitution of H, 5- halogen or the substitution of 6- halogen；
    R5For any one in H, normal-butyl or benzyl；
    R6For any one in methoxyl group, ethyoxyl, p-methylphenyl, p-methoxyphenyl or rubigan.
  2. 2. synthetic method according to claim 1, it is characterised in that：The indoles, ketone and 3- alkylidene indol-2-ones Molar ratio is 1: 3: 1.
  3. 3. synthetic method according to claim 1, it is characterised in that：Described indoles is in indoles or N- methyl indols It is a kind of.
  4. 4. synthetic method according to claim 1, it is characterised in that：Described ketone is acetophenone, melilotal, right One kind in chloro-acetophenone, acetanisole, p-nitroacetophenone or cyclohexanone.
  5. 5. according to the synthetic method described in claim 1 or 2 or 3 or 4, it is characterised in that：Described solvent is dry toluene.
  6. 6. according to the synthetic method described in claim 1 or 2 or 3 or 4, it is characterised in that：Described acidic catalyst is trifluoro Pyrovinic acid.
  7. 7. synthetic method according to claim 6, it is characterised in that：Trifluoromethane sulfonic acid and 3- the alkylidene indoles- The molar ratio of 2- ketone is 0.05: 1.
  8. 8. synthetic method according to claim 1, it is characterised in that：The 3- alkylidenes indol-2-one is 2-（1- benzyls Base -5- chloro-2-oxo indoline -3- subunits）Carboxylic acid, ethyl ester, 2-（The fluoro- 2- oxoindolines -3- of 1- normal-butyls -5- are sub- Base）Carboxylic acid, ethyl ester, 2-（6- chloro-2-oxo indoline -3- subunits）Carboxylate methyl ester, the chloro- 3- of 1- normal-butyls 5- (2- oxos -2- (p-methoxyphenyl) ethylidene) indole-2-ketone, the fluoro- 3- of 1- benzyls 5- (2- oxos -2- (p-methylphenyl) ethylidene) Yin Diindyl quinoline -2- ketone, the chloro- 3- of 1- benzyls 5- (2- oxos -2- (rubigan) ethylidene) indole-2-ketones or the chloro- 3- of 1- benzyls 5- One kind in (2- oxos -2- (p-methylphenyl) ethylidene) indole-2-ketone.
  9. 9. synthetic method according to claim 1, it is characterised in that：The temperature conditionss of described ring-closure reaction are 0~100 DEG C, react 4~24 hours.
  10. 10. synthetic method according to claim 9, it is characterised in that：The reaction temperature of described ring-closure reaction is 80 DEG C, Reaction 16 hours.
CN201710607680.7A 2017-07-24 2017-07-24 A kind of synthetic method of tetrahydrochysene snail compound Pending CN107383027A (en)

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