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Synthesis method for tetrahydrospiro compound

A synthetic method and compound technology, applied in the direction of organic chemistry, etc., to achieve the effect of wide substrate range, simple reaction conditions and high yield

Inactive Publication Date: 2017-11-24
YANGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] There are only a few reports on the synthesis of polysubstituted tetrahydrospiro[carbazole-1,3'-indoline] compounds
In 2011, Carlos F. Barbas, III used 3-vinylindole and ethyl-2-(2-oxoindoline-3-ylidene) ethyl acetate in the catalytic effect of dithiourea chiral catalyst Spiroindoletetrahydrocarbazole was synthesized under (Bin T., GloriaH. T. and Carlos F. B. III, J. Am. Chem. Soc. 2011, 133 , 12354), however, this method uses 20 mol% catalyst, and the raw material needs to be prepared in advance

Method used

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  • Synthesis method for tetrahydrospiro compound
  • Synthesis method for tetrahydrospiro compound
  • Synthesis method for tetrahydrospiro compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of ethyl 1'-benzyl-5'-chloro-9-methyl-2'-oxo-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole-1 ,3'-indoline]-2-carboxylate methyl ester as an example, its reaction formula is as follows:

[0029]

[0030] The preparation method is as follows:

[0031] Under the protection of nitrogen, add in a 10 mL Schlenck tube N -Methyl indole (0.5 mmol, 0.066g), acetophenone (1.5 mmol, 0.180g), 2 mL of dry toluene and trifluoromethanesulfonic acid (5 mol%, 0.004g) were stirred at 60°C for 1.5 hours, Then ethyl 2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)carboxylate (0.5 mmol, 0.170 g) was added and the mixture was stirred at 80°C for 12 hours. TLC detects the reaction process, when the reaction is over, add 5mL water to the system, extract with ethyl acetate (5mL×3), combine the organic layers, and wash the organic layer with anhydrous Na 2 SO 4 Drying, suction filtration under reduced pressure, rotary evaporation of the filtrate, using ethyl acetate and lig...

Embodiment 2

[0034] Example 2: Preparation of 1'-butyl-4-(4-chlorophenyl)-5'-fluoro-9-methyl-2'-oxo-2,3,4,9-tetrahydro with the following structural formula Ethyl spiro[carbazole-1,3'-indoline]-2-carboxylate:

[0035]

[0036] Preparation method: In Example 1, the 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene) ethyl carboxylate used was prepared with an equimolar amount of 2-(1 -n-butyl-5-fluoro-2-oxoindoline-3-ylidene) ethyl carboxylate is replaced, acetophenone is replaced with p-chloroacetophenone of equimolar amount, other steps method and example 1 Same, to get ethyl 1'-butyl-4-(4-chlorophenyl)-5'-fluoro-9-methyl-2'-oxo-2,3,4,9-tetrahydrospiro[carba Azole-1,3'-indoline]-2-carboxylic acid, the isolated yield was 79%, 0.220 g.

[0037] The structural characterization data are as follows:

[0038] m.p.239-241℃; 1 H NMR (400 MHz, CDCl 3 ) 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 (...

Embodiment 3

[0039] Example 3: Preparation of 1'-benzyl-5'-chloro-4-(4-methoxyphenyl)-9-methyl-2'-oxo-2,3,4,9- Ethyl tetrahydrospiro[carbazole-1,3'-indoline]-2-carboxylate:

[0040]

[0041] Preparation method: In Example 1, the acetophenone used is replaced with an equimolar amount of p-methoxyacetophenone, and the other steps are the same as in Example 1 to obtain 1'-benzyl-5'-chloro-4- (4-Methoxyphenyl)-9-methyl-2'-oxo-2,3,4,9-tetrahydrospiro[carbazole-1,3'-indoline]-2-carboxy Acetate ethyl ester, its isolated yield was 88%, 0.266 g.

[0042] The structural characterization data are as follows:

[0043] m.p.207-209℃; 1 H NMR (400 MHz, CDCl 3 ) 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...

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Abstract

Belonging to the technical field of organic synthesis, the invention relates to a synthesis method for a tetrahydrospiro compound. The method includes: under the protection of nitrogen, in the presence of a solvent and an acidic catalyst, carrying out condensation reaction on indole and ketone, then adding 3-alkylene indole-2-one for cyclization reaction, thus obtaining a tetrahydrospiro[carbazole-1, 3'-indoline] compound. The method provided by the invention has the advantages of simple and easily available raw materials, no need for preparation of a substrate in advance, large substrate expansion scope and high yield.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis. Background technique [0002] Many natural products contain tetrahydrocarbazole backbones, some of which have attracted attention due to their biological activity. (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.; H. J. Nat. Prod. 2000, 63 , 125. ) such as tumor growth inhibitors and protein kinase C inhibitors. (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.) Spiroindole also occurs in many natural product...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10
CPCC07D487/10
Inventor 孙晶杨仁银颜朝国韩莹
Owner YANGZHOU UNIV
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