CN107383027A - A kind of synthetic method of tetrahydrochysene snail compound - Google Patents
A kind of synthetic method of tetrahydrochysene snail compound Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 6
- 238000010189 synthetic method Methods 0.000 title claims description 12
- 241000237858 Gastropoda Species 0.000 title claims 2
- 150000002576 ketones Chemical class 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- -1 methoxyl group Chemical group 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 18
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical group CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical class C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 7
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 5
- 150000002475 indoles Chemical class 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims description 3
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims 3
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims 2
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 claims 1
- SCRXASNUPJPFGP-UHFFFAOYSA-N 1-fluoro-3h-indol-2-one Chemical class C1=CC=C2N(F)C(=O)CC2=C1 SCRXASNUPJPFGP-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 125000001118 alkylidene group Chemical group 0.000 claims 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 24
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 10
- QHBJLQMGOJAQLE-UHFFFAOYSA-N spiro[1,2,3a,4,5,6-hexahydroindole-3,1'-carbazole] Chemical class N1CC2(C3CCCC=C13)C=CC=C1C3=CC=CC=C3N=C12 QHBJLQMGOJAQLE-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003377 acid catalyst Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 20
- 238000012512 characterization method Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical group N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 2
- QESTVNWHSYTWFK-UHFFFAOYSA-N 1-benzyl-5-chloro-3-[2-(4-methylphenyl)-2-oxoethylidene]indol-2-one Chemical compound C1=CC(C)=CC=C1C(=O)C=C1C2=CC(Cl)=CC=C2N(CC=2C=CC=CC=2)C1=O QESTVNWHSYTWFK-UHFFFAOYSA-N 0.000 description 2
- OVBSDAIWSOOVLP-UHFFFAOYSA-N 1-benzyl-5-fluoro-3-[2-(4-methylphenyl)-2-oxoethylidene]indol-2-one Chemical compound C(C1=CC=CC=C1)N1C(C(C2=CC(=CC=C12)F)=CC(C1=CC=C(C=C1)C)=O)=O OVBSDAIWSOOVLP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- KCOYHFNCTWXETP-UHFFFAOYSA-N (carbamothioylamino)thiourea Chemical compound NC(=S)NNC(N)=S KCOYHFNCTWXETP-UHFFFAOYSA-N 0.000 description 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- FIRXFHJQGIIJDB-UHFFFAOYSA-N 1-methyl-2,3-dihydroindole Chemical compound C1=CC=C2N(C)CCC2=C1 FIRXFHJQGIIJDB-UHFFFAOYSA-N 0.000 description 1
- LSSICPJTIPBTDD-UHFFFAOYSA-N 2-ethenyl-1h-indole Chemical compound C1=CC=C2NC(C=C)=CC2=C1 LSSICPJTIPBTDD-UHFFFAOYSA-N 0.000 description 1
- YAMMUQMONCMYCX-UHFFFAOYSA-N 3-ethenyl-1h-indole Chemical compound C1=CC=C2C(C=C)=CNC2=C1 YAMMUQMONCMYCX-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- SXWJMFFSUOWBDC-UHFFFAOYSA-N acetaldehyde;benzene Chemical compound CC=O.C1=CC=CC=C1 SXWJMFFSUOWBDC-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
一种四氢螺类化合物的合成方法，属于有机合成技术领域。用氮气保护，在溶剂和酸性催化剂存在的条件下，将吲哚与酮混合进行缩合反应后，再加入3‑亚烷基吲哚‑2‑酮进行环合反应，得到四氢螺[咔唑‑1,3'‑二氢吲哚]类化合物。本发明原料简单易得、底物不需要预先制备、底物拓展范围大、收率高。The invention discloses a method for synthesizing tetrahydrospiro compounds, belonging to the technical field of organic synthesis. Protected with nitrogen, in the presence of a solvent and an acid catalyst, after mixing indole and ketone for condensation reaction, then adding 3-alkylene indole-2-ketone for ring closure reaction to obtain tetrahydrospiro[carbazole ‑1,3'‑indoline] compounds. The raw materials of the invention are simple and easy to obtain, the substrate does not need to be prepared in advance, the expansion range of the substrate is large, and the yield is high.
Description
技术领域technical field
本发明属于有机合成技术领域。The invention belongs to the technical field of organic synthesis.
背景技术Background technique
许多天然产物含有四氢咔唑结构骨架，由于其中一些具有生物活性而引起人们的关注。(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. )例如肿瘤生长抑制剂和蛋白激酶C抑制剂。(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.) 螺吲哚也出现在许多的天然产物中，其中一些具有生物活性，例如人熟知的断肠草生物碱，钩吻碱具有很强的毒性。由于螺吲哚的具有潜在的生物活性以及潜在的药用价值，螺吲哚的合成方法同样引起人们的关注和兴趣。对于螺四氢咔唑结构的的研究在合成以及医药方面都具有重要的意义。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.; Furukawa, H. J. Nat. Prod. 2000, 63 , 125. ) such as tumor growth inhibitors and protein kinase C inhibitors. (Rajasekaran, A.; Thampi, PP Eur. J. Med. Chem. 2005, 40 , 1359. Shaikh, MS; Karpoormath, R.; Thapliyal, N.; Rane, RA; Palkar, MB; Faya, AM; Patel , HM;Alwan, WS; Jain, K.; Hampannavar, GA Anti-Cancer Agents Med. Chem. 2015, 15 , 1049. Siripurapu, U.; Kolanos, R.; Dukat, M.; Roth, BL; Glennon, RA Bioorg. Med. Chem. Lett. 2006, 16 , 3793.) Spiroindole also appears in many natural products, some of which are biologically active, such as the well-known alkaloids of scorpion grass, and kelezine has a strong toxicity. Due to the potential biological activity and potential medicinal value of spiroindole, the synthesis method of spiroindole has also attracted people's attention and interest. The research on the structure of spirotetrahydrocarbazole is of great significance in synthesis and medicine.
目前仅有少数多取代四氢螺[咔唑-1,3'-二氢吲哚]类化合物的合成研究文献报道。2011年，Carlos F. Barbas, III利用3-乙烯基吲哚与乙基-2-(2-氧代二氢吲哚-3-亚基)乙酸乙酯在双硫脲手性催化剂的催化作用下合成了螺吲哚四氢咔唑(Bin T., GloriaH. T. and Carlos F. B. III, J. Am. Chem. Soc.2011, 133, 12354)，但是，该方法用了20 mol%的催化剂，而且原料需要预先制备。2009年华中师范大学肖文精课题组利用2-乙烯基吲哚自身不同的反应位点发生Diels-Alder反应合成四氢咔唑类化合物，( Chen，C.B., Wang, X. F., Cao, Y. J.,Cheng, H. G., and Xiao, W. J., J. Org. Chem. 2009, 74,3533)然而该方法的原料同样需要预先制备。At present, 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 Spiroindole tetrahydrocarbazole was synthesized under the following method (Bin T., GloriaH. T. and Carlos FB III, J. Am. Chem. Soc. 2011, 133 , 12354), however, this method used 20 mol% catalyst , and the raw materials need to be prepared in advance. In 2009, Xiao Wenjing's research group of Central China Normal University used the Diels-Alder reaction of different reaction sites of 2-vinylindole to synthesize tetrahydrocarbazoles (Chen, CB, Wang, XF, Cao, YJ, Cheng , HG, and Xiao, WJ, J. Org. Chem. 2009 , 74 ,3533) However, the raw materials of this method also need to be prepared in advance.
发明内容Contents of the invention
本发明目的在于克服上述问题，提供一种原料简单易得、底物不需要预先制备、底物拓展范围大、收率高的四氢螺[咔唑-1,3'-二氢吲哚]类化合物的合成方法。The purpose of the present invention is to overcome the above problems and provide a tetrahydrospiro[carbazole-1,3'-indoline] with simple and easy-to-obtain raw materials, no pre-preparation of substrates, a wide range of substrate expansion and high yield Synthetic methods of compounds.
本发明技术方案是：用氮气保护，在溶剂和酸性催化剂存在的条件下，将吲哚与酮混合进行缩合反应后，再加入3-亚烷基吲哚-2-酮进行环合反应，得到四氢螺[咔唑-1,3'-二氢吲哚]类化合物。The technical scheme of the present invention is: protect with nitrogen, under the condition that solvent and acid catalyst exist, mix indole and ketone to carry out condensation reaction, then add 3-alkylene indole-2-one to carry out cyclization reaction, obtain Tetrahydrospiro[carbazole-1,3'-indoline] compounds.
其结构式如下：Its structural formula is as follows:
其中，R1为H或甲基中的任意一种；Wherein, R 1 is any one of H or methyl;
R2为C3～C4，且R3为亚甲基CH2；或R2为苯基、对甲基苯基、对甲氧基苯基、对氯苯基或对硝基苯基中的任意一种，且R3为H；R 2 is C 3 ~ C 4 , and R 3 is methylene CH 2 ; or R 2 is phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl or p-nitrophenyl Any one of, and R 3 is H;
烷基、苯基、对甲基苯基、对甲氧基苯基、对氯苯基或对硝基苯基；Alkyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl or p-nitrophenyl;
R3为H或亚甲基CH2；R 3 is H or methylene CH 2 ;
R4为H、5-卤取代或6-卤取代中的任意一种；R 4 is any one of H, 5-halogen substitution or 6-halogen substitution;
R5为H、正丁基或苄基中的任意一种；R is any one of H, n - butyl or benzyl;
R6为甲氧基、乙氧基、对甲基苯基、对甲氧基苯基或对氯苯基中的任意一种。R 6 is any one of methoxy, ethoxy, p-methylphenyl, p-methoxyphenyl or p-chlorophenyl.
本发明的反应通式为：General reaction formula of the present invention is:
本发明反应机理如下：吲哚和酮在酸性条件下进行加成反应，经脱水，进一步发生β-H消除，得到双烯体，之后再与3-亚烷基吲哚-2-酮发生[4+2]环加成，进一步发生芳构化得到四氢螺[咔唑-1,3'-二氢吲哚]类化合物。The reaction mechanism of the present invention is as follows: indole and ketone carry out addition reaction under acidic conditions, through dehydration, β- H is eliminated further, obtain diene body, then with 3-alkylene indole-2-ketone [ 4+2] cycloaddition and further aromatization to obtain tetrahydrospiro[carbazole-1,3'-indoline] compounds.
具体过程式如下：The specific procedure is as follows:
本发明的原料简单易得，反应条件简单，底物范围广且不需要预先制备，无需金属催化剂的参与，产率高。The raw materials of the invention are simple and easy to obtain, the reaction conditions are simple, the range of substrates is wide, no pre-preparation is required, no participation of metal catalysts is required, and the yield is high.
进一步地，本发明所述吲哚、酮和3-亚烷基吲哚-2-酮的投料摩尔比为1∶3∶1。如采用吲哚和酮以1:1投料，则不能反应完全，本发明采用过量的酮以用来消耗吲哚，该比例的条件下反应收率最好。Further, the molar ratio of indoles, ketones and 3-alkylene indol-2-ones in the present invention is 1:3:1. If indole and ketone are fed at a ratio of 1:1, the reaction cannot be complete. The present invention uses excess ketone to consume indole, and the reaction yield is the best under the condition of this ratio.
所述的吲哚为吲哚或N-甲基吲哚中的一种。所述酮为苯乙酮、对甲基苯乙酮、对氯苯乙酮、对甲氧基苯乙酮、对硝基苯乙酮或环己酮中的一种。以该底物进行反应，可以开展大范围的拓展，且收率优异，条件简单，有利于操作。The indole is one of indole or N-methylindole. The ketone is one of acetophenone, p-methylacetophenone, p-chloroacetophenone, p-methoxyacetophenone, p-nitroacetophenone or cyclohexanone. Using the substrate for the reaction can be expanded in a large range, and the yield is excellent, and the conditions are simple, which is beneficial to the operation.
所述的溶剂为干燥甲苯。采用该具体产品，使合成产率达到62%～92%。Described solvent is dry toluene. Using this specific product, the synthesis yield can reach 62%-92%.
为了保障较高的合成产率，所述的酸性催化剂为三氟甲基磺酸。In order to ensure a higher synthesis yield, the acidic catalyst is trifluoromethanesulfonic acid.
所述三氟甲基磺酸和3-亚烷基吲哚-2-酮的投料摩尔比为0.05∶1。该催化剂是此反应的必须的辅助试剂，过多的催化剂浪费资源，过少的催化剂不能完全催化反应，该投料比例可以达到良好的催化效果。The molar ratio of trifluoromethanesulfonic acid to 3-alkylene indol-2-one is 0.05:1. The catalyst is a necessary auxiliary reagent for this reaction. Too much catalyst wastes resources, and too little catalyst cannot completely catalyze the reaction. This feeding ratio can achieve a good catalytic effect.
所述3-亚烷基吲哚-2-酮为2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯、2-（1-正丁基-5-氟-2-氧代二氢吲哚-3-亚基）羧酸乙酯、2-（6-氯-2-氧代二氢吲哚-3-亚基）羧酸甲酯、1-正丁基5-氯-3-(2-氧代-2-(对甲氧基苯基)亚乙基)吲哚啉-2-酮、1-苄基5-氟-3-(2-氧代-2-(对甲基苯基)亚乙基)吲哚啉-2-酮、1-苄基5-氯-3-(2-氧代-2-(对氯苯基)亚乙基)吲哚啉-2-酮或1-苄基5-氯-3-(2-氧代-2-(对甲基苯基)亚乙基)吲哚啉-2-酮中的一种。3-亚烷基吲哚-2-酮由于具有缺电子的共轭双键，其共轭双键容易发生环加成反应，可以便利地构建螺吲哚类化合物，而螺吲哚化合物具有潜在的生物活性。本发明利用吲哚、酮和3-亚烷基吲哚-2-酮的三组分反应，一步构建了四氢螺[咔唑-1,3'-二氢吲哚]类化合物。该方法操作简便并且收率很高。The 3-alkylene indol-2-one is 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene) ethyl carboxylate, 2-(1- n-Butyl-5-fluoro-2-oxoindoline-3-ylidene)carboxylic acid ethyl ester, 2-(6-chloro-2-oxoindoline-3-ylidene)carboxylic acid Methyl ester, 1-n-butyl 5-chloro-3-(2-oxo-2-(p-methoxyphenyl) ethylidene)indolin-2-one, 1-benzyl 5-fluoro- 3-(2-oxo-2-(p-methylphenyl)ethylidene)indolin-2-one, 1-benzyl 5-chloro-3-(2-oxo-2-(p-chloro Phenyl)ethylidene)indoline-2-one or 1-benzyl 5-chloro-3-(2-oxo-2-(p-methylphenyl)ethylidene)indoline-2- One of a kind. 3-Alkylene indol-2-one has an electron-deficient conjugated double bond, and its conjugated double bond is prone to cycloaddition reaction, which can facilitate the construction of spiroindole compounds, and spiroindole compounds have potential biological activity. The invention utilizes the three-component reaction of indole, ketone and 3-alkylene indol-2-one to construct tetrahydrospiro[carbazole-1,3'-indoline] compounds in one step. The method is simple to operate and the yield is high.
另外，所述的环合反应的温度条件为0～100℃，反应4～24小时。更优选地，反应温度为80℃下反应16小时。因为低温时反应时间过长，反应不彻底；温度过高，产生副产物，影响产率。实验表明在该温度下，反应速率最快，产率最高。In addition, the temperature condition of the cyclization reaction is 0-100° C., and the reaction is 4-24 hours. More preferably, the reaction temperature is 16 hours at 80°C. Because the reaction time is too long at low temperature, the reaction is not complete; if the temperature is too high, by-products are produced, which affects the yield. Experiments have shown that at this temperature, the reaction rate is the fastest and the yield is the highest.
具体实施方式detailed description
实施例1：制备乙基1'-苄基-5'-氯-9-甲基-2'-氧代-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸甲酯为例，其反应式如下：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:
制备方法如下：The preparation method is as follows:
在氮气的保护下，在10 mL的 Schlenck管中加入N-甲基吲哚(0.5 mmol, 0.066g)，苯乙酮(1.5 mmol, 0.180g)，2 mL的干燥甲苯和三氟甲磺酸(5 mol%, 0.004g)在60℃搅拌1.5小时，然后加入2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯 (0.5 mmol,0.170g)升温80℃搅拌12小时。TLC检测反应进程，当反应结束后，向体系加入5mL水，用乙酸乙酯萃取(5mL×3)，合并有机层，有机层用无水Na2SO4干燥，减压抽滤，将滤液旋转蒸发，利用乙酸乙酯和轻石油醚作为展开剂，通过硅胶柱层色谱分离得到1'-苄基-5'-氯-9-甲基-2'-氧代-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸甲酯，其分离收率为92%, 0.264 g。Under nitrogen protection, add N -methylindole (0.5 mmol, 0.066g), acetophenone (1.5 mmol, 0.180g), 2 mL of dry toluene and trifluoromethanesulfonic acid in a 10 mL Schlenck tube (5 mol%, 0.004g) was stirred at 60°C for 1.5 hours, then added ethyl 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene)carboxylate (0.5 mmol , 0.170g) was heated to 80°C and stirred for 12 hours. TLC was used to detect the reaction process. When the reaction was over, 5 mL of water was added to the system, extracted with ethyl acetate (5 mL × 3), the organic layers were combined, and the organic layer was dried with anhydrous Na 2 SO 4 , filtered under reduced pressure, and the filtrate was spun Evaporated, using ethyl acetate and light petroleum ether as a developing solvent, separated by silica gel column chromatography to obtain 1'-benzyl-5'-chloro-9-methyl-2'-oxo-4-phenyl-2, Methyl 3,4,9-tetrahydrospiro[carbazole-1,3'-indoline]-2-carboxylate, the isolated yield was 92%, 0.264 g.
结构表征数据如下：The 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) 理论值 C36H32ClN2O3 ([M+H]+): 575.2101. 测量值 575.2107。mp 224-226℃; 1 H NMR (400 MHz, CDCl 3 ) 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, CH 3 ), 2.44 (dd, J 1 = 13.2 Hz, J 2 = 5.6 Hz, 1H, CH), 1.01 (t, J =7.2 Hz, 3H, CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) 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, 120.3, 119.1, 116.5, 110.1, 108.7, 52.8, 45.0, 41.5, 33.1, 29.9, 13.9; 3029, 2936, 2857, 1720, 1606,1487, 1468, 1337, 1244, 1168, 1091, 1019, 929, 813, 748, 700 cm -1 ; MS ( m / z ): HRMS (ESI) Theoretical C 36 H 32 ClN 2 O 3 ([M+H] + ): 575.2101. Found 575.2107.
实施例2：制备结构式如下的1'-丁基-4-（4-氯苯基）-5'-氟-9-甲基-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸乙酯：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:
制备方法：在实施例1中，所用的2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的2-（1-正丁基-5-氟-2-氧代二氢吲哚-3-亚基）羧酸乙酯替换，苯乙酮用等摩尔量的对氯苯乙酮替换，其他步骤方法与实例1相同，得到乙基1'-丁基-4-（4-氯苯基）-5'-氟-9-甲基-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸，其分离收率为79%,0.220 g。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.
结构表征数据如下：The 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) 理论值 C33H33ClFN2O3 ([M+H]+): 559.2164. 测量值559.2186。mp 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 (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, CH 3 ), 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, 2CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) 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 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, 2 1724, 1609, 1473, 1352, 1288, 1195, 1107, 1018, 875, 812, 748, 699 cm -1 ; MS ( m / z ): HRMS (ESI) theoretical C 33 H 33 ClFN 2 O 3 ([ M+H] + ): 559.2164. Measured 559.2186.
实施例3：制备结构式如下的1'-苄基-5'-氯-4-（4-甲氧基苯基）-9-甲基-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸乙酯：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:
制备方法：在实施例1中，所用的苯乙酮用等摩尔量的对甲氧基苯乙酮替换，其他步骤方法与实例1相同，得到1'-苄基-5'-氯-4-（4-甲氧基苯基）-9-甲基-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸乙酯，其分离收率为88%, 0.266 g。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.
结构表征数据如下：The 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) 理论值 C37H34ClN2O4 ([M+H]+): 605.2207. 测量值 605.2222。mp 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), 3.81 (s, 3H, OCH 3 ), 3.44 (d, J = 12.8 Hz, 1H, CH), 3.14-3.05 (m, 1H, CH) , 2.82 (s, 3H,CH 3 ), 2.43-2.38 (m, 1H, CH), 1.01 (t, J = 7.2 Hz, 3H, CH 3 ); 13 C NMR (100 MHz,CDCl 3 ) 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, 128.2, 128.0, 124.0, 122.0, 119.0,116.8, 110.7, 60.8, 55.2 , 52.9, 49.8, 44.9, 40.7, 33.2, 29.9,13.9 ; , 912, 874, 809, 740 cm -1 ; MS ( m / z ): HRMS (ESI) Calc. C 37 H 34 ClN 2 O 4 ([M+H] + ): 605.2207. Measured 605.2222.
实施例4：制备结构式如下的1'-苄基-5'-氯-9-甲基-4-（4-硝基苯基）-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸乙酯：Example 4: Preparation of 1'-benzyl-5'-chloro-9-methyl-4-(4-nitrophenyl)-2'-oxo-2,3,4,9-tetra Ethyl Hydrospiro[carbazole-1,3'-indoline]-2-carboxylate:
制备方法：在实施例1中，所用的苯乙酮用等摩尔量的对硝基苯乙酮替换，其他步骤方法与实例1相同，得到1'-苄基-5'-氯-9-甲基-4-（4-硝基苯基）-2'-氧代-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸乙酯，其分离收率为91%, 0.282 g。Preparation method: In Example 1, the acetophenone used is replaced with an equimolar amount of p-nitroacetophenone, and the other steps are the same as in Example 1 to obtain 1'-benzyl-5'-chloro-9-methyl Ethyl-4-(4-nitrophenyl)-2'-oxo-2,3,4,9-tetrahydrospiro[carbazole-1,3'-indoline]-2-carboxylate Esters, the isolated yield is 91%, 0.282 g.
结构表征数据如下：The 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) 理论值C36H31ClN3O5 ([M+H]+): 620.1952. 测量值 620.1949。mp 269-271℃; 1 H NMR (400 MHz, CDCl 3 ) 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, CH 3 ), 2.64-2.60 ( m, 1H, CH),2.33-2.24 (m, 1H, CH), 0.87 (t, J = 7.2 Hz, 3H, CH 3 ); 13 C NMR (100 MHz, CDCl 3 )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, 125.6, 124.5, 122.5, 120.0, 114.1,110.3, 61.0, 51.4, 45.3, 40.4, 40.3 , 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, 1845, 7 , 700 cm -1 ; MS ( m / z ): HRMS (ESI) Calc. C 36 H 31 ClN 3 O 5 ([M+H] + ): 620.1952. Found 620.1949.
实施例5：制备结构式如下的6'-氯-9-甲基-2'-氧代-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸甲酯：Example 5: Preparation of 6'-chloro-9-methyl-2'-oxo-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole-1,3'-di Methyl indoline]-2-carboxylate:
制备方法：在实施例1中，所用的2-（1-正丁基-5-氟-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的2-（6-氯-2-氧代二氢吲哚-3-亚基）乙酸甲酯替换，其他步骤方法与实例1相同，得到6'-氯-9-甲基-2'-氧代-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2-羧酸甲酯，其分离收率为89%, 0.209 g。Preparation method: In Example 1, ethyl 2-(1-n-butyl-5-fluoro-2-oxoindoline-3-ylidene) carboxylate was used in an equimolar amount of 2-( 6-Chloro-2-oxoindoline-3-ylidene) methyl acetate replacement, other steps are the same as in Example 1, to obtain 6'-chloro-9-methyl-2'-oxo-4- Methyl phenyl-2,3,4,9-tetrahydrospiro[carbazole-1,3'-indoline]-2-carboxylate, the isolated yield was 89%, 0.209 g.
结构表征数据如下：The 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) 理论值C28H24ClN2O3 ([M+H]+): 471.1475.测量值 471.1493。mp 278-280℃; 1 H NMR (400 MHz, CDCl 3 ) 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, CH 3 ), 3.12-3.03 (m, 4H, CH, CH 3 ), 2.46-2.41 (m,1H, CH); 13 C NMR (100 MHz, CDCl 3 ) 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) Calc. for C28H24ClN2O3 ([ M + H] + ): 471.1475 . Found 471.1493.
实施例6：制备结构式如下的1'-丁基-5'-氯-2-（4-甲氧基苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮：Example 6: Preparation of 1'-butyl-5'-chloro-2-(4-methoxybenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[carba Azole-1,3'-indoline]-2'-one:
制备方法：在实施例1中，所用的N-甲基吲哚用等摩尔量的吲哚替换，2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的1-正丁基5-氯-3-(2-氧代-2-(对甲氧基苯基)亚乙基)吲哚啉-2-酮替换其他步骤方法与实例1相同，得到1'-丁基-5'-氯-2-（4-甲氧基苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮，其分离收率为80%, 0.235 g。Preparation method: In Example 1, the N-methylindole used was replaced with an equimolar amount of indole, 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene Base) ethyl carboxylate is replaced by an equimolar amount of 1-n-butyl 5-chloro-3-(2-oxo-2-(p-methoxyphenyl) ethylidene) indoline-2-one The other steps are the same as Example 1 to obtain 1'-butyl-5'-chloro-2-(4-methoxybenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[ Carbazole-1,3'-indolin]-2'-one, the isolated yield is 80%, 0.235 g.
结构表征数据如下：The 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) 理论值 C37H34ClN2O3 ([M+H]+): 589.2258. 测量值 589.2268。mp 204-206℃; 1 H NMR (600 MHz, CDCl 3 ) 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, CH 3 ), 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, CH 3 ); 13 C NMR (150 MHz, CDCl 3 ) 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; 969, 915, 880, 834, 744 cm -1 ; MS ( m / z ): HRMS(ESI) Calc. C 37 H 34 ClN 2 O 3 ([M+H] + ): 589.2258. Measured 589.2268.
实施例7：制备结构式如下的1'-苄基-5'-氟-2-（4-甲基苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮：Example 7: Preparation of 1'-benzyl-5'-fluoro-2-(4-methylbenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole -1,3'-indoline]-2'-one:
制备方法：在实施例1中，所用的N-甲基吲哚用等摩尔的吲哚替换，2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的1-苄基5-氟-3-(2-氧代-2-(对甲基苯基)亚乙基)吲哚啉-2-酮替换，其他步骤方法与实例1相同，得到1'-苄基-5'-氟-2-（4-甲基苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮，其分离收率为73%, 0.215g。Preparation method: In Example 1, the N-methylindole used was replaced with equimolar indole, 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene ) Ethyl carboxylate is replaced with an equimolar amount of 1-benzyl 5-fluoro-3-(2-oxo-2-(p-methylphenyl) ethylidene) indoline-2-one, other steps The method is the same as in Example 1 to obtain 1'-benzyl-5'-fluoro-2-(4-methylbenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole- 1,3'-indoline]-2'-one, the isolated yield is 73%, 0.215g.
结构表征数据如下：The 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) 理论值 C40H32FN2O2 ([M+H]+): 591.2248. 测量值 591.2456。mp 260-262℃; 1 H NMR (600 MHz, CDCl 3 ) 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,CH 3 ); 13 C NMR (150 MHz, CDCl 3 ) 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, 128.5, 128.4, 12 , 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, 11.6, 3KBr, 6 ; : 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) Calc. for C 40 H 32 FN 2 O 2 ([M+H] + ): 591.2248. Found 591.2456.
实施例8：制备结构式如下的1'-苄基-5'-氯-2-（4-氯苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮：Example 8: Preparation of 1'-benzyl-5'-chloro-2-(4-chlorobenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole- 1,3'-Indoline]-2'-one:
制备方法：在实施例1中，所用的N-甲基吲哚用等摩尔量的吲哚替换，2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的1-苄基5-氯-3-(2-氧代-2-(对氯苯基)亚乙基)吲哚啉-2-酮替换，其他步骤方法与实例1相同，得到1'-苄基-5'-氯-2-（4-氯苯甲酰基）-4-苯基-2,3,4,9-四氢螺[咔唑-1,3'-二氢吲哚] -2'-酮，其分离收率为78%, 0.244g。Preparation method: In Example 1, the N-methylindole used was replaced with an equimolar amount of indole, 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene base) Carboxylic acid ethyl ester is replaced with 1-benzyl 5-chloro-3-(2-oxo-2-(p-chlorophenyl) ethylidene) indoline-2-one in equimolar amount, other steps The method is the same as in Example 1 to obtain 1'-benzyl-5'-chloro-2-(4-chlorobenzoyl)-4-phenyl-2,3,4,9-tetrahydrospiro[carbazole-1 ,3'-indoline] -2'-one, the isolated yield was 78%, 0.244g.
结构表征数据如下：The 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) 理论值 C39H29Cl2N2O2 ([M+H]+): 627.1606.测量值 627.1593。mp 297-299℃; 1 H NMR (400 MHz, CDCl 3 ) 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); (100 MHz, CDCL 3 ) Δ: 197.2, 176.3, 144.2, 142.8, 140.0, 136.4, 135.8, 133.5, 131.8,131.8, 129.7, 129.1, 128.5, 128.0, 127.6, 126.8,126.6.6 , 123.3, 122.4, 120.1, 119.7, 115.5, 110.8, 110.6, 53.7, 49.1, 44.5,41.4, 33.7; , 1358, 1332, 1272, 1242, 1192, 1168, 1126, 1075, 1026, 975, 912, 875,815, 744, 701 cm -1 ; MS ( m / z ): HRMS (ESI) Theoretical C 39 H 29 Cl 2 N 2 O 2 ([M+H] + ): 627.1606. Measured 627.1593.
实施例9：制备结构式如下的1'-苄基-5'-氯-5-（4-甲基苯甲酰基）-1,2,3,4,4a，5,7,11c八氢螺[苯并[c]咔唑-6,3'-二氢吲哚] - 2'-酮：Example 9: Preparation of 1'-benzyl-5'-chloro-5-(4-methylbenzoyl)-1,2,3,4,4a,5,7,11c octahydrospiro[ Benzo[ c ]carbazole-6,3'-indoline]-2'-one:
制备方法：在实施例1中，所用的N-甲基吲哚用等摩尔量的吲哚替换，2-（1-苄基-5-氯-2-氧代二氢吲哚-3-亚基）羧酸乙酯用等摩尔量的1-苄基5-氯-3-(2-氧代-2-(对甲基苯基)亚乙基)吲哚啉-2-酮替换，苯乙酮用等摩尔量的环己酮替换，其他步骤方法与实例1相同，得到1'-苄基-5'-氯-5-（4-甲基苯甲酰基）-1,2,3,4,4a，5,7,11c八氢螺[苯并[c]咔唑-6,3'-二氢吲哚] - 2'-酮，其分离收率为62%, 0.181 g。Preparation method: In Example 1, the N-methylindole used was replaced with an equimolar amount of indole, 2-(1-benzyl-5-chloro-2-oxoindoline-3-ylidene Base) ethyl carboxylate is replaced with an equimolar amount of 1-benzyl 5-chloro-3-(2-oxo-2-(p-methylphenyl) ethylidene) indoline-2-one, benzene Ethanone is replaced with cyclohexanone in an equimolar amount, and the other steps are the same as in Example 1 to obtain 1'-benzyl-5'-chloro-5-(4-methylbenzoyl)-1,2,3, 4,4a, 5,7,11c octahydrospiro[benzo[ c ]carbazole-6,3'-indoline]-2'-one, the isolated yield was 62%, 0.181 g.
结构表征数据如下：The 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) 理论值 C38H33ClN2NaO2 ([M+Na]+): 607.2128. 测量值 607.2114。mp 259-261℃; 1 H NMR (600 MHz, CDCl 3 ) 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,CH 3 ), 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); 13 C NMR (150 MHz, CDCl 3 ) 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, 127. , 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 (KBr3,5) υ, 2: 2 , 1719, 1604, 1480, 1440, 1391, 1328, 1255, 1163, 1112, 1075,1026, 954, 820, 742, 700 cm -1 ; MS ( m / z ): HRMS (ESI) theoretical C 38 H 33 ClN 2 NaO 2 ([M+Na] + ): 607.2128. Measured 607.2114.
Claims (10)
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
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