CN117486782A - N-substituted carbazole derivative and preparation method and application thereof - Google Patents
N-substituted carbazole derivative and preparation method and application thereof Download PDFInfo
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- -1 N-substituted carbazole Chemical class 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 31
- 230000035484 reaction time Effects 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 abstract description 57
- 239000003814 drug Substances 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000001093 anti-cancer Effects 0.000 abstract description 6
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- 239000000047 product Substances 0.000 description 22
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- 150000001716 carbazoles Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
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- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- APYQRKDHRDGCBK-UHFFFAOYSA-N 1,4-dimethyl-9h-carbazole Chemical group N1C2=CC=CC=C2C2=C1C(C)=CC=C2C APYQRKDHRDGCBK-UHFFFAOYSA-N 0.000 description 2
- HDETUOZJFUNSKG-UHFFFAOYSA-N 1-methoxy-3-methyl-9h-carbazole Chemical compound C12=CC=CC=C2NC2=C1C=C(C)C=C2OC HDETUOZJFUNSKG-UHFFFAOYSA-N 0.000 description 2
- QPTWWBLGJZWRAV-UHFFFAOYSA-N 2,7-dibromo-9h-carbazole Chemical compound BrC1=CC=C2C3=CC=C(Br)C=C3NC2=C1 QPTWWBLGJZWRAV-UHFFFAOYSA-N 0.000 description 2
- PJRGCJBBXGNEGD-UHFFFAOYSA-N 2-bromo-9h-carbazole Chemical compound C1=CC=C2C3=CC=C(Br)C=C3NC2=C1 PJRGCJBBXGNEGD-UHFFFAOYSA-N 0.000 description 2
- SVWKIGRDISDRLO-UHFFFAOYSA-N 4-(oxiran-2-ylmethoxy)-9h-carbazole Chemical compound C=1C=CC=2NC3=CC=CC=C3C=2C=1OCC1CO1 SVWKIGRDISDRLO-UHFFFAOYSA-N 0.000 description 2
- STJXCDGCXVZHDU-UHFFFAOYSA-N 7H-Dibenzo[c,g]carbazole Chemical compound N1C2=CC=C3C=CC=CC3=C2C2=C1C=CC1=CC=CC=C12 STJXCDGCXVZHDU-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241001120493 Arene Species 0.000 description 2
- 238000006658 Graebe-Ullmann reaction Methods 0.000 description 2
- BRHDRZIVFAZVOI-UHFFFAOYSA-N N-(4,4-dimethoxy-3,5-dimethylcyclohexa-2,5-dien-1-ylidene)-4-methylbenzenesulfonamide Chemical compound COC1(OC)C(C)=CC(C=C1C)=NS(=O)(=O)c1ccc(C)cc1 BRHDRZIVFAZVOI-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 125000005842 heteroatom Chemical group 0.000 description 2
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- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
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- YHYKLKNNBYLTQY-UHFFFAOYSA-N 1,1-diphenylhydrazine Chemical compound C=1C=CC=CC=1N(N)C1=CC=CC=C1 YHYKLKNNBYLTQY-UHFFFAOYSA-N 0.000 description 1
- HIAGSPVAYSSKHL-UHFFFAOYSA-N 1-methyl-9h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1C(C)=CC=C2 HIAGSPVAYSSKHL-UHFFFAOYSA-N 0.000 description 1
- ZBJLUVHQIPUCPM-UHFFFAOYSA-N 1-phenylbenzotriazole Chemical compound C1=CC=CC=C1N1C2=CC=CC=C2N=N1 ZBJLUVHQIPUCPM-UHFFFAOYSA-N 0.000 description 1
- QCDCAUMDNNCNAU-UHFFFAOYSA-N 2-(6-hydroxy-1-nitrocyclohexa-2,4-dien-1-yl)phenol Chemical class [N+](=O)([O-])C1(C(C=CC=C1)O)C=1C(=CC=CC=1)O QCDCAUMDNNCNAU-UHFFFAOYSA-N 0.000 description 1
- LOQQFCPPDBFFSO-UHFFFAOYSA-N 2-chloro-9h-carbazole Chemical compound C1=CC=C2C3=CC=C(Cl)C=C3NC2=C1 LOQQFCPPDBFFSO-UHFFFAOYSA-N 0.000 description 1
- IMLDYQBWZHPGJA-UHFFFAOYSA-N 2-phenyl-9h-carbazole Chemical compound C1=CC=CC=C1C1=CC=C2C3=CC=CC=C3NC2=C1 IMLDYQBWZHPGJA-UHFFFAOYSA-N 0.000 description 1
- LTBWKAYPXIIVPC-UHFFFAOYSA-N 3-bromo-9h-carbazole Chemical compound C1=CC=C2C3=CC(Br)=CC=C3NC2=C1 LTBWKAYPXIIVPC-UHFFFAOYSA-N 0.000 description 1
- OYIGWMXXIFYAGD-UHFFFAOYSA-N 3-iodo-9h-carbazole Chemical compound C1=CC=C2C3=CC(I)=CC=C3NC2=C1 OYIGWMXXIFYAGD-UHFFFAOYSA-N 0.000 description 1
- IAWRFMPNMXEJCK-UHFFFAOYSA-N 3-phenyl-9h-carbazole Chemical compound C1=CC=CC=C1C1=CC=C(NC=2C3=CC=CC=2)C3=C1 IAWRFMPNMXEJCK-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008436 biogenesis Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
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- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
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- FQKSBRCHLNOAGY-UHFFFAOYSA-N indolo[2,3-a]carbazole Chemical compound C1=CC=C2N=C3C4=NC5=CC=CC=C5C4=CC=C3C2=C1 FQKSBRCHLNOAGY-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000006476 reductive cyclization reaction Methods 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
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- 229910021654 trace metal Inorganic materials 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides an N-substituted carbazole derivative, a preparation method and application thereof, wherein the structure of the N-substituted carbazole derivative is shown as a formula I or a formula II, and the N-substituted carbazole derivative is structurally modified based on carbazole, is a lead compound with potential anticancer activity, and has important significance for improving and improving the efficacy of the existing medicament and creating new anticancer medicaments. The synthesis of the N-substituted carbazole derivative of the invention increases the expansion possibility of the range of reaction substrates and biological activity, and the preparation method is simple, mild in condition, low in cost and environment-friendly.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a novel N-substituted carbazole derivative, and a preparation method and application thereof.
Background
Cancer is the second leading cause of death worldwide, next to cardiovascular disease, chemotherapy is still the most important treatment for most human cancers, however many chemotherapeutic drugs have limitations such as systemic toxicity, low selectivity and resistance (Dai Y, cai X, bi X, et al Synthesis and anti-cancer evaluation of folic acid-peptide-paclitaxel conjugates for addressing drug resistance, J.Med. Chem. 171 (2019) 104-115). There is therefore an urgent need to find new, effective, safe anticancer drugs.
The research on active natural products is one of the important ways of developing medicine sources and developing new medicines at present. Carbazole and its derivatives are of great interest as a common alkaloid because of their planar tricyclic backbones and numerous biological activities. The large conjugated system, the strong intramolecular electron transfer capability and the higher thermal stability and photochemical stability lead the conjugated system to be widely applied in the fields of photoelectric materials, dyes and the like. In addition, the advantages of good drug-like properties, ease of structural modification, etc. have led to the development of carbazole and its derivatives as drugs or drug intermediates (Schmidt a W, reddy K R, knoelker H J. Occurrenc, biogenesis, and synthesis of biologically active carbazole alkaloids. [ J ]. Chemiform, 2012, 43 (33): 3193-3328), for example the following compounds:
。
carbazole derivatives can be selectively combined with HTGG-quadruplex (target of anticancer drugs) DNA, and can effectively prevent the diffusion of cancer cells. Aiming at the work of structural modification and biological activity research of natural carbazole and synthetic carbazole and derivatives thereof, the method provides great help for the design and development of carbazole drugs with potential anticancer activity.
The synthesis of N-substituted carbazole derivatives reported in the current literature is mainly realized by methods such as Graebe-Ullmann (Graebe-Ullmann) reaction, cadougan-Sundberg (Kaduo-Mordberg) reaction, transition metal catalytic reaction and the like.
As early as 1986, graebe and Ullmann et al utilized aminodiphenylamine to undergo diazotization reaction to obtain 1-phenylbenzotriazole 1-2 and synthesize carbazole compound 1-3, and the reaction scheme is as follows:
。
cadougan et al developed a method for obtaining carbazole compounds by reducing nitro groups to rings in the presence of organophosphorus reagents (Freeman A W, urvoy M, criswell M E. Triphenyl phosphines-Mediated Reductive Cyclization of 2-Nitrobiphenols: A Practical and Convenient Synthesis of Carbazoles (IV) [ J ]. The Journal of Organic Chemistry, 2005, 70 (13): 5014-5019), the reaction formula is as follows:
。
in 2008 Ackermann et al (Ackermann L, althamer A. Domino N-H/C-H Bond Activation: palladium-Catalyzed Synthesis of Annulated Heterocycles Using Dichloro (hetero) arenes [ J ]. ChemInform, 2007, 38 (25)) synthesized carbazole derivatives 3-3 in one pot by Palladium-catalyzed (Pd catalyst) activation of Domino N-H/C-H bonds in the presence of ligands (ligand) and bases from aniline 3-1 or substituted anilines and ortho-dihalo (hetero) arenes 3-2 as starting materials, the reaction scheme is as follows:
。
although some progress has been made in the current methods for preparing N-substituted carbazole derivatives, these classical methods involve mostly cumbersome multi-step processes, generally resulting in lower overall yields of N-substituted carbazole derivatives. They generally have the following disadvantages: 1) The reaction generally requires a longer reaction time; 2) High temperature; 3) Protons are used with high water solubility and high boiling point organic solvents; 4) Using a carcinogenic solvent; 5) The high cost and toxicity of the transition metal and ligand, as well as the trace metal contamination in the final product, require significant time and financial expenditures to handle.
Therefore, further development of new N-substituted carbazole derivatives and methods for their preparation are of great importance in the art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an N-substituted carbazole derivative, and a preparation method and application thereof.
To achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides an N-substituted carbazole derivative, wherein the structure of the N-substituted carbazole derivative is shown as a formula I or a formula II:
r in formula I 1 And R is 3 Independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclic group, R 1 And R is 3 Is linked to the aromatic ring in the form of a single bond or condensed to a cyclic structure with the aromatic ring in the form of a single bond, the dotted line representing the presence or absence of this moiety; r is R 2 Represents any one of H, halogen or methyl, methoxy, tert-butyl or trifluoromethyl;
r in formula II 1 And R is 3 Independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclic group, R 1 And R is 3 Is connected with the aromatic ring in the position of single bond or condensed with the aromatic ring in the position of single bond to form a cyclic structure;
ts represents p-toluenesulfonyl, me represents methyl.
In the present invention, the C1-C4 alkyl group may be a C1, C2, C3 or C4 alkyl group, and for example, may be methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.
Preferably, the oxygen-containing heterocyclic group is selected from oxiranemethoxy, 4, 5-tetramethyl-1, 3, 2-dioxaboryl, and the like.
Preferably, the N-substituted carbazole derivative is any one of the following compounds:
；
wherein Ts represents p-toluenesulfonyl, me represents methyl, and Ph represents phenyl.
In another aspect, the present invention provides a method for preparing an N-substituted carbazole derivative as described above, the method comprising the steps of:
reacting a compound shown in a formula III or a formula IV with a compound shown in a formula V under the action of Lewis acid to obtain the N-substituted carbazole derivative;
。
preferably, when the compound of formula I is prepared, the molar ratio of the compound of formula III or the compound of formula IV to the compound of formula V is 1.2 to 1.5:1, for example 1.2:1, 1.3:1, 1.4:1 or 1.5:1.
Preferably, when preparing the compound of formula II, the compound of formula III and the compound of formula V are reacted under the action of Lewis acid, wherein the molar ratio of the compound of formula III to the compound of formula V is 2.1-3:1, such as 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1 or 3:1.
Preferably, the lewis acid may be added in an amount of 0.1 to 0.5 times equivalent to the compound represented by formula III or formula IV, for example, 0.1 times equivalent, 0.2 times equivalent, 0.3 times equivalent, 0.4 times equivalent, or 0.5 times equivalent.
Preferably, the lewis acid is selected from any one or a mixture of at least two of p-toluene sulfonic acid, trifluoroacetic acid, acetic acid, benzoic acid, CPA (binaphthol phosphate) or diphenyl phosphate.
Preferably, the lewis acid is preferably diphenyl phosphate when preparing the compound of formula I and p-toluenesulfonic acid when preparing the compound of formula II.
Preferably, the reaction is carried out in an organic solvent selected from any one or a mixture of at least two of dichloromethane, carbon tetrachloride, toluene, acetonitrile, 1, 4-dioxane, ethyl acetate, DCE (1.2-dichloroethane), TBME (methyl tert-butyl ether) or trifluoroethanol.
Preferably, the organic solvent is selected from acetonitrile when preparing the compound of formula I, and trifluoroethanol when preparing the compound of formula II.
Preferably, the temperature of the reaction is from room temperature to 100 ℃, e.g. 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃, and the reaction time is from 0.1 to 12 hours, e.g. 0.1 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.
The method also comprises the operation of purifying the crude product by silica gel chromatography to obtain the target compound shown in the formula I, II after the reaction is finished.
In another aspect, the present invention provides the use of an N-substituted carbazole derivative as described above in the preparation of an anticancer drug.
Compared with the prior art, the invention has the following beneficial effects:
(1) The N-substituted carbazole derivative is structurally modified based on carbazole, is a lead compound with potential anticancer activity, and has important significance for improving and improving the efficacy of the existing medicines and creating new anticancer medicines. The synthesis of the N-substituted carbazole derivative of the invention simultaneously increases the range of reaction substrates and the expansion possibility of biological activity.
(2) The preparation method of the N-substituted carbazole derivative has mild condition, simple process, low cost and environmental friendliness; the method is carried out under the action of stoichiometric Lewis acid, is convenient, low in cost and easy to process, and avoids the use of transition metal and expensive ligand; the reaction condition is mild, and the high-efficiency reaction can be realized at normal temperature; no dangerous carcinogenic reagent is used and has good substrate applicability.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Carbazole or indolo [2,3-a ] carbazole and N- (4, 4-dimethoxy-3, 5-dimethylcyclohex-2, 5-diene-1-subunit) -4-methylbenzenesulfonamide are used as reaction raw materials, diphenyl phosphate is used as a catalyst, meCN is used as a solvent, and different substituted N-substituted carbazole derivatives are obtained through reaction at 60 ℃, wherein the reaction formula is as follows:
representative examples 1-16 are selected below to illustrate strategies for the functional synthesis of carbazole alkaloids and obtaining novel N-substituted carbazole derivatives.
Example 1
Name: n- (2- (9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
Carbazole (75.2 mg,0.45mmo 1), N- (4, 4-dimethoxy-3, 5-dimethylcyclohex-2, 5-dien-1-ylidene) -4-methylbenzenesulfonamide (100.6 mg,0.3 mmol), diphenyl phosphate (0.06 mmol), and MeCN (1.5 mL) were added to a 5mL clean reaction flask, and the reaction flask was left to stand at 60℃with stirring. The reaction system was allowed to stand for 2 hours, then the reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was separated by column chromatography (petroleum ether/ethyl acetate) to give the objective product N- (2- (9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as a white solid in 83% yield.
1 HNMR(600MHz,DMSO-d6):δ=11.40(s,1H),8.10(d,J=8.1Hz,2H),7.60(s,1H),7.58(s,1H),7.49(d,J=8.1Hz,1H),7.43(d,J=1.8Hz,2H),7.39(dd,J=9.7,1.2Hz,2H),7.22–7.14(m,2H),7.06(s,2H),3.61(s,3H),2.41(s,3H),2.17(s,6H)ppm。
13 CNMR(151MHz,DMSO-d 6 ):δ=155.6,143.6,140.5,138.8,137.5,137.4,132.3,131.4,129.9,128.4,127.7,126.7,126.2,122.8,122.2,121.5,120.7,119.0,111.4,111.3,79.3,59.4,21.2,16.0ppm。
Example 2
Name: n- (4-methoxy-3, 5-dimethyl-2- (1-methyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 1-methylcarbazole, the reaction time was prolonged to 3H, and the rest of the procedure was the same as in example 1, to give the target product N- (4-methoxy-3, 5-dimethyl-2- (1-methyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 93%.
1 HNMR(600MHz,CDCl 3 ):δ=8.08(d,J=10.4Hz,1H),7.91(dd,J=10.7,4.9Hz,1H),7.72(d,J=1.8Hz,1H),7.64(t,J=8.0Hz,2H),7.43(dd,J=8.9,4.4Hz,1H),7.39(dd,J=8.1,1.1Hz,1H),7.31–7.27(m,2H),7.25–7.19(m,1H),7.16–7.13(m,1H),7.01(s,2H),3.67(s,3H),2.54(s,1H),2.46(d,J=4.1Hz,5H),2.21(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.8,143.2,139.8,139.4,138.3,138.0,137.8,137.7,137.5,133.3,133.3,131.6,131.6,129.3,129.3,128.3,127.9,127.9,127.5,126.8,126.0,124.1,123.4,122.9,122.4,121.2,120.5,119.9,119.7,119.6,118.5,118.0,111.0,110.9,59.6,31.5,22.6,21.6,21.0,16.9,16.1,14.1,14.1ppm。
Example 3
Name: n- (4-methoxy-3, 5-dimethyl-2- (4- (oxiran-2-ylmethoxy) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 4- (oxiran-2-ylmethoxy) -9H-carbazole and the reaction time was extended to 8H, the rest of the procedure was the same as in example 1 to give the target product N- (4-methoxy-3, 5-dimethyl-2- (4- (oxiran-2-ylmethoxy) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in 71% yield as a white solid.
1 HNMR(600MHz,CDCl 3 ):δ=8.29(d,J=7.9Hz,1H),8.21(s,1H),7.66(s,1H),7.64(s,1H),7.39(dd,J=7.8,7.0Hz,1H),7.37(d,J=7.5Hz,1H),7.30(s,1H),7.29(s,1H),7.25–7.23(m,1H),7.16(d,J=8.5Hz,1H),7.10(d,J=8.5Hz,1H),7.07(s,2H),3.65(s,3H),3.59(s,1H),2.98–2.96(m,1H),2.83(s,1H),2.46(s,3H),2.37(t,J=5.7Hz,1H),2.19(s,6H),1.59(s,1H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.6,151.9,143.4,140.6,139.4,137.8,136.9,131.2,129.4,129.3,128.1,128.0,126.9,126.0,125.8,123.3,121.6,120.2,117.8,110.3,106.6,59.6,50.9,44.4,21.6,16.2ppm。
Example 4
Name: n- (2- (1, 4-dimethyl-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The procedure used in example 1 was repeated except for substituting 1, 4-dimethyl-9H-carbazole in an equimolar amount to give N- (2- (1, 4-dimethyl-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide, the target product of which had the above-mentioned structure, as a white solid in 95% yield.
1 HNMR(600MHz,CDCl 3 ):δ=8.46(s,1H),8.05(d,J=8.0Hz,1H),7.76(s,1H),7.74(s,1H),7.45(d,J=7.9Hz,1H),7.42–7.38(m,1H),7.34(s,1H),7.32(s,1H),7.24–7.20(m,1H),7.12(s,2H),7.07(s,1H),3.71(d,J=4.7Hz,3H),2.84(s,3H),2.50(s,3H),2.44(s,3H),2.26(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.1,143.3,139.8,138.2,137.6,137.4,131.4,131.3,130.7,129.2,127.9,127.2,126.9,125.0,124.1,122.4,121.9,119.3,117.4,110.7,59.5,21.5,16.4,16.1,15.7ppm。
Example 5
Name: n- (2- (3-iodo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 3-iodo-9H-carbazole, the reaction time was prolonged to 16H, and the rest of the procedure was the same as in example 1 to give the target product N- (2- (3-iodo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 90%.
1 HNMR(600MHz,DMSO-d 6 )δ=11.65(s,1H),8.63(s,1H),8.27(d,J=1.5Hz,1H),7.74(dd,J=8.5,1.6Hz,1H),7.69(s,1H),7.67(s,1H),7.52(dd,J=11.8,8.5Hz,3H),7.45(d,J=8.5Hz,1H),7.38(dd,J=8.6,1.9Hz,1H),7.16(s,2H),3.69(s,3H),3.46(d,J=2.2Hz,2H),2.60–2.59(m,1H),2.26(s,6H)ppm。
13 CNMR(151MHz,DMSO-d 6 )δ=155.6,143.6,140.5,138.8,137.5,137.4,132.3,131.4,129.9,128.4,127.7,126.7,126.2,122.8,122.2,121.5,120.7,119.0,111.4,111.3,79.3,59.4,21.2,16.0ppm。
Example 6
Name: n- (2- (2-chloro-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 2-chloro-9H-carbazole, the reaction time was prolonged to 3H, and the rest of the procedure was the same as in example 1 to give the target product N- (2- (2-chloro-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 70%.
1 HNMR(600MHz,DMSO-d 6 )δ=11.54(s,1H),8.12(dd,J=9.7,5.2Hz,2H),7.58(s,1H),7.56(s,1H),7.53(d,J=1.8Hz,1H),7.43(t,J=8.2Hz,3H),7.23(d,J=2.1Hz,1H),7.21–7.17(m,1H),7.04(s,2H),3.61(s,3H),2.42(s,3H),2.16(s,6H)ppm。
13 CNMR(151MHz,DMSO-d 6 )δ=155.7,143.6,141.1,139.2,137.4,137.3,132.9,131.4,130.6,129.9,128.4,127.7,127.1,122.3,122.2,121.9,121.7,121.2,119.2,111.8,111.0,79.3,59.4,55.1,21.2,16.0ppm。
Example 7
Name: n- (2- (2-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 2-bromo-9H-carbazole, the reaction time was prolonged to 8H, and the rest of the procedure was the same as in example 1, to give the target product N- (2- (2-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in a white solid with a yield of 67%.
1 HNMR(600MHz,CDCl 3 ):δ=8.18(s,1H),7.90(s,1H),7.78(d,J=8.3Hz,1H),7.64(s,1H),7.62(s,1H),7.55(d,J=1.5Hz,1H),7.30–7.29(m,2H),7.28(d,J=1.3Hz,3H),6.99(s,2H),3.67(s,3H),2.46(s,3H),2.21(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=156.0,143.4,140.7,138.4,137.6,137.3,133.8,131.7,129.4,129.4,128.3,127.9,127.2,127.2,124.2,123.1,122.9,121.9,121.6,121.1,119.7,113.7,111.1,59.6,21.6,16.2,15.8ppm。
Example 8
Name: n- (4-methoxy-3, 5-dimethyl-2- (2-phenyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 2-phenyl-9H-carbazole and the reaction time was extended to 18H, the rest of the procedure was the same as in example 1, giving the target product N- (4-methoxy-3, 5-dimethyl-2- (2-phenyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 53%.
1 HNMR(600MHz,CDCl 3 ):δ=8.37(s,1H),7.92(d,J=8.4Hz,2H),7.71(s,1H),7.69(s,1H),7.47(dd,J=8.1,1.1Hz,1H),7.45(d,J=1.1Hz,1H),7.44(s,1H),7.42–7.40(m,5H),7.39(s,1H),7.37(s,1H),7.31–7.29(m,1H),6.40(s,2H),3.66(s,3H),2.58(s,3H),2.07(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.6,143.6,140.7,140.4,140.1,138.8,138.3,136.5,131.9,130.7,130.2,129.5,129.0,128.4,127.8,127.2,126.4,123.0,122.7,120.3,120.0,119.8,113.1,111.1,59.8,21.8,16.1ppm。
Example 9
Name: n- (2- (3-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 3-bromo-9H-carbazole, the reaction time was prolonged to 18H, and the rest of the procedure was the same as in example 1, to give the target product N- (2- (3-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 92%.
1 HNMR(600MHz,DMSO-d 6 ):δ=11.57(s,1H),8.39(s,1H),8.19(d,J=1.2Hz,1H),7.60(s,1H),7.58(s,1H),7.51(dd,J=8.6,1.5Hz,1H),7.47(d,J=2.7Hz,1H),7.45(d,J=2.7Hz,1H),7.42(s,1H),7.40(s,1H),7.29(dd,J=8.6,1.8Hz,1H),7.06(s,2H),3.60(s,3H),2.41(s,3H),2.16(s,6H)ppm。
13 CNMR(151MHz,DMSO-d 6 ):δ=155.7,143.6,139.3,139.2,137.4,137.3,132.8,131.4,129.9,128.6,128.5,127.7,127.7,124.3,123.4,122.2,121.9,113.3,111.8,111.1,59.4,21.2,16.0ppm。
Example 10
Name: n- (4-methoxy-3, 5-dimethyl-2- (3-phenyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 3-phenyl-9H-carbazole and the reaction time was extended to 18H, the rest of the procedure was the same as in example 1, giving the target product N- (4-methoxy-3, 5-dimethyl-2- (3-phenyl-9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 87%.
1 HNMR(600MHz,CDCl 3 ):δ=8.17(d,J=0.9Hz,2H),7.97(s,1H),7.69(d,J=1.3Hz,1H),7.67(dd,J=3.4,1.4Hz,2H),7.66–7.65(m,1H),7.63(s,1H),7.47(t,J=7.6Hz,3H),7.36(d,J=7.4Hz,1H),7.32(t,J=2.2Hz,2H),7.29(s,1H),7.27(s,1H),7.02(s,2H),3.67(s,3H),2.45(s,3H),2.22(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.9,143.3,141.8,139.4,138.9,137.7,137.5,133.4,133.2,131.7,129.3,128.7,128.3,127.9,127.2,127.2,126.6,125.9,123.8,123.5,121.2,118.9,111.1,110.9,59.6,21.6,16.2ppm。
Example 11
Name: n- (2, 7-dibromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 2, 7-dibromo-9H-carbazole, and the reaction time was prolonged to 24 hours, and the other steps were the same as in example 1, to give the objective product N- (2, 7-dibromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 53%.
1 HNMR(600MHz,CDCl 3 ):δ=8.28(s,1H),7.91(s,1H),7.73(s,1H),7.71(s,1H),7.65(d,J=8.3Hz,1H),7.56(dd,J=5.3,3.2Hz,2H),7.32(s,1H),7.31(s,1H),7.29(dd,J=8.3,1.5Hz,1H),7.13(d,J=5.9Hz,2H),3.66(s,3H),2.49(s,3H),2.20(d,J=8.0Hz,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.9,143.8,140.8,139.3,136.9,135.8,131.6,131.4,129.4,129.3,128.4,128.3,128.3,123.4,123.1,122.7,122.4,121.4,121.3,120.1,115.7,114.0,59.6,21.6,16.2ppm。
Example 12
Name: n- (4-methoxy-3, 5-dimethyl-2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazole and the reaction time was prolonged to 18H, the rest of the procedure was the same as in example 1, giving the target product N- (4-methoxy-3, 5-dimethyl-2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in a white solid with a yield of 90%.
1 HNMR(600MHz,CDCl 3 ):δ=8.42(s,2H),7.85(d,J=8.3Hz,1H),7.83(d,J=2.0Hz,1H),7.63(s,1H),7.61(s,1H),7.41–7.36(m,2H),7.28(d,J=3.7Hz,2H),7.25(s,1H),7.00(s,2H),3.66(s,3H),2.46(s,3H),2.22(s,6H),1.40(s,12H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=156.0,143.3,142.2,138.4,137.6,137.5,133.6,132.6,131.7,129.4,128.5,127.8,127.7,127.4,123.6,122.6,121.0,111.0,110.2,83.6,59.5,24.8,21.5,16.1ppm。
Example 13
Name: n- (2- (7H-dibenzo [ c, g ] carbazol-7-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 7H-dibenzo [ c, g ] carbazole and the reaction time was prolonged to 8H, the rest of the procedure was the same as in example 1, to give the target product N- (2- (7H-dibenzo [ c, g ] carbazol-7-yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 51%.
1 HNMR(600MHz,CDCl 3 ):δ=9.00(s,1H),8.79(d,J=8.1Hz,1H),8.71(d,J=8.7Hz,1H),8.45(dd,J=8.1,1.0Hz,1H),7.95(dd,J=5.9,3.3Hz,1H),7.82(s,1H),7.80(s,1H),7.76(s,1H),7.66(d,J=8.7Hz,1H),7.58–7.55(m,1H),7.54–7.51(m,1H),7.46–7.42(m,2H),7.34(s,1H),7.33(s,1H),7.27(s,1H),7.18(s,2H),3.60(s,3H),2.46(s,3H),2.15(s,6H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=155.7,143.8,137.1,136.9,136.5,134.6,134.5,131.5,129.7,129.5,128.9,128.2,127.8,127.4,127.2,125.5,125.3,125.2,124.8,124.7,123.8,123.2,118.0,116.8,114.9,112.2,59.5,21.6,16.2ppm。
Example 14
Name: n- (4-methoxy-2- (1-methoxy-3-methyl-9H-carbazol-9-yl) -3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The carbazole used in example 1 was replaced with an equimolar amount of 1-methoxy-3-methyl-9H-carbazole, the reaction time was prolonged to 8H, and the rest of the procedure was the same as in example 1 to give the target product N- (4-methoxy-2- (1-methoxy-3-methyl-9H-carbazol-9-yl) -3, 5-dimethylphenyl) -4-methylbenzenesulfonamide as above in the form of a white solid with a yield of 75%.
1 HNMR(600MHz,CDCl 3 ):δ=8.05(s,1H),7.81(s,1H),7.79(s,1H),7.77(d,J=1.7Hz,1H),7.66(s,1H),7.62(d,J=8.2Hz,1H),7.31(s,1H),7.28(d,J=4.3Hz,2H),7.22(d,J=8.5Hz,1H),7.16(dd,J=8.5,2.0Hz,1H),7.00(s,1H),6.82(s,1H),4.89(s,3H),3.89(s,2H),3.66(s,2H),2.45(s,1H),2.42(s,4H),2.33(s,2H),2.20(s,3H)ppm。
13 CNMR(151MHz,CDCl 3 ):δ=157.6,155.8,143.6,143.2,139.8,138.9,138.2,137.8,137.6,133.2,131.6,129.7,129.3,128.3,127.9,126.4,125.1,123.9,121.5,120.1,119.6,115.8,110.5,92.3,59.6,55.4,21.5,21.5,16.7,16.1ppm。
Example 15
Name: n- (2, 7-bis (trifluoromethyl) indolo [2,3-a ] carbazol-11 (12H) -yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The procedure used in example 1 was repeated except for using the same molar amount of 2, 7-bis (trifluoromethyl) indolo [2,3-a ] carbazole instead of the carbazole used in example 1 to extend the reaction time to 12 hours, to obtain the desired product N- (2, 7-bis (trifluoromethyl) indolo [2,3-a ] carbazol-11 (12H) -yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide having the structure as above as a white solid in 75% yield.
1 HNMR(600MHz,DMSO-d6):δ=12.17(s,1H),11.75(s,1H),8.86(d,J=8.3Hz,1H),8.24(s,1H),8.15–8.07(m,1H),7.70(dd,J=8.4,1.2Hz,1H),7.64–7.59(m,3H),7.55(d,J=8.3Hz,2H),7.45(d,J=8.1Hz,2H),7.16(s,2H),3.56(s,3H),2.46(s,3H),2.11(s,6H)。
Example 16
N- (2- (3- (tert-butyl) -8-chloroindolo [2,3-a ] carbazole-11 (12H) -yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide
The procedure used in example 1 was repeated except for using an equimolar amount of 2- (3- (tert-butyl) -8-chloroindolo [2,3-a ] carbazole instead of the carbazole used in example 1 to extend the reaction time to 12 hours, to give the desired product N- (2- (3- (tert-butyl) -8-chloroindolo [2,3-a ] carbazol-11 (12H) -yl) -4-methoxy-3, 5-dimethylphenyl) -4-methylbenzenesulfonamide having the structure as above as a white solid in a yield of 72%.
1 HNMR(600MHz,DMSO-d6):δ=11.48(s,1H),11.18(s,1H),8.33(s,1H),7.99(s,1H),7.74(d,J=8.6Hz,1H),7.66(dd,J=16.0,8.3Hz,3H),7.60(s,1H),7.52(d,J=8.5Hz,1H),7.47(d,J=8.1Hz,2H),7.42(d,J=8.6Hz,1H),7.12(s,2H),3.56(s,3H),2.45(s,3H),2.10(s,6H),1.41(s,9H)。
Carbazole and N- (4, 4-dimethoxy-3, 5-dimethylcyclohex-2, 5-diene-1-subunit) -4-methylbenzenesulfonamide are used as reaction raw materials, p-toluenesulfonic acid is used as a catalyst, trifluoroethanol is used as a solvent, and the reaction is carried out for 10-30min at room temperature to obtain a compound of a formula II, wherein the reaction formula is as follows:
representative examples 17-21 are selected below to illustrate the synthetic strategy for novel N-substituted carbazole derivatives.
Example 17
Name: n- (2- (9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -4-methylbenzenesulphonamide
Carbazole (16 mg,0.1 mmol 1), N- (4, 4-dimethoxy-3, 5-dimethylcyclohex-2, 5-dien-1-ylidene) -4-methylbenzenesulfonamide (83 mg,0.25 mmol), p-toluenesulfonic acid (0.02 mmol), and trifluoroethanol (0.5 mL) were added to a 5mL clean reaction flask, and the reaction flask was left at room temperature with stirring. The reaction system is continued for 10min, then the reaction is stopped, the solvent is removed by reduced pressure distillation, and the residue is separated by column chromatography (petroleum ether/ethyl acetate) to obtain the target product N- (2- (9H-carbazole-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulfonamide) phenyl) -4-methylbenzenesulfonamide as a white solid with the yield of 86 percent.
1 HNMR(400MHz,CDCl 3 )δ=8.37(s,1H),7.90(s,2H),7.63(s,2H),7.61(s,2H),7.29(s,2H),7.27(s,2H),7.23(d,J=1.4Hz,4H),6.99(s,4H),3.67(s,6H),2.46(s,6H),2.22(s,12H)。
13 CNMR(151MHz,CDCl 3 )δ=155.9,143.4,139.1,137.6,137.3,133.4,131.7,129.4,128.2,127.8,127.2,123.4,121.5,111.2,77.2,77.0,76.7,59.6,21.5,16.1。
Example 18
Name: n- (2- (2-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -4-methylbenzenesulphonamide
The carbazole used in example 17 was replaced with an equimolar amount of 2-bromo-9H-carbazole, the reaction time was prolonged to 20min, and the rest of the procedure was the same as in example 17, to give the target product N- (2- (2-bromo-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -4-methylbenzenesulfonamide as above in a white solid with a yield of 62%.
1 HNMR(400MHz,CDCl 3 )δ=8.55(s,1H),7.96(s,1H),7.94(d,J=1.8Hz,1H),7.70(s,1H),7.68(s,1H),7.64(s,1H),7.62(s,1H),7.51(s,1H),7.31(s,2H),7.29(s,2H),7.22(s,1H),7.21(d,J=1.8Hz,1H),7.14(s,2H),7.01(s,2H),3.68(s,3H),3.67(s,3H),2.48(s,3H),2.46(s,3H),2.23(s,6H),2.22(s,6H)。
13 CNMR(151MHz,CDCl 3 )δ=156.0,155.8,143.8,143.5,140.1,139.2,137.5,137.2,136.9,135.8,133.8,131.8,131.4,131.1,129.4,129.3,128.3,128.2,128.2,127.9,127.4,123.2,123.2,123.0,122.7,121.6,115.7,111.5,59.6,59.6,21.6,21.6,16.2。
Example 19
Name: n- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulfamido) phenyl) -N- (4-methoxy-3, 5-dimethyl-2- (4- (oxiran-2-ylmethoxy) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide
The carbazole used in example 17 was replaced with an equimolar amount of 4- (oxiran-2-ylmethoxy) -9H-carbazole and the reaction time was prolonged to 30min, the remaining procedure was the same as in example 17 to give the target product N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -N- (4-methoxy-3, 5-dimethyl-2- (4- (oxiran-2-ylmethoxy) -9H-carbazol-9-yl) phenyl) -4-methylbenzenesulfonamide as above in 35% yield as a white solid.
1 HNMR(400MHz,CDCl 3 )δ=8.47(s,1H),8.12(d,J=2.0Hz,1H),7.63(s,1H),7.61(d,J=2.0Hz,2H),7.59(s,1H),7.39(dd,J=8.6,2.1Hz,1H),7.29(s,1H),7.27(s,1H),7.23(s,1H),7.19(d,J=8.9Hz,2H),7.12(d,J=8.6Hz,1H),7.07(s,2H),7.06(s,1H),7.03(s,2H),3.67–3.63(m,6H),2.45(s,3H),2.40(s,3H),2.19(s,6H),2.18(s,7H)。
13 CNMR(151MHz,CDCl 3 )δ=156.2,155.9,143.7,143.3,141.4,138.8,137.8,137.6,137.6,136.9,133.9,131.9,131.4,129.6,129.5,129.5,128.9,128.2,128.1,127.8,127.4,126.1,124.1,122.1,117.7,111.0,107.1,59.8,59.7,50.7,44.3,21.7,21.7,16.4,16.2。
Example 20
Name: n- (2- (7H-dibenzo [ c, g ] carbazol-7-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -4-methylbenzenesulphonamide
The procedure used in example 17 was repeated except for substituting an equimolar amount of 7H-dibenzo [ c, g ] carbazole for 15min to give N- (2- (7H-dibenzo [ c, g ] carbazol-7-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulfonamide) phenyl) -4-methylbenzenesulfonamide as the objective product having the above-mentioned structure as a white solid in 55% yield.
1 HNMR(400MHz,CDCl 3 )δ=8.47(s,1H),8.12(d,J=2.0Hz,1H),7.63(s,1H),7.61(d,J=2.0Hz,2H),7.59(s,1H),7.39(dd,J=8.6,2.1Hz,1H),7.29(s,1H),7.27(s,1H),7.23(s,1H),7.21–7.18(m,2H),7.12(d,J=8.6Hz,1H),7.07(s,2H),7.06(s,1H),7.03–7.00(m,3H),3.65(s,3H),3.65(d,J=1.7Hz,4H),2.43(d,J=18.7Hz,7H),2.19(s,6H),2.18(s,8H)。
13 CNMR(151MHz,CDCl 3 )δ=156.1,155.7,143.6,143.2,141.2,138.7,137.7,137.5,137.5,136.7,133.8,131.7,131.3,129.5,129.3,128.8,128.1,128.0,127.7,127.3,125.9,124.0,122.0,117.6,110.9,107.0,59.7,59.6,50.5,44.2,21.6,21.6,16.2,16.1。
Example 21
Name: n- (2- (1, 4-dimethyl-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulphonamido) phenyl) -4-methylbenzenesulphonamide
The carbazole used in example 17 was replaced with an equimolar amount of 1, 4-dimethyl-9H-carbazole, and the reaction time was prolonged to 20min, and the rest of the procedure was the same as in example 17, to give the target product N- (2- (1, 4-dimethyl-9H-carbazol-9-yl) -4-methoxy-3, 5-dimethylphenyl) -N- (3-methoxy-2, 4-dimethyl-6- ((4-methylphenyl) sulfonamide) phenyl) -4-methylbenzenesulfonamide as above in a white solid with a yield of 78%.
1 HNMR(400MHz,CDCl 3 )δ=8.45(s,1H),7.89(d,J=1.5Hz,1H),7.64–7.61(m,4H),7.29(d,J=6.7Hz,4H),7.25–7.24(m,2H),7.00(s,2H),6.99(s,2H),6.95(s,1H),3.67(s,3H),3.66(s,3H),2.67(s,3H),2.46(s,3H),2.45(s,3H),2.38(s,3H),2.20(s,12H)。
13 CNMR(151MHz,CDCl 3 )δ=155.8,155.2,143.4,143.4,138.9,138.8,137.6,137.6,137.4,137.3,133.2,131.6,131.5,131.4,131.3,129.4,129.3,128.1,128.0,127.9,127.9,126.8,126.6,124.5,123.1,121.9,117.9,111.3,59.6,21.5,21.5,16.4,16.2,16.1,15.6。
The applicant states that the present invention is illustrated by the above examples as well as the preparation and use thereof, but the present invention is not limited to, i.e., does not necessarily mean that the present invention must be practiced in dependence upon the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. The N-substituted carbazole derivative is characterized in that the structure of the N-substituted carbazole derivative is shown as a formula I or a formula II:
；
in formula IR 1 And R is 3 Independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclic group, R 1 And R is 3 Is linked to the aromatic ring in the form of a single bond or condensed to a cyclic structure with the aromatic ring in the form of a single bond, the dotted line representing the presence or absence of this moiety; r is R 2 Represents any one of H, halogen or methyl, methoxy, tert-butyl or trifluoromethyl;
r in formula II 1 And R is 3 Independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclic group, R 1 And R is 3 Is connected with the aromatic ring in the position of single bond or condensed with the aromatic ring in the position of single bond to form a cyclic structure;
ts represents p-toluenesulfonyl, me represents methyl.
2. The N-substituted carbazole derivative according to claim 1, characterized in that the oxygen-containing heterocyclic group is selected from oxiranemethoxy, 4, 5-tetramethyl-1, 3, 2-dioxaboryl.
3. The N-substituted carbazole derivative according to claim 1, characterized in that the N-substituted carbazole derivative is any one of the following compounds:
；
；
；
wherein Ts represents p-toluenesulfonyl, me represents methyl, and Ph represents phenyl.
4. A method for producing an N-substituted carbazole derivative according to any one of claims 1 to 3, characterized in that the production method comprises the steps of:
reacting a compound shown in a formula III or a formula IV with a compound shown in a formula V under the action of Lewis acid to obtain the N-substituted carbazole derivative;
。
5. the preparation method according to claim 4, wherein the molar ratio of the compound of formula III or the compound of formula IV to the compound of formula V is 1.2-1.5:1 when preparing the compound of formula I;
when the compound shown in the formula II is prepared, the compound shown in the formula III and the compound shown in the formula V are reacted under the action of Lewis acid, and the mol ratio of the compound shown in the formula III to the compound shown in the formula V is 2.1-3:1.
6. The process according to claim 4, wherein the Lewis acid is added in an amount of 0.1 to 0.5 equivalent to the compound of formula III or formula IV;
the Lewis acid is selected from any one or a mixture of at least two of p-toluenesulfonic acid, trifluoroacetic acid, acetic acid, benzoic acid, binaphthol phosphate or diphenyl phosphate.
7. The process according to claim 4, wherein the reaction is carried out in an organic solvent selected from any one or a mixture of at least two of dichloromethane, carbon tetrachloride, toluene, acetonitrile, 1, 4-dioxane, ethyl acetate, 1, 2-dichloroethane, methyl t-butyl ether, and trifluoroethanol.
8. The process of claim 7, wherein the organic solvent is selected from acetonitrile when preparing the compound of formula I and trifluoroethanol when preparing the compound of formula II.
9. The process according to claim 4, wherein the reaction temperature is from room temperature to 100℃and the reaction time is from 0.1 to 12 hours.
10. Use of an N-substituted carbazole derivative according to any one of claims 1 to 3 in the preparation of anticancer drugs.
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