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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- CN117486782A CN117486782A CN202311843699.3A CN202311843699A CN117486782A CN 117486782 A CN117486782 A CN 117486782A CN 202311843699 A CN202311843699 A CN 202311843699A CN 117486782 A CN117486782 A CN 117486782A
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- -1 N-substituted carbazole Chemical class 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 29
- 230000035484 reaction time Effects 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 11
- 150000007517 lewis acids Chemical class 0.000 claims description 11
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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 group 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
- 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 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 230000009471 action Effects 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 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
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 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 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 abstract description 59
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000005977 Ethylene Substances 0.000 description 6
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 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
- 239000002994 raw material Substances 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000002829 reductive effect Effects 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 compound 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
- 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
- 206010059866 Drug resistance Diseases 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
- 238000004440 column chromatography Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- YOJKKXRJMXIKSR-UHFFFAOYSA-N 1-nitro-2-phenylbenzene Chemical group [O-][N+](=O)C1=CC=CC=C1C1=CC=CC=C1 YOJKKXRJMXIKSR-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
- 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
- 241001120493 Arene Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000006658 Graebe-Ullmann reaction Methods 0.000 description 1
- 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 1
- 230000004913 activation Effects 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
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 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
- 239000004615 ingredient Substances 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
- 239000000463 material Substances 0.000 description 1
- 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
- 239000002547 new drug Substances 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
- 230000005693 optoelectronics Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000006476 reductive cyclization reaction Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910021654 trace metal Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
本发明提供一种N‑取代咔唑衍生物及其制备方法和应用，所述N‑取代咔唑衍生物的结构如式I或式II所示，本发明的N‑取代咔唑衍生物以咔唑为基础进行了结构修饰，是具有潜在抗癌活性的先导化合物，对现有药物药效的改进提升及抗癌新药的创制具有重要意义。本发明的N‑取代咔唑衍生物的合成同时也增加了反应底物范围和生物活性的拓展可能，制备方法简单，条件温和、成本低、环境友好。The present invention provides an N-substituted carbazole derivative and its preparation method and application. The structure of the N-substituted carbazole derivative is shown in Formula I or Formula II. The N-substituted carbazole derivative of the present invention is represented by The structure has been modified based on carbazole, which is a lead compound with potential anti-cancer activity. It is of great significance to the improvement of the efficacy of existing drugs and the creation of new anti-cancer drugs. The synthesis of N-substituted carbazole derivatives of the present invention also increases the scope of reaction substrates and the possibility of expanding biological activity. The preparation method is simple, the conditions are mild, the cost is low, and the environment is friendly.
Description
技术领域Technical field
本发明属于药物合成领域，涉及一种新型N-取代咔唑衍生物及其制备方法和应用。The invention belongs to the field of drug synthesis and relates to a novel N-substituted carbazole derivative and its preparation method and application.
背景技术Background technique
癌症是世界范围内仅次于心血管疾病的第二大死亡原因，目前化疗仍然是大多数人类癌症最重要的治疗方法，然而许多化疗药物都存在全身毒性、选择性低和耐药性等局限性（Dai Y, Cai X, Bi X, et al. Synthesis and anti-cancer evaluation of folicacid-peptide-paclitaxel conjugates for addressing drug resistance, J. Med.Chem. 171 (2019) 104-115）。因此迫切需要发现新的、有效的、安全的抗癌药物。Cancer is the second leading cause of death after cardiovascular disease worldwide. Currently, chemotherapy is still the most important treatment for most human cancers. However, many chemotherapy drugs have limitations such as systemic toxicity, low selectivity, and drug resistance. (Dai Y, Cai X, Bi X, et al. Synthesis and anti-cancer evaluation of folicacid-peptide-paclitaxel conjugates for addressing drug resistance, J. Med. Chem. 171 (2019) 104-115). Therefore, there is an urgent need to discover new, effective, and safe anticancer drugs.
研究活性天然产物，是目前开辟药源、开发新药的重要途径之一。咔唑及其衍生物作为一种常见生物碱，因其具有的平面三环骨架以及众多的生物活性而备受关注。大的共轭体系、强的分子内电子转移能力以及较高的热稳定性和光化学稳定性使得其在光电材料、染料等领域得到广泛应用。此外，良好的类药性质、易于结构修饰等优点促使咔唑及其衍生物被当作药物或药物中间体被加以开发（Schmidt A W, Reddy K R, Knoelker H J.Occurrence, biogenesis, and synthesis of biologically active carbazolealkaloids.[J].Cheminform, 2012, 43(33):3193-3328），例如如下化合物：Studying active natural products is currently one of the important ways to explore drug sources and develop new drugs. As a common alkaloid, carbazole and its derivatives have attracted much attention due to their planar tricyclic skeleton and numerous biological activities. Its large conjugated system, strong intramolecular electron transfer ability, and high thermal and photochemical stability make it widely used in optoelectronic materials, dyes and other fields. In addition, the advantages of good drug-like properties and easy structural modification have prompted carbazole and its derivatives to be developed as drugs or drug intermediates (Schmidt A W, Reddy K R, Knoelker H J. Occurrence, biogenesis, and synthesis of biologically active carbazolealkaloids.[J].Cheminform, 2012, 43(33):3193-3328), such as the following compounds:
。 .
咔唑衍生物可以选择性地与HTGG-四链体（抗癌药物的靶标）DNA结合，能有效阻止癌细胞的扩散。针对天然与合成咔唑及其衍生物结构修饰及生物活性研究的工作，对潜在有抗癌活性咔唑类药物的设计开发提供了极大的帮助。Carbazole derivatives can selectively bind to HTGG-quadruplex DNA (the target of anti-cancer drugs) and can effectively prevent the spread of cancer cells. Work on the structural modification and biological activity of natural and synthetic carbazole and its derivatives has provided great help for the design and development of carbazole drugs with potential anti-cancer activity.
目前文献中报道的N-取代咔唑衍生物的合成主要是通过Graebe-Ullmann（格雷贝-乌尔曼）反应、Cadogan-Sundberg（卡多根-桑德伯格）反应以及过渡金属催化反应等方法来实现的。The synthesis of N-substituted carbazole derivatives currently reported in the literature is mainly through Graebe-Ullmann reaction, Cadogan-Sundberg reaction and transition metal catalyzed reaction. method to achieve.
早在1986年，Graebe和Ullmann等利用氨基二苯胺经重氮化反应得到1-苯基苯并三唑1-2并转化合成咔唑化合物1-3，反应流程如下：As early as 1986, Graebe and Ullmann et al. used diazotization reaction of aminodiphenylamine to obtain 1-phenylbenzotriazole 1-2 and converted it to synthesize carbazole compound 1-3. The reaction process is as follows:
。 .
Cadogan等开发出一种2-硝基联苯化合物在有机磷试剂存在下，硝基被还原成环得到咔唑类化合物的方法（Freeman A W, Urvoy M , Criswell M E .Triphenylphosphine -Mediated Reductive Cyclization of 2-Nitrobiphenyls: APractical and Convenient Synthesis of Carbazoles (IV)[J].The Journal ofOrganic Chemistry, 2005, 70(13):5014-5019），反应式如下：Cadogan et al. developed a method in which the nitro group of 2-nitrobiphenyl compounds is reduced to a ring in the presence of an organophosphorus reagent to obtain carbazole compounds (Freeman A W, Urvoy M, Criswell M E. Triphenylphosphine -Mediated Reductive Cyclization of 2 -Nitrobiphenyls: APractical and Convenient Synthesis of Carbazoles (IV)[J].The Journal ofOrganic Chemistry, 2005, 70(13):5014-5019), the reaction formula is as follows:
。 .
2008年Ackermann等人（Ackermann L , Althammer A .Domino N-H/C-H BondActivation: Palladium-Catalyzed Synthesis of Annulated Heterocycles UsingDichloro (hetero)arenes.[J].ChemInform, 2007, 38(25)）将苯胺3-1或取代苯胺和邻二卤(杂)芳烃3-2为原料在配体（ligand）和碱（base）存在下通过钯催化（Pd catalyst）的多米诺N-H/C-H键活化一锅合成咔唑衍生物3-3，反应式如下：In 2008, Ackermann et al. (Ackermann L, Althammer A. Domino N-H/C-H BondActivation: Palladium-Catalyzed Synthesis of Annulated Heterocycles UsingDichloro (hetero)arenes. [J]. ChemInform, 2007, 38(25)) aniline 3-1 or Substituted aniline and ortho-dihalo(hetero)arene 3-2 are used as raw materials, and carbazole derivative 3 is synthesized in one pot through domino N-H/C-H bond activation of Pd catalyst in the presence of ligand and base. -3, the reaction formula is as follows:
。 .
尽管现有制备N-取代咔唑衍生物的方法已经取得了一定进展，但是，这些经典方法大多涉及繁琐的多步骤过程，通常使N-取代咔唑衍生物的总收率较低。它们通常存在以下缺点：1）反应通常需要较长的反应时间；2）高温；3）使用质子与高水溶性和高沸点有机溶剂；4）使用致癌溶剂；5）过渡金属和配体的高成本和毒性，以及最终产品中的微量金属污染，都需要耗费大量的时间和财力去处理。Although existing methods for preparing N-substituted carbazole derivatives have made some progress, most of these classical methods involve tedious multi-step processes, which usually result in low overall yields of N-substituted carbazole derivatives. They usually have the following disadvantages: 1) the reaction usually requires a long reaction time; 2) high temperature; 3) the use of protons with highly water-soluble and high-boiling point organic solvents; 4) the use of carcinogenic solvents; 5) the high concentration of transition metals and ligands. The cost and toxicity, as well as trace metal contamination in the final product, require significant time and financial resources to deal with.
因此，在本领域中开发新的N-取代咔唑衍生物及其制备方法的进一步开发具有重要意义。Therefore, the further development of new N-substituted carbazole derivatives and their preparation methods is of great significance in this field.
发明内容Contents of the invention
针对现有技术的不足，本发明的目的在于提供一种N-取代咔唑衍生物及其制备方法和应用。In view of the shortcomings of the existing technology, the object of the present invention is to provide an N-substituted carbazole derivative and its preparation method and application.
为达此目的，本发明采用以下技术方案：To achieve this goal, the present invention adopts the following technical solutions:
一方面，本发明提供一种N-取代咔唑衍生物，所述N-取代咔唑衍生物的结构如式I或式II所示：On the one hand, the present invention provides an N-substituted carbazole derivative, the structure of the N-substituted carbazole derivative is as shown in Formula I or Formula II:
式I中R1和R3独立地选自H、C1-C4烷基、卤素、苯基、杂芳基、甲氧基或含氧杂环基中的任意一种，R1和R3以单键的形式与所在芳环连接或者与所在芳环稠合成环状结构，虚线代表有或者没有此部分基团；R2代表H、卤素或甲基、甲氧基、叔丁基或三氟甲基中的任意一种；In formula I, R 1 and R 3 are independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclyl, and R 1 and R 3 are The form of a single bond is connected to the aromatic ring or fused with the aromatic ring to form a cyclic structure. The dotted line represents the presence or absence of this part of the group; R 2 represents H, halogen or methyl, methoxy, tert-butyl or trifluoro Any of the methyl groups;
式II中R1和R3独立地选自H、C1-C4烷基、卤素、苯基、杂芳基、甲氧基或含氧杂环基中的任意一种，R1和R3以单键的形式与所在芳环连接或者与所在芳环稠合成环状结构；In Formula II, R 1 and R 3 are independently selected from any one of H, C1-C4 alkyl, halogen, phenyl, heteroaryl, methoxy or oxygen-containing heterocyclyl, and R 1 and R 3 are The form of a single bond is connected to the aromatic ring or condensed with the aromatic ring to form a cyclic structure;
Ts代表对甲苯磺酰基，Me代表甲基。Ts represents p-toluenesulfonyl group and Me represents methyl group.
在本发明中，所述C1-C4烷基可以为C1、C2、C3或C4烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基等。In the present invention, the C1-C4 alkyl group may be C1, C2, C3 or C4 alkyl group, for example, it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.
优选地，所述含氧杂环基选自环氧乙烷甲氧基、4,4,5,5-四甲基-1,3,2-二氧杂硼烷基等。Preferably, the oxygen-containing heterocyclic group is selected from the group consisting of ethylene oxide methoxy group, 4,4,5,5-tetramethyl-1,3,2-dioxaboranyl group, and the like.
优选地，所述N-取代咔唑衍生物为如下化合物中的任意一种：Preferably, the N-substituted carbazole derivative is any one of the following compounds:
； ;
其中Ts代表对甲苯磺酰基，Me代表甲基，Ph代表苯基。Among them, Ts represents p-toluenesulfonyl group, Me represents methyl group, and Ph represents phenyl group.
另一方面，本发明提供了一种如上所述的N-取代咔唑衍生物的制备方法，所述制备方法包括以下步骤：On the other hand, the present invention provides a preparation method of N-substituted carbazole derivatives as described above, which preparation method includes the following steps:
式III或者式IV所示化合物与式V所示化合物，在路易斯酸的作用下反应得到所述N-取代咔唑衍生物；The compound represented by formula III or formula IV and the compound represented by formula V react under the action of Lewis acid to obtain the N-substituted carbazole derivative;
。 .
优选地，制备式I化合物时，所述式III所示化合物或者式IV所示化合物与式V所示化合物的摩尔比为1.2~1.5:1，例如1.2:1、1.3:1、1.4:1或1.5:1。Preferably, when preparing the compound of formula I, 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, such as 1.2:1, 1.3:1, 1.4:1 Or 1.5:1.
优选地，制备式II化合物时，利用式III所示化合物与式V所示化合物，在路易斯酸的作用下反应得到，所述式III所示化合物与式V所示化合物的摩尔比为2.1-3:1，例如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或3:1。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, and 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.
优选地，所述路易斯酸的加入量可为式III或者式IV所示化合物的0.1-0.5倍当量，例如0.1倍当量、0.2倍当量、0.3倍当量、0.4倍当量或0.5倍当量。Preferably, the added amount of the Lewis acid can be 0.1-0.5 times the equivalent of the compound represented by Formula III or Formula IV, such as 0.1 times the equivalent, 0.2 times the equivalent, 0.3 times the equivalent, 0.4 times the equivalent or 0.5 times the equivalent.
优选地，所述路易斯酸选自对甲苯磺酸、三氟乙酸、乙酸、苯甲酸、磷酸CPA（联萘酚磷酸酯）或磷酸二苯酯中的任意一种或至少两种的混合物。Preferably, 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, CPA phosphate (binaphtyl phosphate) or diphenyl phosphate.
优选地，制备式I化合物时，所述路易斯酸优选磷酸二苯酯，制备式II化合物时，所述路易斯酸优选对甲苯磺酸。Preferably, when preparing the compound of formula I, the Lewis acid is preferably diphenyl phosphate, and when preparing the compound of formula II, the Lewis acid is preferably p-toluenesulfonic acid.
优选地，所述反应在有机溶剂中进行，所述有机溶剂选自二氯甲烷、四氯化碳、甲苯、乙睛、1,4-二氧六环、乙酸乙酯、DCE（1.2-二氯乙烷）、TBME（甲基叔丁基醚）或三氟乙醇中的任意一种或至少两种的混合物。Preferably, the reaction is carried out in an organic solvent selected from dichloromethane, carbon tetrachloride, toluene, acetonitrile, 1,4-dioxane, ethyl acetate, DCE (1.2-dioxane Any one or a mixture of at least two of ethyl chloride), TBME (tert-butyl methyl ether) or trifluoroethanol.
优选地，制备式I化合物时，所述有机溶剂选自乙睛，制备式II化合物时，所述有机溶剂选自三氟乙醇。Preferably, when preparing the compound of formula I, the organic solvent is selected from acetonitrile, and when preparing the compound of formula II, the organic solvent is selected from trifluoroethanol.
优选地，所述反应的温度为室温-100℃，例如20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃或100℃，反应时间为0.1-12小时，例如0.1小时、0.5小时、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时或12小时。Preferably, the temperature of the reaction is room temperature-100°C, such as 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C , 80℃, 85℃, 90℃, 95℃ or 100℃, the reaction time is 0.1-12 hours, such as 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.
在本发明所述反应结束后还包括对粗产物进行硅胶色谱纯化得到式I、II所示目标化合物的操作。After the reaction of the present invention is completed, it also includes the operation of purifying the crude product by silica gel chromatography to obtain the target compounds represented by formulas I and II.
另一方面，本发明提供了如上所述的N-取代咔唑衍生物在抗癌药物制备中的应用。On the other hand, the present invention provides the use of the N-substituted carbazole derivative as described above in the preparation of anti-cancer drugs.
相对于现有技术，本发明具有以下有益效果：Compared with the existing technology, the present invention has the following beneficial effects:
（1）本发明的N-取代咔唑衍生物以咔唑为基础进行了结构修饰，是具有潜在抗癌活性的先导化合物，对现有药物药效的改进提升及抗癌新药的创制具有重要意义。本发明的N-取代咔唑衍生物的合成同时也增加了反应底物范围和生物活性的拓展可能。(1) The N-substituted carbazole derivative of the present invention is structurally modified based on carbazole and is a lead compound with potential anti-cancer activity. It is important for improving the efficacy of existing drugs and creating new anti-cancer drugs. significance. The synthesis of N-substituted carbazole derivatives of the present invention also increases the possibility of expanding the scope of reaction substrates and biological activities.
（2）本发明的N-取代咔唑衍生物的制备方法条件温和、工艺简单、成本低、环境友好的制备新型取代咔唑衍生物的方法；该方法在化学计量的路易斯酸的作用下进行，方便，廉价，易于处理，避免了过渡金属及昂贵配体的使用；反应条件温和，常温下即可高效反应；无危险致癌试剂的使用且具有良好的底物适用性。(2) The preparation method of N-substituted carbazole derivatives of the present invention is a method for preparing novel substituted carbazole derivatives with mild conditions, simple process, low cost and environmental friendliness; the method is carried out under the action of stoichiometric Lewis acid , convenient, cheap, easy to handle, avoiding the use of transition metals and expensive ligands; the reaction conditions are mild, and the reaction can be efficient at room temperature; there is no use of dangerous carcinogenic reagents and good substrate applicability.
具体实施方式Detailed ways
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。The technical solution of the present invention will be further described below through specific implementations. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.
以咔唑或吲哚并[2,3-a]咔唑和N-(4,4-二甲氧基-3,5-二甲基环己-2,5-二烯-1-亚基)-4-甲基苯磺酰胺为反应原料，以磷酸二苯酯为催化剂，以MeCN为溶剂，在60℃下反应，获得了不同取代的N-取代咔唑衍生物，反应式如下：Using carbazole or indolo[2,3-a]carbazole and N-(4,4-dimethoxy-3,5-dimethylcyclohexan-2,5-diene-1-ylidene) )-4-methylbenzenesulfonamide was used as the reaction raw material, diphenyl phosphate was used as the catalyst, and MeCN was used as the solvent. The reaction was carried out at 60°C to obtain N-substituted carbazole derivatives with different substitutions. The reaction formula is as follows:
下面选择了其中具有代表性的实施例1-16，对咔唑类生物碱功能化合成并获得新型N-取代咔唑衍生物的策略进行说明。Representative Examples 1-16 are selected below to illustrate the strategy of functionalizing carbazole alkaloids to synthesize and obtain novel N-substituted carbazole derivatives.
实施例1Example 1
名称：N-(2-(9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
向5mL干净的反应瓶中加入咔唑（75.2mg,0.45mmo1）、N-(4,4-二甲氧基-3,5-二甲基环己-2,5-二烯-1-亚基)-4-甲基苯磺酰胺（100.6mg,0.3mmol）、磷酸二苯酯（0.06mmol）和MeCN（1.5mL），将反应瓶置于60℃下搅拌反应。反应体系持续2h后停止反应，减压蒸馏除去溶剂，将残余物经柱层析分离（石油醚/乙酸乙酯）得到目标产物N-(2-(9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为83%。Add carbazole (75.2 mg, 0.45 mmol), N-(4,4-dimethoxy-3,5-dimethylcyclohexan-2,5-diene-1-ylidene) to a clean 5 mL reaction bottle. (100.6 mg, 0.3 mmol), diphenyl phosphate (0.06 mmol) and MeCN (1.5 mL). Place the reaction flask at 60°C and stir for reaction. The reaction was stopped after the reaction system continued for 2 hours, the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (petroleum ether/ethyl acetate) to obtain the target product N-(2-(9H-carbazol-9-yl)-4 -Methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 83%.
1HNMR(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。 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.
13CNMR(151MHz,DMSO-d6):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。 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.
实施例2Example 2
名称：N-(4-甲氧基-3,5-二甲基-2-(1-甲基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-3,5-dimethyl-2-(1-methyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的1-甲基咔唑代替，反应时间延长至3h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-3,5-二甲基-2-(1-甲基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为93%。The carbazole used in Example 1 was replaced with an equal molar amount of 1-methylcarbazole, the reaction time was extended to 3 h, and the remaining steps were the same as in Example 1 to obtain the target product N-(4-methoxy with the above structure -3,5-Dimethyl-2-(1-methyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide, white solid, yield 93%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.8,143.2,139.8,139.4,138.3,138.0,137.8,137.7,137.5,133.3,133.3,131.6,131.6,129.3,129.3,128.3,127.9,12 7.9,127.5,126.8 ,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.
实施例3Example 3
名称：N-(4-甲氧基-3,5-二甲基-2-(4-(环氧乙烷-2-基甲氧基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-3,5-dimethyl-2-(4-(ethylene oxide-2-ylmethoxy)-9H-carbazol-9-yl)phenyl) -4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的4-(环氧乙烷-2-基甲氧基)-9H-咔唑代替，反应时间延长至8h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-3,5-二甲基-2-(4-(环氧乙烷-2-基甲氧基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为71%。The carbazole used in Example 1 was replaced with an equal molar amount of 4-(ethylene oxide-2-ylmethoxy)-9H-carbazole, the reaction time was extended to 8h, and the remaining steps were the same as in Example 1. Obtain the target product N-(4-methoxy-3,5-dimethyl-2-(4-(ethylene oxide-2-ylmethoxy)-9H-carbazol-9-yl) with the above structure )Phenyl)-4-methylbenzenesulfonamide, white solid, yield 71%.
1HNMR(600MHz,CDCl3):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。 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=8.5 Hz,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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.6,151.9,143.4,140.6,139.4,137.8,136.9,131.2,129.4,129.3,128.1,128.0,126.9,126.0,125.8,123.3,121.6,12 0.2,117.8,110.3 ,106.6,59.6,50.9,44.4,21.6,16.2ppm.
实施例4Example 4
名称：N-(2-(1,4-二甲基-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(1,4-dimethyl-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的1,4-二甲基-9H-咔唑代替，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(1,4-二甲基-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为95%。The carbazole used in Example 1 was replaced with an equal molar amount of 1,4-dimethyl-9H-carbazole, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-(1, 4-Dimethyl-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 95%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.1,143.3,139.8,138.2,137.6,137.4,131.4,131.3,130.7,129.2,127.9,127.2,126.9,125.0,124.1,122.4,121.9,11 9.3,117.4,110.7 ,59.5,21.5,16.4,16.1,15.7ppm.
实施例5Example 5
名称：N-(2-(3-碘-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(3-iodo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的3-碘-9H-咔唑代替，反应时间延长至16h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(3-碘-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为90%。The carbazole used in Example 1 was replaced with an equal molar amount of 3-iodo-9H-carbazole, the reaction time was extended to 16 h, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-() with the above structure 3-iodo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 90%.
1HNMR(600MHz,DMSO-d6)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。 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.
13CNMR(151MHz,DMSO-d6)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。 13 CNMR (151MHz, DMSO-d 6 )δ=155.6,143.6,140.5,138.8,137.5,137.4,132.3,131.4,129.9,128.4,127.7,126.7,126.2,122.8,122.2,121.5,120.7,1 19.0,111.4, 111.3,79.3,59.4,21.2,16.0ppm.
实施例6Example 6
名称：N-(2-(2-氯-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(2-chloro-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2-氯-9H-咔唑代替，反应时间延长至3h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(2-氯-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为70%。The carbazole used in Example 1 was replaced with an equal molar amount of 2-chloro-9H-carbazole, the reaction time was extended to 3h, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-() with the above structure 2-Chloro-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 70%.
1HNMR(600MHz,DMSO-d6)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。 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.
13CNMR(151MHz,DMSO-d6)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。 13 CNMR (151MHz, DMSO-d 6 )δ=155.7,143.6,141.1,139.2,137.4,137.3,132.9,131.4,130.6,129.9,128.4,127.7,127.1,122.3,122.2,121.9,121.7,1 21.2,119.2, 111.8,111.0,79.3,59.4,55.1,21.2,16.0ppm.
实施例7Example 7
名称：N-(2-(2-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(2-bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2-溴-9H-咔唑代替，反应时间延长至8h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(2-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为67%。The carbazole used in Example 1 was replaced with an equal molar amount of 2-bromo-9H-carbazole, the reaction time was extended to 8 h, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-( with the above structure 2-Bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 67%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=156.0,143.4,140.7,138.4,137.6,137.3,133.8,131.7,129.4,129.4,128.3,127.9,127.2,127.2,124.2,123.1,122.9,12 1.9,121.6,121.1 ,119.7,113.7,111.1,59.6,21.6,16.2,15.8ppm.
实施例8Example 8
名称：N-(4-甲氧基-3,5-二甲基-2-(2-苯基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-3,5-dimethyl-2-(2-phenyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2-苯基-9H-咔唑代替，反应时间延长至18h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-3,5-二甲基-2-(2-苯基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为53%。The carbazole used in Example 1 was replaced with an equal molar amount of 2-phenyl-9H-carbazole, the reaction time was extended to 18 h, and the remaining steps were the same as in Example 1 to obtain the target product N-(4- Methoxy-3,5-dimethyl-2-(2-phenyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide, white solid, yield 53%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.6,143.6,140.7,140.4,140.1,138.8,138.3,136.5,131.9,130.7,130.2,129.5,129.0,128.4,127.8,127.2,126.4,12 3.0,122.7,120.3 ,120.0,119.8,113.1,111.1,59.8,21.8,16.1ppm.
实施例9Example 9
名称：N-(2-(3-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(3-bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的3-溴-9H-咔唑代替，反应时间延长至18h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(3-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为92%。The carbazole used in Example 1 was replaced with an equal molar amount of 3-bromo-9H-carbazole, the reaction time was extended to 18 h, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-() with the above structure 3-Bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 92%.
1HNMR(600MHz,DMSO-d6):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。 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.
13CNMR(151MHz,DMSO-d6):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。 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.
实施例10Example 10
名称：N-(4-甲氧基-3,5-二甲基-2-(3-苯基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-3,5-dimethyl-2-(3-phenyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的3-苯基-9H-咔唑代替，反应时间延长至18h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-3,5-二甲基-2-(3-苯基-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为87%。The carbazole used in Example 1 was replaced with an equal molar amount of 3-phenyl-9H-carbazole, the reaction time was extended to 18h, and the remaining steps were the same as in Example 1 to obtain the target product N-(4- Methoxy-3,5-dimethyl-2-(3-phenyl-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide, white solid, yield 87%.
1HNMR(600MHz,CDCl3):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。 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 .
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.9,143.3,141.8,139.4,138.9,137.7,137.5,133.4,133.2,131.7,129.3,128.7,128.3,127.9,127.2,127.2,126.6,12 5.9,123.8,123.5 ,121.2,118.9,111.1,110.9,59.6,21.6,16.2ppm.
实施例11Example 11
名称：N-(2-(2,7-二溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(2,7-dibromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2,7-二溴-9H-咔唑代替，反应时间延长至24h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(2,7-二溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为53%。The carbazole used in Example 1 was replaced with an equal molar amount of 2,7-dibromo-9H-carbazole, the reaction time was extended to 24h, and the remaining steps were the same as in Example 1 to obtain the target product N-( with the above structure 2-(2,7-Dibromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield is 53%.
1HNMR(600MHz,CDCl3):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。 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=5.9 Hz,2H),3.66(s,3H),2.49(s,3H),2.20(d,J=8.0Hz,6H)ppm.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.9,143.8,140.8,139.3,136.9,135.8,131.6,131.4,129.4,129.3,128.4,128.3,128.3,123.4,123.1,122.7,122.4,12 1.4,121.3,120.1 ,115.7,114.0,59.6,21.6,16.2ppm.
实施例12Example 12
名称：N-(4-甲氧基-3,5-二甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-3,5-dimethyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2) -(yl)-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的3-（4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基）-9H-咔唑代替，反应时间延长至18h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-3,5-二甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为90%。The carbazole used in Example 1 was an equimolar amount of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-9H-carbazole. Instead, the reaction time was extended to 18h, and the remaining steps were the same as in Example 1 to obtain the target product N-(4-methoxy-3,5-dimethyl-2-(3-(4,4,5) with the above structure ,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide, white solid, yield is 90%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=156.0,143.3,142.2,138.4,137.6,137.5,133.6,132.6,131.7,129.4,128.5,127.8,127.7,127.4,123.6,122.6,121.0,11 1.0,110.2,83.6 ,59.5,24.8,21.5,16.1ppm.
实施例13Example 13
名称：N-(2-(7H-二苯并[c,g]咔唑-7-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(7H-Dibenzo[c,g]carbazol-7-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的7H-二苯并[c,g]咔唑代替，反应时间延长至8h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(7H-二苯并[c,g]咔唑-7-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为51%。The carbazole used in Example 1 was replaced with an equal molar amount of 7H-dibenzo[c,g]carbazole, the reaction time was extended to 8 h, and the remaining steps were the same as in Example 1 to obtain the target product N- with the above structure. (2-(7H-Dibenzo[c,g]carbazol-7-yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, The yield is 51%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=155.7,143.8,137.1,136.9,136.5,134.6,134.5,131.5,129.7,129.5,128.9,128.2,127.8,127.4,127.2,125.5,125.3,12 5.2,124.8,124.7 ,123.8,123.2,118.0,116.8,114.9,112.2,59.5,21.6,16.2ppm.
实施例14Example 14
名称：N-(4-甲氧基-2-(1-甲氧基-3-甲基-9H-咔唑-9-基)-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(4-methoxy-2-(1-methoxy-3-methyl-9H-carbazol-9-yl)-3,5-dimethylphenyl)-4-methyl benzene sulfonamide
在实施例1中所用的咔唑用等摩尔量的1-甲氧基-3-甲基-9H-咔唑代替，反应时间延长至8h，其余步骤与实施例1相同，得到结构如上的目标产物N-(4-甲氧基-2-(1-甲氧基-3-甲基-9H-咔唑-9-基)-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为75%。The carbazole used in Example 1 was replaced with an equal molar amount of 1-methoxy-3-methyl-9H-carbazole. The reaction time was extended to 8 h. The remaining steps were the same as in Example 1 to obtain the target with the above structure. Product N-(4-methoxy-2-(1-methoxy-3-methyl-9H-carbazol-9-yl)-3,5-dimethylphenyl)-4-methylbenzene Sulfonamide, white solid, yield 75%.
1HNMR(600MHz,CDCl3):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。 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.
13CNMR(151MHz,CDCl3):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。 13 CNMR (151MHz, CDCl 3 ): δ=157.6,155.8,143.6,143.2,139.8,138.9,138.2,137.8,137.6,133.2,131.6,129.7,129.3,128.3,127.9,126.4,125.1,12 3.9,121.5,120.1 ,119.6,115.8,110.5,92.3,59.6,55.4,21.5,21.5,16.7,16.1ppm.
实施例15Example 15
名称：N-(2-(2,7-双(三氟甲基)吲哚并[2,3-a]咔唑-11(12H)-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name: N-(2-(2,7-bis(trifluoromethyl)indolo[2,3-a]carbazol-11(12H)-yl)-4-methoxy-3,5- Dimethylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2,7-双(三氟甲基)吲哚并[2,3-a]咔唑代替，反应时间延长至12h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(2,7-双(三氟甲基)吲哚并[2,3-a]咔唑-11(12H)-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为75%。The carbazole used in Example 1 was replaced with an equal molar amount of 2,7-bis(trifluoromethyl)indolo[2,3-a]carbazole, and the reaction time was extended to 12h. The remaining steps were the same as in Example 1 is the same, and the target product N-(2-(2,7-bis(trifluoromethyl)indolo[2,3-a]carbazole-11(12H)-yl)-4-methyl with the above structure is obtained Oxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 75%.
1HNMR(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)。 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).
实施例16Example 16
名称N-(2-(3-(叔丁基)-8-氯吲哚并[2,3-a]咔唑-11(12H)-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺Name N-(2-(3-(tert-butyl)-8-chloroindolo[2,3-a]carbazol-11(12H)-yl)-4-methoxy-3,5-di Methylphenyl)-4-methylbenzenesulfonamide
在实施例1中所用的咔唑用等摩尔量的2-(3-(叔丁基)-8-氯吲哚并[2,3-a]咔唑代替，反应时间延长至12h，其余步骤与实施例1相同，得到结构如上的目标产物N-(2-(3-(叔丁基)-8-氯吲哚并[2,3-a]咔唑-11(12H)-基)-4-甲氧基-3,5-二甲基苯基)-4-甲基苯磺酰胺，白色固体，产率为72%。The carbazole used in Example 1 was replaced with an equal molar amount of 2-(3-(tert-butyl)-8-chloroindolo[2,3-a]carbazole, the reaction time was extended to 12h, and the remaining steps In the same manner as Example 1, the target product N-(2-(3-(tert-butyl)-8-chloroindolo[2,3-a]carbazole-11(12H)-yl)- with the above structure was obtained 4-Methoxy-3,5-dimethylphenyl)-4-methylbenzenesulfonamide, white solid, yield 72%.
1HNMR(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)。 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).
以咔唑和N-(4,4-二甲氧基-3,5-二甲基环己-2,5-二烯-1-亚基)-4-甲基苯磺酰胺为反应原料，以对甲苯磺酸为催化剂，以三氟乙醇为溶剂，室温下反应10-30min，得到式II化合物，反应式如下：Using carbazole and N-(4,4-dimethoxy-3,5-dimethylcyclohexan-2,5-diene-1-ylidene)-4-methylbenzenesulfonamide as reaction raw materials, Using p-toluenesulfonic acid as the catalyst and trifluoroethanol as the solvent, react at room temperature for 10-30 minutes to obtain the compound of formula II. The reaction formula is as follows:
下面选择了其中具有代表性的实施例17-21，对新型N-取代咔唑衍生物的合成策略进行说明。Representative Examples 17-21 are selected below to illustrate the synthesis strategy of new N-substituted carbazole derivatives.
实施例17Example 17
名称：N-(2-(9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺Name: N-(2-(9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2,4-dimethyl Base-6-((4-methylphenyl)sulfonamide)phenyl)-4-methylbenzenesulfonamide
向5mL干净的反应瓶中加入咔唑（16mg,0.1mmo1）、N-(4,4-二甲氧基-3,5-二甲基环己-2,5-二烯-1-亚基)-4-甲基苯磺酰胺（83mg,0.25mmol）、对甲苯磺酸（0.02mmol）和三氟乙醇（0.5mL），将反应瓶置于室温下搅拌反应。反应体系持续10min后停止反应，减压蒸馏除去溶剂，将残余物经柱层析分离（石油醚/乙酸乙酯）得到目标产物N-(2-(9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺，白色固体，产率为86%。Add carbazole (16mg, 0.1mmo1), N-(4,4-dimethoxy-3,5-dimethylcyclohexan-2,5-diene-1-ylidene) to a clean 5mL reaction bottle )-4-methylbenzenesulfonamide (83 mg, 0.25 mmol), p-toluenesulfonic acid (0.02 mmol) and trifluoroethanol (0.5 mL), place the reaction bottle at room temperature and stir for reaction. The reaction was stopped after the reaction system continued for 10 minutes, the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (petroleum ether/ethyl acetate) to obtain the target product N-(2-(9H-carbazol-9-yl)-4 -Methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2,4-dimethyl-6-((4-methylphenyl)sulfonamido)phenyl )-4-methylbenzenesulfonamide, white solid, yield 86%.
1HNMR(400MHz,CDCl3)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)。 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).
13CNMR(151MHz,CDCl3)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。 13 CNMR (151MHz, CDCl 3 )δ=155.9,143.4,139.1,137.6,137.3,133.4,131.7,129.4,128.2,127.8,127.2,123.4,121.5,111.2,77.2,77.0,76.7,59.6,2 1.5,16.1.
实施例18Example 18
名称：N-(2-(2-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺Name: N-(2-(2-bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2, 4-Dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide
在实施例17中所用的咔唑用等摩尔量的2-溴-9H-咔唑代替，反应时间延长至20min，其余步骤与实施例17相同，得到结构如上的目标产物N-(2-(2-溴-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺，白色固体，产率为62%。The carbazole used in Example 17 was replaced with an equal molar amount of 2-bromo-9H-carbazole, the reaction time was extended to 20 min, and the remaining steps were the same as in Example 17 to obtain the target product N-(2-() with the above structure 2-Bromo-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2,4-dimethyl-6- ((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide, white solid, yield 62%.
1HNMR(400MHz,CDCl3)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)。 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).
13CNMR(151MHz,CDCl3)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。 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.
实施例19Example 19
名称：N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-N-(4-甲氧基-3,5-二甲基-2-(4-(环氧乙烷-2-基甲氧基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺Name: N-(3-methoxy-2,4-dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-N-(4-methoxy-3,5 -Dimethyl-2-(4-(ethylene oxide-2-ylmethoxy)-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide
在实施例17中所用的咔唑用等摩尔量的4-(环氧乙烷-2-基甲氧基)-9H-咔唑代替，反应时间延长至30min，其余步骤与实施例17相同，得到结构如上的目标产物N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-N-(4-甲氧基-3,5-二甲基-2-(4-(环氧乙烷-2-基甲氧基)-9H-咔唑-9-基)苯基)-4-甲基苯磺酰胺，白色固体，产率为35%。The carbazole used in Example 17 was replaced with an equal molar amount of 4-(ethylene oxide-2-ylmethoxy)-9H-carbazole, the reaction time was extended to 30 min, and the remaining steps were the same as in Example 17. Obtain the target product N-(3-methoxy-2,4-dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-N-(4-methoxy) with the structure as above -3,5-Dimethyl-2-(4-(ethylene oxide-2-ylmethoxy)-9H-carbazol-9-yl)phenyl)-4-methylbenzenesulfonamide, white Solid, yield 35%.
1HNMR(400MHz,CDCl3)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)。 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).
13CNMR(151MHz,CDCl3)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。 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.
实施例20Example 20
名称：N-(2-(7H-二苯并[c,g]咔唑-7-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺Name: N-(2-(7H-Dibenzo[c,g]carbazol-7-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy Base-2,4-dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide
在实施例17中所用的咔唑用等摩尔量的7H-二苯并[c,g]咔唑代替，反应时间延长至15min，其余步骤与实施例17相同，得到结构如上的目标产物N-(2-(7H-二苯并[c,g]咔唑-7-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺，白色固体，产率为55%。The carbazole used in Example 17 was replaced with an equal molar amount of 7H-dibenzo[c,g]carbazole, the reaction time was extended to 15 min, and the remaining steps were the same as in Example 17 to obtain the target product N- with the above structure. (2-(7H-Dibenzo[c,g]carbazol-7-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2, 4-Dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide, white solid, yield 55%.
1HNMR(400MHz,CDCl3)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)。 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).
13CNMR(151MHz,CDCl3)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。 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.
实施例21Example 21
名称：N-(2-(1,4-二甲基-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺Name: N-(2-(1,4-dimethyl-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy Base-2,4-dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide
在实施例17中所用的咔唑用等摩尔量的1,4-二甲基-9H-咔唑代替，反应时间延长至20min，其余步骤与实施例17相同，得到结构如上的目标产物N-(2-(1,4-二甲基-9H-咔唑-9-基)-4-甲氧基-3,5-二甲基苯基)-N-(3-甲氧基-2,4-二甲基-6-((4-甲基苯基)磺酰胺基)苯基)-4-甲基苯磺酰胺，白色固体，产率为78%。The carbazole used in Example 17 was replaced with an equal molar amount of 1,4-dimethyl-9H-carbazole. The reaction time was extended to 20 min. The remaining steps were the same as in Example 17 to obtain the target product N- with the above structure. (2-(1,4-dimethyl-9H-carbazol-9-yl)-4-methoxy-3,5-dimethylphenyl)-N-(3-methoxy-2, 4-Dimethyl-6-((4-methylphenyl)sulfonamido)phenyl)-4-methylbenzenesulfonamide, white solid, yield 78%.
1HNMR(400MHz,CDCl3)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)。 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).
13CNMR(151MHz,CDCl3)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。 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.
申请人声明，本发明通过上述实施例来说明本发明的N-取代咔唑衍生物及其制备以及其应用，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。The applicant declares that the present invention uses the above examples to illustrate the N-substituted carbazole derivatives of the present invention and their preparation and applications. However, the present invention is not limited to the above examples, which does not mean that the present invention must rely on the above implementations. Example can be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of raw materials of the product of the present invention, addition of auxiliary ingredients, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.
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