CN114702453B - 11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法 - Google Patents
11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法 Download PDFInfo
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- -1 11- (trifluoromethyl) -dibenzo [ b, e ] [1,4] diazepine series compound Chemical class 0.000 title claims description 69
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims abstract description 42
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical compound C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 36
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 39
- 239000000758 substrate Substances 0.000 abstract description 28
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 abstract description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 abstract 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 13
- 230000006837 decompression Effects 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 description 4
- 150000002527 isonitriles Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- PCBLLVOSVHORQA-UHFFFAOYSA-N n-phenyl-4-(trifluoromethyl)aniline Chemical compound C1=CC(C(F)(F)F)=CC=C1NC1=CC=CC=C1 PCBLLVOSVHORQA-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical class N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- FFJWPGGBISIFHI-UHFFFAOYSA-N 1-methylnaphthalen-2-amine Chemical compound C1=CC=C2C(C)=C(N)C=CC2=C1 FFJWPGGBISIFHI-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- NZDVQIKGLZNHOC-UHFFFAOYSA-N 5h-benzo[d][1,2]benzodiazepine Chemical compound N1N=CC2=CC=CC=C2C2=CC=CC=C12 NZDVQIKGLZNHOC-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- IJNQJQRKLLCLMC-UHFFFAOYSA-N n-methylnaphthalen-2-amine Chemical compound C1=CC=CC2=CC(NC)=CC=C21 IJNQJQRKLLCLMC-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000004765 promyelocyte Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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Abstract
本发明公开了11‑(三氟甲基)‑二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法,属有机化学技术领域。采用邻芳胺基异氰为反应底物,以Togni’s试剂为三氟甲基化试剂,在四丁基氯化铵和碳酸氢钠的作用下,于1,4‑二氧六环溶剂中,80℃下反应3~4小时,即可高效制备11‑(三氟甲基)‑二苯并[b,e][1,4]二氮杂卓系列化合物。本发明合成的11‑(三氟甲基)‑二苯并[b,e][1,4]二氮杂卓系列化合物具有良好的生物活性和潜在的药物应用价值。本发明的方法操作简便高效,条件温和,区域选择性好,在有机化学技术领域属重要创新,填补了一步法合成三氟甲基化的二苯并二氮杂卓系列化合物方法的空白。
Description
技术领域
本发明属有机化学技术领域,具体涉及11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法。
背景技术
二苯并二氮杂卓类化合物是一类含七元氮杂环的三并环结构化合物,该类化合物具有良好的生物活性,普遍存在于医学药物中((a) Cao, K.; Yan, J.; Yan, F.; Yin,T. Mol. Divers. 2021,25, 1111.(b) Miyanaga, S.; Sakurai, H.; Saiki, I.;Onaka, H.; Igarashi, Y. Bioorg. Med. Chem. Lett. 2010,20, 963.)。例如,氯氮平是用于治疗精神分裂症的非典型抗精神病药物的代表之一((a) Shin, S. Y.; Choi, B.H.; Ko, J.; Kim, S. H.; Kim, Y. S.; Lee, Y. H. Cell. Signal. 2006, 18, 1876.(b) Hamilton, D. Arch. Psychiat. Nurs.1990, 278.);地苯西平可用于治疗抑郁症((a) Zahradnik, I.; Minarovic, I.; Zahradnikova, A. J. Pharmacol. Exp. Ther.2008, 324, 977. (b) Attwood, D.; Gibson, J. J. Pharm. Pharmac. 1978, 30,176.);另外HX531是一种RXR拮抗剂,因为它对类视黄醇诱导人早幼粒细胞HL-6011的细胞分化具有抑制作用(Masayuki, E.; Hiroki, U.; Kiminori, O.; Hiroshi, F.; Emiko,K.;Ghislaine, C.; Hinrich, G.; Motonori, T.; Yuichi, H.; Koichi, S.;Hiroyuki, K. Chem. Pharm. Bull.1999, 47, 1778.)。另一方面,在氟基团中,三氟甲基是农用化学品、药物和材料的重要元素((a) Upadhyay, C.; Chaudhary, M.; DeOliveira, R. N.; Borbas, A.; Kempaiah, P.; Singh, P.; Rathi, B. Expert. Opin. Drug. Dis.2020, 15, 705. (b) Purser, S.; Moore, P. R.; Swallow, S.;Gouverneur, V. Chem. Soc. Rev.2008, 37, 320.)。由于其独特的物理、化学和生理特性,包括良好的代谢稳定性、混溶性和亲脂性,将三氟甲基引入杂环骨架已引起有机合成者的极大关注。
目前,已开发很多策略将 CF3 基团引入杂环化合物((a) Gakh, A. A.;Shermolovich, Y. Curr. Top. Med. Chem.2014, 14, 952. (b) Nagib, D. A.;MacMillan, D. W. Nature. 2011, 480, 224.)。近些年来,化学家们广泛利用邻位官能团化异腈的分子内环化来构建含CF3的五元、六元氮杂环化合物((a) Mao, S.; Wang, H.;Liu, L.; Wang, X.; Zhou, M. D.; Li, L. Adv. Synth. Catal. 2020, 362, 2274.(b) Wang, L.; Studer, A. Org. Lett. 2017, 19, 5701. (c) Leifert, D.;Artiukhin, D. G.; Neugebauer, J.; Galstyan, A.; Strassert, C. A.; Studer, A.Chem. Commun. (Camb).2016, 52, 5997. (d) Tong, K.; Zheng, T.; Zhang, Y.; Yu,S. Adv. Synth. Catal. 2015, 357, 3681. (e) Zhang, B.; Muck-Lichtenfeld, C.;Daniliuc, C. G.; Studer, A. Angew. Chem. Int. Ed. Engl.2013, 52, 10792.)。目前主要集中合成含CF3的吲哚、喹啉、异喹啉和吡啶等化合物,而构建含CF3的二苯并二氮杂卓类七元氮杂环化合物尚未报道。
发明内容
鉴于三氟甲基化的二苯并二氮杂卓类化合物的潜在应用价值,本发明旨在提供一种11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物,并提供无过渡金属催化、基于邻芳胺异氰的串联三氟甲基化和环化的方法来合成所述11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物。
本发明提供的11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物,具有式3所示的结构:
其中,
R1选自氢、C1~C18的烷基、C1~C18的烷氧基、卤素原子;
R2选自氢、C1~C18的烷基、C1~C18的烷氧基、卤素原子、酯基、三氟甲基;
R3选自C1~C18的烷基、C1~C18的烷氧基。
进一步地,所述R1选自氢、甲基、乙基、叔丁基、甲氧基、乙氧基、氟、氯、溴、碘;R2选自氢、甲基、乙基、叔丁基、甲氧基、乙氧基、氟、氯、溴、碘、酯基、三氟甲基;R3选自甲基、乙基、甲氧基、乙氧基。
所述11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物的制备方法,包括以下步骤:
在有机溶剂中,使式1所示的邻芳胺异氰与式2所示的Togni’s试剂在四丁基卤化铵和碱的参与下反应,得到式3所示的11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物;
;
其中,
R1选自氢、C1~C18的烷基、C1~C18的烷氧基、卤素原子;
R2选自氢、C1~C18的烷基、C1~C18的烷氧基、卤素原子、酯基、三氟甲基;
R3选自C1~C18的烷基、C1~C18的烷氧基。
进一步地,所述四丁基卤化铵为四丁基氯化铵、四丁基溴化铵或四丁基碘化铵,其中四丁基氯化铵效果最佳。
进一步地,所述碱为三乙胺、叔丁醇钾、碳酸氢钠或氟化钾,其中碳酸氢钠效果最佳。
进一步地,所述式1所示的邻芳胺异氰、式2所示的Togni’s试剂、四丁基卤化铵和碱的摩尔比可以为1:1.5:0.2:2。
进一步地,所述反应在70~90℃下进行,其中80℃最佳。
进一步地,所述有机溶剂为乙腈、四氢呋喃、乙醇或1,4-二氧六环,其中1,4-二氧六环效果最佳。
进一步地,所述有机溶剂的用量为使所述式1所示的邻芳胺基异氰的浓度为0.1M。
所述11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物具有潜在的生理活性和药理活性,比如抗抑郁剂、抗惊厥、镇静、镇痛、抗肿瘤等方面的活性。通过对癌细胞的毒性研究发现,此类化合物对胃癌细胞SGC7901、肝癌细胞HepG2、宫颈癌细胞HeLa和急性白血病早幼粒细胞白血病细胞HL60等具有一定的抑制作用。因此,所述11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物可以用于制备抗抑郁、抗惊厥、镇静、镇痛、抗肿瘤等的药物。
本发明的有益效果包括:
1)本发明的方法使用四丁基氯化铵无机盐为催化剂,避免了过渡金属催化剂的使用,大大降低了反应成本,同时为后处理带来很大方便;
2)本发明的方法属重要创新,填补目前还未开发一步法合成三氟甲基化二苯并二氮杂卓系列化合物方法的空白;
3)本发明的方法条件温和,操作简便,底物适用性广和反应时间短,并且具有原子经济性优势;
4)本发明合成的11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物具有良好的生物活性和潜在的药物应用价值,有效促进了有机氟化合物化学和杂环化合物化学的发展。
具体实施方式
在本发明中,在无过渡金属催化下,以邻芳胺基异氰为反应底物,Togni’s试剂为三氟甲基源,成功实现了11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物的生成。本发明的原理为:以邻芳胺基异氰为反应底物,Togni’s试剂为三氟甲基化试剂,以四丁基氯化铵为催化剂和碳酸氢钠为碱,在1,4-二氧六环溶剂中,80℃下反应;在该反应体系中,Togni’s试剂产生三氟甲基自由基,随后进行异腈的自由基加成、环化过程,最终构建三氟甲基化二苯并二氮杂卓系列化合物。
在具体实现时,可以包括以下步骤:空气氛围下,以0.9~1.1当量邻芳胺异氰为反应底物,1.35~1.65当量Togni’s试剂为三氟甲基化试剂,加入18~22 mol%四丁基卤化铵和1.8~2.2当量碱于有机溶剂中,80℃下反应3~4小时,即可高效制备11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物,反应过程通过TLC监测,反应结束后减压旋干,经快速柱层析提纯目标产物;反应方程式如下:
其中,R1选自氢、甲基、甲氧基、叔丁基、卤素原子等基团;R2选自氢、甲基、甲氧基、卤素原子、酯基、三氟甲基等基团;R3选自甲基、乙基等基团。
本发明以邻芳胺基异氰为反应底物合成11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物,该反应需要与异氰邻位的芳胺参与反应。所述邻芳胺基异氰为2-异氰基-N-甲基-N-苯基苯胺、2-异氰基-N-(4-甲氧基苯基)-N-甲基苯胺、N-(4-(叔丁基)苯基)-2-异氰基-N-甲基苯胺、N-(4-氟苯基)-2-异氰基-N-甲基苯胺、2-异氰基-N,3-二甲基-N-苯基苯胺、3-氯-2-异氰基-N-甲基-N-苯基苯胺、2-异氰基-4-甲氧基-N-甲基-N-苯基苯胺、2-异氰基-N-甲基-N-苯基-4-(三氟甲基)苯胺、2-异氰基-N,5-二甲基-N-苯基苯胺、5-氯-2-异氰基-N-甲基-N-苯基苯胺、N-(2-异氰苯基)-N-甲基萘-2-胺或N-乙基-2-异氰基-N-苯基苯胺等。
所述四丁基卤化铵为四丁基氯化铵、四丁基溴化铵或四丁基碘化铵,其中四丁基氯化铵效果最佳。
所述碱为三乙胺、叔丁醇钾、碳酸氢钠或氟化钾,其中碳酸氢钠效果最佳。
所述底物原料邻芳胺基异氰、Togni’s试剂、四丁基卤化铵试剂和碱的优选摩尔比为1:1.5:0.2:2。
所述有机溶剂为乙腈、四氢呋喃、乙醇或1,4-二氧六环,其中1,4-二氧六环效果最佳。
所述有机溶剂量为使邻芳胺基异氰的浓度为0.1M。
其具体操作为:空气氛围下,采用0.9~1.1当量邻芳胺基异氰为反应底物,1.35~1.65当量Togni’s试剂为三氟甲基化试剂,加入18~22 mol%四丁基氯化铵和1.8~2.2当量碳酸氢钠,于1,4-二氧六环溶剂中,70~90℃下反应3~4小时即可制备11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物。反应过程通过TLC监测,反应结束后进行减压旋干,经快速柱层析提纯目标产物。
以下结合实施例对本发明进行进一步的说明,旨在解释本发明,不能理解为对本发明的限制。
实施例1:
空气氛围中,向反应试管分别加入2-异氰基-N-甲基-N-苯基苯胺(0.2 mmol, 1.0equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20 mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使2-异氰基-N-甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净的产品5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2a。产率:90%。
1H NMR (400 MHz, CDCl3) δ 7.45 – 7.35 (m, 2H), 7.31 – 7.17 (m, 2H),7.13 – 7.03 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.21(s, 3H).
13C NMR (100 MHz, CDCl3) δ 158.4, 157.5 (q, J C-F = 32.7 Hz), 146.9,140.5, 132.7, 128.8, 128.2, 128.0 (q, J C-F = 2.6 Hz), 124.5, 124.1, 123.7,120.3 (q, J C-F = 277.8 Hz), 118.3, 118.2, 37.0.
19F NMR (376 MHz, CDCl3) δ -67.0 (s, 3F).
实施例2:
空气氛围中,向反应试管分别加入2-异氰基-N-(4-甲氧基苯基)-N-甲基苯胺(0.2mmol, 1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使2-异氰基-N-(4-甲氧基苯基)-N-甲基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品2-甲氧基-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2b。产率:75%。
1H NMR (400 MHz, CDCl3) δ 7.30 – 7.19 (m, 2H), 7.12 – 7.04 (m, 1H),7.02 – 6.88 (m, 4H), 3.75 (s, 3H), 3.19 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 156.7 (q, J C-F = 32.8 Hz), 155.7, 151.3,147.3, 140.4, 128.8, 128.2, 124.8, 124.2, 120.2 (q, J C-F = 277.6 Hz), 118.8,118.4, 117.8, 112.7 (q, J C-F = 2.7 Hz), 55.7, 37.0.
19F NMR (376 MHz, CDCl3) δ -67.0 (s, 3F).
实施例2主要考察了苯环对位连接甲氧基给电子基团底物的适用性。实施例结果表明苯环对位连接甲氧基给电子基团底物同样适用此反应生成2-甲氧基-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例3:
空气氛围中,向反应试管分别加入N-(4-(叔丁基)苯基)-2-异氰基-N-甲基苯胺(0.22 mmol, 1.1 equiv),Togni’s试剂(0.33 mmol, 1.65 equiv),四丁基氯化铵(0.044mmol, 22 mol%)和碳酸氢钠(0.44 mmol, 2.2 equiv),再加入1,4-二氧六环溶液,使N-(4-(叔丁基)苯基)-2-异氰基-N-甲基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品2-(叔丁基)-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2c。产率:54%。
1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.6, 2.1 Hz, 1H), 7.40 (s,1H), 7.29 – 7.17 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.97 – 6.89 (m, 2H), 3.20(s, 3H), 1.26 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 157.8 (q, J C-F = 32.3 Hz), 155.8, 147.1,146.5, 140.5, 129.7, 128.7, 128.2, 124.8 (q, J C-F = 2.8 Hz), 124.3, 123.6,120.3 (q, J C-F = 277.8 Hz), 118.1, 117.6, 36.9, 34.3, 31.2.
19F NMR (376 MHz, CDCl3) δ -66.8 (s, 3F).
实施例3主要考察了苯环对位连接具有空间位阻给电子基团(叔丁基)底物的适用性。实施例结果表明具有空间位阻底物同样也能适用此反应得到2-(叔丁基)-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例4:
空气氛围中,向反应试管分别加入N-(4-氟苯基)-2-异氰基-N-甲基苯胺(0.18mmol, 0.9 equiv),Togni’s试剂(0.27 mmol, 1.35 equiv),四丁基氯化铵(0.036 mmol,18 mol%)和碳酸氢钠(0.36 mmol, 1.8 equiv),再加入1,4-二氧六环溶液,使N-(4-氟苯基)-2-异氰基-N-甲基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品2-氟-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2d。产率:90%。
1H NMR (400 MHz, CDCl3) δ 7.31 – 7.21 (m, 2H), 7.18 – 7.06 (m, 3H),7.02 – 6.92 (m, 2H), 3.21 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 158.8 (d, J C-F = 242.6 Hz), 155.8 (q, J C-F =34.8 Hz), 154.1 (d, J C-F = 2.5 Hz), 146.7, 140.2, 129.1, 128.3, 125.2 (d, J C-F= 7.0 Hz), 124.6, 120.0 (q, J C-F = 277.5 Hz), 119.5 (d, J C-F = 22.6 Hz), 119.3(d, J C-F = 8.2 Hz), 118.2, 114.5 (dq, J C-F = 24.5, 2.8 Hz), 37.2.
19F NMR (376 MHz, CDCl3) δ -67.3 (s, 3F), -118.6 (s, F).
实施例4主要考察了苯环对位连接吸电子基团(氟原子)底物的适用性。实施例结果表明连接氟原子底物能以高收率得到2-氟-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例5:
空气氛围中,向反应试管分别加入2-异氰基-N,3-二甲基-N-苯基苯胺(0.2 mmol,1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20 mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使2-异氰基-N,3-二甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品5,9-二甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2e。产率:52%。
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.40 (m, 2H), 7.15 (t, J = 7.8 Hz,1H), 7.12 – 7.07 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H),6.83 (d, J = 8.1 Hz, 1H), 3.23 (s, 3H), 2.36 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 158.6, 156.1 (q, J C-F = 32.8 Hz), 147.2,138.8, 136.3, 132.5, 128.5, 127.8 (q, J C-F = 2.7 Hz), 126.0, 124.5, 123.6,120.3 (q, J C-F = 277.6 Hz), 118.1, 115.7, 37.2, 18.2.
19F NMR (376 MHz, CDCl3) δ -67.1 (s, 3F).
实施例5主要考察了与异氰邻位为给电子基团(甲基)底物的适用性。实施例结果表明该底物能以中等收率得到5,9-二甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例6:
空气氛围中,向反应试管分别加入3-氯-2-异氰基-N-甲基-N-苯基苯胺(0.2mmol, 1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使3-氯-2-异氰基-N-甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品9-氯-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2f。产率:74%。
1H NMR (400 MHz, CDCl3) δ 7.52 – 7.37 (m, 2H), 7.21 – 7.09 (m, 3H),7.03 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 7.0, 2.5 Hz, 1H), 3.23 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 158.2 (q, J C-F = 33.2 Hz), 158.1, 148.9,137.5, 133.0, 132.0, 128.9, 128.0 (q, J C-F = 2.5 Hz), 125.4, 124.3, 124.1,120.1 (q, J C-F = 277.9 Hz), 118.5, 116.6, 37.2.
19F NMR (376 MHz, CDCl3) δ -67.3 (s, 3F).
实施例6主要考察了与异氰邻位为吸电子基团(氯原子)底物的适用性。实施例结果表明该底物能以良好收率得到9-氯-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例7:
空气氛围中,向反应试管分别加入2-异氰基-4-甲氧基-N-甲基-N-苯基苯胺(0.18mmol, 0.9 equiv),Togni’s试剂(0.27 mmol, 1.35 equiv),四丁基氯化铵(0.036 mmol,18 mol%)和碳酸氢钠(0.36 mmol, 1.8 equiv),再加入1,4-二氧六环溶液,使2-异氰基-4-甲氧基-N-甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品8-甲氧基-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2g。产率:64%。
1H NMR (400 MHz, CDCl3) δ 7.51 – 7.38 (m, 2H), 7.12 – 7.04 (m, 1H),7.01 (d, J = 8.2 Hz, 1H), 6.92 – 7.76 (m, 3H), 3.77 (s, 3H), 3.20 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 159.0, 158.0 (q, J C-F = 32.6 Hz), 156.6,141.2, 139.9, 132.7, 128.0 (q, J C-F = 2.7 Hz), 124.0, 123.5, 120.2 (q, J C-F =277.7 Hz), 118.8, 117.8, 115.3, 111.9, 55.6, 37.0.
19F NMR (376 MHz, CDCl3) δ -67.0 (s, 3F).
实施例7主要考察了与异氰间位为给电子基团(甲氧基)底物的适用性。实施例结果表明该底物同样能适用该反应得到8-甲氧基-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例8:
空气氛围中,向反应试管分别加入2-异氰基-N-甲基-N-苯基-4-(三氟甲基)苯胺(0.2 mmol, 1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04mmol, 20 mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使2-异氰基-N-甲基-N-苯基-4-(三氟甲基)苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品5-甲基-8,11-双(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2h。产率:51%。
1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.52 – 7.40 (m, 3H), 7.14 (t,J = 7.6 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 3.28 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 158.9 (q, J C-F = 33.3 Hz), 157.5, 150.0,140.4, 133.2, 128.1 (q, J C-F = 2.7 Hz), 126.8 (q, J C-F = 33.2 Hz), 125.6 (q,J C-F = 3.8 Hz), 125.5 (q, J C-F = 3.7 Hz), 124.2, 124.0, 123.8 (q, J C-F = 270.1Hz), 120.0 (q, J C-F = 277.6 Hz), 118.6, 37.1.
19F NMR (376 MHz, CDCl3) δ -62.4 (s, 3F), δ -67.3 (s, 3F).
实施例8主要考察了与异氰间位为吸电子基团(三氟甲基)底物的适用性。实施例结果表明该底物也能适用此反应,以中等收率得到5-甲基-8,11-双(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例9:
空气氛围中,向反应试管分别加入2-异氰基-N,5-二甲基-N-苯基苯胺(0.22mmol, 1.1 equiv),Togni’s试剂(0.33 mmol, 1.65 equiv),四丁基氯化铵(0.044 mmol,22 mol%)和碳酸氢钠(0.44 mmol, 2.2 equiv),再加入1,4-二氧六环溶液,使2-异氰基-N,5-二甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品5,7-二甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2i。产率:82%。
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.36 (m, 2H), 7.17 (d, J = 8.0 Hz,1H), 7.13 – 7.05 (m, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H),6.78 (s, 1H), 3.24 (s, 3H), 2.33 (s, 3H).
NMR (100 MHz, CDCl3) δ 158.2, 156.6 (q, J C-F = 32.5 Hz), 146.6,139.2, 138.1, 132.5, 128.1, 127.9 (q, J C-F = 2.7 Hz), 125.2, 124.3, 123.6,120.3 (q, J C-F = 277.6 Hz), 119.0, 118.1, 37.0, 21.2.
19F NMR (376 MHz, CDCl3) δ -66.8 (s, 3F).
实施例9主要考察了与异氰对位为给电子基团(甲基)底物的适用性。实施例结果表明该底物能以高收率得到5,7-二甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例10:
空气氛围中,向反应试管分别加入5-氯-2-异氰基-N-甲基-N-苯基苯胺(0.2mmol, 1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使5-氯-2-异氰基-N-甲基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品7-氯-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2j。产率:76%。
1H NMR (400 MHz, CDCl3) δ 7.51 – 7.38 (m, 2H), 7.19 (d, J = 8.4 Hz,1H), 7.16 – 7.06 (m, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.98 – 6.92 (m, 1H), 3.22(s, 3H).
13C NMR (100 MHz, CDCl3) δ 157.7 (q, J C-F = 33.0 Hz), 157.5, 147.6,139.0, 135.0, 132.9, 129.1, 128.0 (q, J C-F = 2.7 Hz), 124.6, 124.1, 124.0,120.1 (q, J C-F = 277.6 Hz), 118.9, 118.4, 37.1.
19F NMR (376 MHz, CDCl3) δ -67.0 (s, 3F).
实施例10主要考察了与异氰对位为吸电子基团(氯原子)底物的适用性。实施例结果表明此类底物能以良好收率得到7-氯-5-甲基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
实施例11:
空气氛围中,向反应试管分别加入N-(2-异氰苯基)-N-甲基萘-2-胺(0.2 mmol,1.0 equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20 mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使N-(2-异氰苯基)-N-甲基萘-2-胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品7-甲基-13-(三氟甲基)-7H-苯并[b]萘并[2,1-e][1,4]二氮杂卓2k。产率:47%。
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 9.0 Hz, 1H), 7.74 – 7.60 (m,2H), 7.46 – 7.38 (m, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 – 7.14 (m, 2H), 7.12– 6.98 (m, 2H), 6.89 (d, J = 7.9 Hz, 1H), 3.26 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 162.1 (q, J C-F = 33.5 Hz), 160.1, 147.6,142.1, 133.1, 131.5, 130.4, 128.1, 127.9, 127.5, 126.6, 125.3, 124.7, 124.6(q, J C-F = 3.5 Hz), 119.9 (q, J C-F = 278.9 Hz), 118.5, 117.8, 116.8, 36.7.
19F NMR (376 MHz, CDCl3) δ -64.4 (s, 3F)
实施例11主要考察与氮连接的2-萘基在此反应的适用性。实施例结果表明,此类底物同样能反应生成7-甲基-13-(三氟甲基)-7H-苯并[b]萘并[2,1-e][1,4]二氮杂卓化合物。
实施例12:
空气氛围中,向反应试管分别加入N-乙基-2-异氰基-N-苯基苯胺(0.2 mmol, 1.0equiv),Togni’s试剂(0.3 mmol, 1.5 equiv),四丁基氯化铵(0.04 mmol, 20 mol%)和碳酸氢钠(0.4 mmol, 2.0 equiv),再加入1,4-二氧六环溶液,使N-乙基-2-异氰基-N-苯基苯胺浓度为0.1M,在80℃下反应3~4小时,具体反应时间通过TLC监测。反应结束后减压旋干,经快速柱层析提纯后得到纯净产品5-乙基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓2k。产率:76%。
1H NMR (400 MHz, CDCl3) δ 7.46 – 7.38 (m, 2H), 7.31 – 7.26 (m, 1H),7.25 – 7.19 (m, 1H), 7.14 – 7.04 (m, 2H), 7.01 (d, J = 8.5 Hz, 1H), 6.95 (d,J = 8.1 Hz, 1H), 3.72 – 3.59 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 157.2 (q, J C-F = 32.7 Hz), 157.1, 145.7,141.2, 132.6, 128.6, 127.9, 127.8 (q, J C-F = 2.7 Hz), 125.0, 124.4, 123.7,120.3 (q, J C-F = 277.5 Hz), 119.3, 119.2, 42.8, 13.2.
19F NMR (376 MHz, CDCl3) δ -67.1 (s, 3F).
实施例12主要考察与氮连接乙基在此反应的适用性。实施例结果表明,N-乙基底物能以良好收率得到5-乙基-11-(三氟甲基)-5H-二苯并[b,e][1,4]二氮杂卓化合物。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.具有式3所示结构的化合物的制备方法,包括以下步骤:
在有机溶剂中,使式1所示的邻芳胺异氰与式2所示的Togni’s试剂在四丁基卤化铵和碱的参与下反应,得到式3所示的11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物;
其中,
R1选自氢、氟;
R2选自氢、甲基、氯;
R3选自甲基、乙基;
所述反应在70~90℃下进行,所述四丁基卤化铵为四丁基氯化铵,所述碱为碳酸氢钠。
2.根据权利要求1所述的方法,其特征在于:所述式1所示的邻芳胺异氰、式2所示的Togni’s试剂、四丁基卤化铵和碱的摩尔比为1:1.5:0.2:2。
3.根据权利要求1所述的方法,其特征在于:所述有机溶剂为乙腈、四氢呋喃、乙醇或1,4-二氧六环。
4.根据权利要求3所述的方法,其特征在于:所述有机溶剂的用量为使所述式1所示的邻芳胺基异氰的浓度为0.1M。
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