CN118026942B - 11-Iodo-dibenzo [ b, e ] [1,4] diazepine compound, and preparation method and application thereof - Google Patents
11-Iodo-dibenzo [ b, e ] [1,4] diazepine compound, and preparation method and application thereof Download PDFInfo
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- -1 11-Iodo-dibenzo [ b, e ] [1,4] diazepine compound Chemical class 0.000 title abstract description 51
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 23
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 7
- 201000010881 cervical cancer Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 5
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 claims 3
- 210000004765 promyelocyte Anatomy 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 abstract description 8
- 230000026045 iodination Effects 0.000 abstract description 7
- 238000006192 iodination reaction Methods 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000001590 oxidative effect Effects 0.000 abstract description 5
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 201000000980 schizophrenia Diseases 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 150000008533 dibenzodiazepines Chemical class 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000000758 substrate Substances 0.000 description 22
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 19
- 239000011630 iodine Substances 0.000 description 18
- 229910052740 iodine Inorganic materials 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 14
- 239000003480 eluent Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
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- 239000011541 reaction mixture Substances 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N isonitrile group Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 3
- 125000006575 electron-withdrawing group Chemical group 0.000 description 3
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 3
- 229960005017 olanzapine Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 2
- AVNZBHMSMNYZHE-UHFFFAOYSA-N 2-isocyano-N-methyl-N-phenylaniline Chemical compound [N+](#[C-])C1=C(N(C2=CC=CC=C2)C)C=CC=C1 AVNZBHMSMNYZHE-UHFFFAOYSA-N 0.000 description 2
- OJWYYSVOSNWCCE-UHFFFAOYSA-N 2-methoxyethyl hypofluorite Chemical group COCCOF OJWYYSVOSNWCCE-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126650 Compound 3f Drugs 0.000 description 2
- MQHWKMUMIXMQIT-UHFFFAOYSA-N N-ethyl-2-isocyano-N-phenylaniline Chemical compound CCN(C1=CC=CC=C1)C(C=CC=C1)=C1[N+]#[C-] MQHWKMUMIXMQIT-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 239000003693 atypical antipsychotic agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002527 isonitriles Chemical class 0.000 description 2
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 2
- 229960000423 loxapine Drugs 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- NZYPBHIQCHSPJY-UHFFFAOYSA-N 3-chloro-2-isocyano-N-methyl-N-phenylaniline Chemical compound ClC=1C(=C(N(C2=CC=CC=C2)C)C=CC=1)[N+]#[C-] NZYPBHIQCHSPJY-UHFFFAOYSA-N 0.000 description 1
- MOJITDGLROJRQO-UHFFFAOYSA-N 5-chloro-2-isocyano-N-methyl-N-phenylaniline Chemical compound CN(C1=CC=CC=C1)C(C=C(C=C1)Cl)=C1[N+]#[C-] MOJITDGLROJRQO-UHFFFAOYSA-N 0.000 description 1
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 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
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 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
- 229960004170 clozapine Drugs 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000007655 dibenzoazepines Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000005732 thioetherification reaction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a dibenzodiazepine derivative, in particular to an 11-iodine-dibenzo [ b, e ] [1,4] diazepine compound and a preparation method and application thereof. Under the condition of no metal catalysis, I 2 is taken as an iodination reagent in the presence of an oxidant, and the serial iodination cyclization based on o-arylamino aryl isonitrile is developed to synthesize the 11-iodo-dibenzo [ b, e ] [1,4] diazepine compound. The 11-iodo-dibenzo [ b, e ] [1,4] diazepine compound has good application prospect in preparing medicines for treating or preventing cancers, schizophrenia or depression.
Description
Technical Field
The invention relates to a dibenzodiazepine derivative, in particular to an 11-iodine-dibenzo [ b, e ] [1,4] diazepine compound and a preparation method and application thereof.
Background
Dibenzoazepine derivatives are a unique class of azacycles, are commonly found in various drugs and natural products, and have good biological activity and pharmaceutical activity. Olanzapine (Olanzapine) is an atypical neuroleptic, for example, and has antagonistic properties, and loxapine (Loxapine) is also useful in the treatment of schizophrenia. On the other hand, the C-I bond promotes the organic molecule to be further functionalized due to higher reactivity, and organic iodides are often used as organic synthesis intermediates, for example, iodinated hydrocarbon can be subjected to Suzuki coupling reaction, sonogashira reaction and the like, and the pre-functionalization of the C-I bond is rapidly developing.
Since organic iodides can be effective precursors in organic synthesis, strategies have been presented to introduce iodine atoms into nitrogen heterocyclic compounds by iodine cyclization. In recent years, many chemists have used isocyano to react with iodinating agents to build nitrogen heterocycles. The isocyano-group in the isonitrile is one of the effective groups for preparing nitrogen heterocycle, and especially the ortho-functionalized aryl isonitrile reacts with various electrophilic, nucleophilic and free radical reagents to synthesize five-membered and six-membered nitrogen heterocycle. The method for constructing the nitrogen heterocycle by the isonitrile compound and the iodination reagent is significant, but is limited to the synthesis of the iodo-five-membered and six-membered nitrogen heterocycle.
Disclosure of Invention
Based on the above, the invention provides 11-iodo-dibenzo [ b, e ] [1,4] diazepine compounds, and preparation methods and applications thereof, which at least solve one problem in the prior art.
In a first aspect, the present invention provides a compound (11-iodo-dibenzo [ b, e ] [1,4] diazepine compound) represented by formula 3-1 or formula 3-2:
，，
Wherein R 1 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, ester group, halogen atom and other groups;
r 2 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, halogen atom and other groups;
r 3 is selected from C1-C18 alkyl groups and other groups;
r 4 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, halogen atom and other groups.
In some preferred embodiments, R 1 is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, fluorine, chlorine, bromine, and the like;
R 2 is selected from hydrogen, methyl, ethyl, tertiary butyl, methoxy, ethoxy, fluorine atom, chlorine atom, bromine atom and other groups;
r 3 is selected from methyl, ethyl and other groups;
r 4 is selected from hydrogen, methyl, ethyl, tertiary butyl, methoxy, ethoxy, fluorine, chlorine, bromine and other groups.
In some preferred embodiments, the compound represented by formula 3-1 or formula 3-2 is one of the compounds represented by the following structural formulas:
，，，
，，，
，，，
，，，
，。
In a second aspect, the present invention provides a method for preparing the compound represented by formula 3-1 or formula 3-2, comprising the steps of:
Reacting a compound (o-arylamino aryl isonitrile) shown in a formula 1-1 or a formula 1-2 with elemental iodine (I 2) in the presence of an oxidant to obtain a compound shown in a formula 3-1 or a formula 3-2;
，，
Wherein R 1、R2、R3 and R 4 are as defined above.
In the preparation method, possible reaction mechanisms are: iodine generates electrophilic substances under the action of an oxidant, then the isonitrile group of the o-arylamino aryl isonitrile is polarized by the electrophilic substances to generate an intermediate, the intermediate is subjected to intramolecular cyclization to generate a seven-membered ring intermediate, and finally the seven-membered ring intermediate is deprotonated to obtain a final product.
In some preferred embodiments, the compound represented by formula 1-1 or formula 1-2 is selected from the group consisting of 2-isocyano-N-methyl-N-phenylaniline, 2-isocyano-N, 3-dimethyl-N-phenylaniline, 3-chloro-2-isocyano-N-methyl-N-phenylaniline, 2-isocyano-N-methyl-N-phenyl-4- (trifluoromethyl) phenylaniline, 4-bromo-2-isocyano-N-methyl-diphenylamine, 3-isocyano-4- (methyl (phenyl) amino) benzoic acid ethyl ester, 2-isocyano-4-methoxy-N-methyl-N-phenylaniline, 5-chloro-2-isocyano-N-methyl-N-phenylaniline, N- (4- (t-butyl) phenyl) -2-isocyano-N-methylaniline, 2-isocyano-N, 5-dimethyl-N-phenylaniline, N- (2-isocyano-phenyl) -N-methylnaphthalene-2-amine, N-ethyl-2-isocyano-N-phenylaniline, and the like.
In some preferred embodiments, the oxidizing agent is selected from t-butyl peroxide (TBHP), di-t-butyl peroxide (DTBP), azobisisobutyronitrile (AIBN), and the like, with TBHP being most effective.
In some preferred embodiments, the molar ratio of the compound represented by formula 1-1 or formula 1-2, elemental iodine, and oxidizing agent is 2:1:1.
In some preferred embodiments, the reaction is carried out in a solvent that is one or more of benzotrifluoride (PhCF 3), toluene, tetrahydrofuran (THF), 1, 4-dioxane, etc., with PhCF 3 being most effective. The solvent amount is such that the concentration of ortho-arylamino aryl isocyanides is 0.1M.
In some preferred embodiments, the reaction is carried out under an air atmosphere.
In a third aspect, the invention provides an application of the compound shown in the formula 3-1 or the formula 3-2 in preparing a medicament for treating or preventing cancer, schizophrenia or depression.
The compound shown in the formula 3-1 or the formula 3-2 can be found to have an anti-tumor effect by testing the influence of the compound shown in the formula 3-1 or the formula 3-2 on the biological activities of cells such as gastric cancer cells SGC7901, liver cancer cells HepG2, cervical cancer cells Hela and acute leukemia promyelocytic cells HL60 by using a CCK-8 method. Furthermore, the compound represented by the formula 3-1 or the formula 3-2 contains dibenzodiazepine Zhuo Gujia and has the same parent skeleton as the drugs currently used for the treatment of the anti-schizophrenia drug clozapine, the anti-depression drug dibenzazepine, and the atypical neuroleptic olanzapine, and thus the compound represented by the formula 3-1 or the formula 3-2 is likely to have similar biological activities. In addition, the C-I bond in the compound shown in the formula 3-1 or the formula 3-2 has high reactivity, so that not only can the common Suzuki reaction and Sonogashira and other coupling reactions be performed, but also the trifluoromethyl, carbonylation and thioetherification reactions can be generated in high yield.
In some preferred embodiments, the cancer is gastric cancer, liver cancer, cervical cancer or leukemia.
Due to the adoption of the technical scheme, the embodiment of the invention has at least the following beneficial effects:
(1) Under the condition of no metal catalysis, under the condition of existence of an oxidant, I 2 is taken as an iodination reagent, the serial iodination cyclization based on o-arylamino aryl isonitrile is developed, the 11-iodo-dibenzo [ b, e ] [1,4] diazepine compound is efficiently synthesized, and the method has mild condition, high efficiency, good functional group compatibility, strong operability and strong practicability and can effectively realize gram-scale reaction;
(2) In the compound represented by the formula 3-1 or the formula 3-2, the position of R 1 is not limited to the ortho position of the isonitrile group, and may be any position on the benzene ring to which the isonitrile group is attached.
Detailed Description
The following is a clear and complete description of the conception and technical effects produced thereby to fully illustrate the objects, aspects, and effects of the present invention.
Reacting a compound (o-arylamino aryl isonitrile) shown in a formula 1-1 or a formula 1-2 with elemental iodine (I 2) in the presence of an oxidizing agent to obtain a compound shown in a formula 3-1 or a formula 3-2;
，，
，，
Wherein R 1 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, ester group, halogen atom and other groups;
r 2 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, halogen atom and other groups;
r 3 is selected from C1-C18 alkyl groups and other groups;
r 4 is selected from hydrogen, C1-C18 alkyl, C1-C18 alkoxy, halogen atom and other groups.
The reaction does not need metal catalysis conditions, and the serial iodination cyclization based on the o-arylamino aryl isonitrile is developed to efficiently synthesize the iodo-benzo seven-membered nitrogen heterocycle. In the specific operation, 1 equivalent of o-arylamino aryl isocyanide is taken as a reaction substrate, 0.5 equivalent of elemental iodine is taken as an iodination reagent, 1 equivalent of oxidant is added into an organic solvent to react for 5 hours at normal temperature, so that the 11-iodo-dibenzo [ b, e ] [1,4] diazepine compounds can be efficiently synthesized, the reaction process is monitored by TLC, and after the reaction is finished, the target product is purified by vacuum spin drying and flash column chromatography.
Example 1
3a
2-Isocyano-N-methyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were each added to a dry tube containing magnetons under an air atmosphere and 2mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 5-methyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine 3a was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) in 93% yield.
1H NMR (400 MHz, CDCl3) δ 7.45 (d,J= 7.6 Hz, 1H), 7.26 (t,J= 7.6 Hz, 1H), 7.08 (t,J= 8.4 Hz, 2H), 6.97 (q,J= 7.8 Hz, 2H), 6.84 (d,J= 8.0 Hz, 1H), 6.76 (d,J= 8.0 Hz, 1H), 3.16 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.6, 145.9, 141.3, 133.4, 133.19, 133.16, 132.8, 127.6, 127.1, 124.3, 123.3, 118.6, 117.6, 37.2.
Example 2
3b
2-Isocyano-N, 3-dimethyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 5, 9-dimethyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine 3b was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 94% yield.
1H NMR (400 MHz, CDCl3) δ 7.41 (dd,J= 7.8, 1.0 Hz, 1H), 7.26 – 7.19 (m, 1H), 7.00 – 6.92 (m, 2H), 6.80 (d,J= 7.4 Hz, 1H), 6.73 (d,J= 8.1 Hz, 1H), 6.68 (d,J= 8.1 Hz, 1H), 3.11 (s, 3H), 2.23 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.7, 146.2, 140.0, 134.9, 133.4, 132.9, 132.6, 131.0, 127.4, 125.8, 123.2, 117.7, 116.0, 37.4, 18.4.
Example 2 is a major examination of the applicability of a substrate with an electron donating group in the ortho position to the isocyanate, and the results show that the substrate can give 5, 9-dimethyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine compounds in higher yields.
Example 3
3c
9-Chloro-2-isocyano-N-methyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (mill, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 9-chloro-5-methyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine 3c was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 90% yield.
1H NMR (400 MHz, CDCl3) δ 7.51 (dd,J= 7.6, 1.2 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.12 – 6.99 (m, 3H), 6.85 – 6.77 (m, 2H), 3.20 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.1, 147.8, 138.4, 133.9, 133.6, 133.0, 132.9, 130.8, 127.8, 125.1, 123.7, 118.0, 116.9, 37.5.
Example 3 mainly examines the applicability of a substrate with an electron withdrawing group (chlorine atom) in the ortho position to the isocyanate, and the result shows that the substrate can obtain 9-chloro-5-methyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine compound with higher yield.
Example 4
3d
8-Chloro-2-isocyano-N-methyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (mill, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 8-chloro-5-methyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine 3d was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 77% yield.
1H NMR (400 MHz, CDCl3) δ 7.47– 7.40 (m, 1H), 7.29 – 7.22 (m, 1H), 7.06 (d,J= 2.0 Hz, 1H), 7.03 – 6.96 (m, 2H), 6.73 (d,J= 8.4 Hz, 2H), 3.11 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.2, 144.6, 142.0, 134.7, 133.5, 133.2, 133.02, 129.3, 127.3, 126.8, 123.6, 119.4, 117.7, 37.2.
Example 4 mainly examines the applicability of a substrate which is an electron withdrawing group (chlorine atom) with the meta position of isocyanide, and the result shows that the substrate can obtain 8-chloro-5-methyl-11-iodo-5H-dibenzo [ b, e ] [1,4] diazepine compound with a medium yield.
Example 5
3e
8-Methoxy-2-isocyano-N-methyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (mill, 0.1mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 11-iodo-8-methoxy-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine 3e was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 91% yield.
1H NMR (400 MHz, CDCl3) δ 7.54 (dd,J= 7.8, 0.8 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.07 (t,J= 7.6 Hz, 1H), 6.84 (t,J= 7.4 Hz, 2H), 7.79 – 7.72 (m, 2H), 3.76 (s, 3H), 3.21 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 156.4, 155.2, 142.0, 139.0, 134.0, 133.5, 133.1, 132.8, 123.1, 119.0, 117.3, 114.0, 111.2, 55.6, 37.2.
Example 5 is a major examination of the applicability of a substrate with an electron donating group (methoxy) in the meta position to isocyanide, and the result shows that the substrate can obtain the 11-iodo-8-methoxy-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine compound in a higher yield.
Example 6
3f
2-Isocyano-N, 7-dimethyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 11-iodo-5, 7-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine 3f was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 95% yield.
1H NMR (400 MHz, CDCl3) δ 7.49 (d,J= 7.8 Hz, 1H), 7.33– 7.26 (m, 1H), 7.07 – 6.98 (m, 2H), 6.81 (t,J= 8.7 Hz, 2H), 6.70 (s, 1H), 3.19 (s, 3H), 2.26 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.5, 145.7, 139.0, 137.8, 133.4, 133.1, 132.7, 132.3, 127.0, 125.0, 123.3, 119.3, 117.6, 37.2, 21.2.
Example 6 is a major examination of the applicability of a substrate having an electron donating group (methyl) para to isocyanide, and shows that the substrate can give 11-iodo-5, 7-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine compounds in high yields.
Example 7
3g
7-Bromo-2-isocyano-N-methyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product, 7-bromo-11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine, 3g, was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) in 75% yield.
1H NMR (400 MHz, CDCl3) δ 7.51 (d,J= 7.9 Hz, 1H), 7.34 (t,J= 7.8 Hz, 1H), 7.15 (dd,J= 8.4, 1.7 Hz, 1H), 7.07 (t,J= 7.6 Hz, 1H), 7.04 – 6.98 (m, 2H), 6.81 (d,J= 8.2 Hz, 1H), 3.19 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 153.8, 146.9, 140.2, 133.8, 133.4, 133.1, 133.0, 128.3, 127.3, 123.8, 122.0, 121.4, 117.9, 37.3.
Example 7 is a major examination of the applicability of a substrate with an electron withdrawing group (bromine atom) in the para position to isocyanide, and the results show that the substrate can give 7-bromo-11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine compounds in moderate yields.
Example 8
3h
2-Isocyano-N, 6-dimethyl-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 11-iodo-5, 6-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine 3H was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) in 80% yield.
1H NMR (400 MHz, CDCl3) δ 7.59 (dd,J= 7.9, 1.2 Hz, 1H), 7.40 – 7.34 (m, 1H), 7.16 (t,J= 7.6 Hz, 1H), 7.11 – 7.01 (m, 4H), 3.18 (s, 3H), 2.37 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 153.3, 144.7, 142.2, 136.2, 135.7, 134.1, 133.1, 131.7, 130.3, 125.9, 125.1, 125.1, 124.8, 40.1, 19.0.
Example 8 mainly examines the applicability of a substrate in which the 6-position of the benzene ring linked to the isocyano group is an electron donating group (methyl), and the result shows that the substrate can obtain 11-iodo-5, 6-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine compound in good yield.
Example 9
3i
2-Isocyano-N- (4-methoxyphenyl) -N-methylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were each added to a dry tube containing magnetons under an air atmosphere and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 11-iodo-2-methoxy-5-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine 3i was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) in 76% yield.
1H NMR (400 MHz, CDCl3) δ 7.19 – 7.10 (m, 2H), 7.05 – 6.98 (m, 2H), 6.92 – 6.85 (m, 2H), 6.76 (d,J= 8.9 Hz, 1H), 3.76 (s, 3H), 3.17 (s, 3H).
13C NMR (100MHz, CDCl3) δ 155.4, 147.5, 146.3, 141.3, 133.8, 132.4, 127.7, 127.1, 124.1, 118.9, 118.6, 118.2, 117.6, 55.7, 37.2.
Example 9 the applicability of the para position of the benzene ring as an electron donating group (methoxy) substrate was mainly examined and the results showed that this substrate gave 11-iodo-2-methoxy-5-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine compound in moderate yield.
Example 10
3j
2-Isocyano-N- (4-chlorophenyl) -N-methylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere and 2mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5 mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 2-chloro-11-iodo-5-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine 3j was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) in 82% yield.
1H NMR (400 MHz, CDCl3) δ 7.46 (d,J= 2.4 Hz, 1H), 7.25 (dd,J= 8.7, 2.4 Hz, 1H), 7.18 – 7.13 (m, 2H), 7.08 – 7.01 (m, 1H), 6.92 – 6.87 (m, 1H), 6.75 (d,J= 8.7 Hz, 1H), 3.18 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 153.1, 145.5, 141.1, 134.3, 132.8, 132.6, 130.4, 128.6, 127.9, 127.3, 124.6, 119.0, 118.6, 37.3.
Example 10 mainly examines the applicability of benzene ring para to electron donor group (methoxy) substrate, and the result shows that the substrate can obtain 2-chloro-11-iodo-5-dimethyl-5H-dibenzo [ b, e ] [1,4] diazepine compound in good yield.
Example 11
3k
N- (2-isocyanatophenyl) -N-methylnaphthalen-2-amine (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 13-iodo-7-methyl-7H-benzo [ b ] naphtho [2,1-e ] [1,4] diazepine 3k was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) to give 81% yield.
1H NMR (400 MHz, CDCl3) δ 8.36 (d,J= 8.5 Hz, 1H), 7.84 (d,J= 9.0 Hz, 1H), 7.73 (d,J= 8.1 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.42 – 7.35 (m, 1H), 7.21 (dd,J= 7.5, 1.9 Hz, 1H), 7.13 (d,J= 9.0 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.94 (dd,J= 7.7, 1.6 Hz, 1H), 3.35 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 154.1, 146.5, 143.4, 132.5, 131.0, 130.8, 130.0, 127.8, 126.7, 126.5, 126.2, 125.9, 125.7, 125.4, 124.6, 118.8, 116.9, 37.0.
Example 11 is a major examination of the applicability of the reaction of nitrogen-linked 2-naphthyl groups, and the results indicate that such substrates can likewise react to form 13-iodo-7-methyl-7H-benzo [ b ] naphtho [2,1-e ] [1,4] diazepine compounds.
Example 12
3l
N-ethyl-2-isocyano-N-phenylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were separately added to a dry tube containing magnetons under an air atmosphere, and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The expected product 11-iodo-5-ethyl-5H-dibenzo [ b, e ] [1,4] diazepine 3l was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) in 91% yield.
1H NMR (400 MHz, CDCl3) δ 7.51 (d,J= 8.0 Hz, 1H), 7.31 (t,J= 7.8 Hz, 1H), 7.20– 7.11 (m, 2H), 7.07 – 6.99 (m, 2H), 6.89 (d,J= 8.0 Hz, 1H), 6.81 (d,J= 8.0 Hz, 1H), 3.64 (q,J= 6.9 Hz, 2H), 1.22 (t,J= 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 153.4, 144.6, 142.3, 134.1, 132.9, 132.7, 132.7, 127.5, 126.9, 124.3, 123.4, 119.6, 118.8, 43.0, 13.3.
Example 12 is a major examination of the applicability of the reaction herein with nitrogen-linked ethyl groups, and the results show that the N-ethyl substrate gives 11-iodo-5-ethyl-5H-dibenzo [ b, e ] [1,4] diazepine compounds in good yields.
Example 13
3m，3m'
2-Isocyano-N- (3-bromophenyl) -N-methylaniline (0.2 mmol,1.0 equiv), elemental iodine (ground, 0.1 mmol,0.5 equiv) and TBHP (18.1 mg,1.0 equiv) were each added to a dry tube containing magnetons under an air atmosphere and 2 mL PhCF 3 was injected to dissolve the mixture. The reaction mixture was stirred at room temperature for 5 hours. The reaction was checked by TLC. After completion of the reaction, quenched with 5mL saturated Na 2S2O3, extracted with dichloromethane (3×5 mL), the organic layer was dried over anhydrous Na 2SO4 and the solvent was removed by rotary evaporation. The products 3-bromo 11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine 3m and 1-bromo 11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine 3m' were purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) to give yields of 28% and 62%, respectively.
3m1H NMR (400 MHz, CDCl3) δ 7.30 (d,J= 8.4 Hz, 1H), 7.15 – 7.06 (m, 3H), 6.98 (t,J= 7.5 Hz, 1H), 6.90 (s, 1H), 6.83 (d,J= 8.0 Hz, 1H), 3.14 (s, 4H).
13C NMR (100 MHz, CDCl3) δ 155.2, 145.2, 141.2, 134.4, 132.0, 131.5, 127.8, 127.5, 127.2, 126.4, 124.7, 121.1, 118.8, 37.3.
3n'1H NMR (400 MHz, CDCl3) δ 7.25 (d,J= 7.9 Hz, 1H), 7.20 (dd,J= 7.3, 1.8 Hz, 1H), 7.14 – 7.05 (m, 3H), 6.94 (d,J= 7.9 Hz, 1H), 6.90 (d,J= 8.2 Hz, 1H), 3.22 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 159.0, 145.4, 142.7, 131.7, 129.3, 128.9, 127.7, 126.8, 125.8, 124.7, 122.6, 118.6, 115.9, 37.1.
Example 13 is a major examination of the applicability of the nitrogen-linked meta-substituents of the benzene ring in this reaction, and shows that the substrates of the nitrogen-linked meta-substituents of the benzene ring produce two products, 3-bromo 11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine and 1-bromo 11-iodo-5-methyl-5H-dibenzo [ b, e ] [1,4] diazepine, in 28% and 62% yields, respectively.
Example 14
The CCK-8 method is adopted to detect proliferation inhibition effects of the compound 3f prepared in the example 6 and the compound 3m prepared in the example 13 on cells such as gastric cancer cells SGC7901, liver cancer cells HepG2, cervical cancer cells Hela and acute leukemia promyelocytic HL60 respectively, and according to biological activity results obtained by testing, the compound 3f and the compound 3m are found to show obvious biological activity, and refer to Table 1.
TABLE 1 semi-inhibitory concentration of 11-iodo-dibenzo [ b, e ] [1,4] diazepine Compounds on cancer cells
From the data results in table 1, it can be clearly seen that the novel compound obtained by the preparation method provided by the embodiment of the invention has good inhibition effect on cells such as gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell Hela and acute leukemia promyelocytic HL60, and the like, which shows that the 11-iodo-dibenzo [ b, e ] [1,4] diazepine compound has good application prospect in preparing medicines for resisting gastric cancer, liver cancer, cervical cancer and leukemia.
The present invention is not limited to the above embodiments, but is merely preferred embodiments of the present invention, and the present invention should be considered as being within the scope of the present invention as long as the technical effects of the present invention are achieved by the same or equivalent means. Various modifications and variations are possible in the technical solution and/or in the embodiments within the scope of the invention.
Claims (1)
1. The application of a compound shown in the formula 3f in preparing a medicament for treating or preventing cancer, wherein the cancer is gastric cancer, liver cancer, cervical cancer or leukemia; the half-inhibition concentration of the compound shown in the formula 3f on gastric cancer cells SGC7901 is 1.5 mu M/L, the half-inhibition concentration of the compound shown in the formula 3f on liver cancer cells HepG2 is 0.7 mu M/L, the half-inhibition concentration of the compound shown in the formula 3f on cervical cancer cells Hela is 1.8 mu M/L, and the half-inhibition concentration of the compound shown in the formula 3f on acute leukemia promyelocyte HL60 is 1.0 mu M/L;
3f。
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