CN115073495A - Indoline compound and preparation method thereof - Google Patents
Indoline compound and preparation method thereof Download PDFInfo
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- CN115073495A CN115073495A CN202210951115.3A CN202210951115A CN115073495A CN 115073495 A CN115073495 A CN 115073495A CN 202210951115 A CN202210951115 A CN 202210951115A CN 115073495 A CN115073495 A CN 115073495A
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- Prior art keywords
- substituted
- alkyl
- formula
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- aryl
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- -1 Indoline compound Chemical class 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 87
- 150000002476 indolines Chemical class 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 74
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 238000013032 photocatalytic reaction Methods 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 230000001681 protective effect Effects 0.000 claims description 7
- 229910052741 iridium Inorganic materials 0.000 claims description 5
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FMKQPMDFNYNYAG-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine Chemical compound FC1=CC(F)=CC=C1C1=CC=C(C(F)(F)F)C=N1 FMKQPMDFNYNYAG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- WFMNHCSATCWAAQ-UHFFFAOYSA-M potassium;2,2-dimethylpropanoate Chemical compound [K+].CC(C)(C)C([O-])=O WFMNHCSATCWAAQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- JFJNVIPVOCESGZ-UHFFFAOYSA-N 2,3-dipyridin-2-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CN=C1C1=CC=CC=N1 JFJNVIPVOCESGZ-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000011941 photocatalyst Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- VSANUNLQSRKIQA-UHFFFAOYSA-K trichlororuthenium hexahydrate Chemical compound O.O.O.O.O.O.Cl[Ru](Cl)Cl VSANUNLQSRKIQA-UHFFFAOYSA-K 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 238000006555 catalytic reaction Methods 0.000 abstract description 8
- 238000006462 rearrangement reaction Methods 0.000 abstract description 6
- 150000001336 alkenes Chemical class 0.000 abstract description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 3
- 150000004696 coordination complex Chemical class 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 239000000654 additive Substances 0.000 abstract 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 238000001514 detection method Methods 0.000 description 23
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 21
- 239000010409 thin film Substances 0.000 description 21
- 239000007858 starting material Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229940124530 sulfonamide Drugs 0.000 description 7
- 150000003456 sulfonamides Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 2
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 102000007590 Calpain Human genes 0.000 description 2
- 108010032088 Calpain Proteins 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229940068911 chloride hexahydrate Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VOAPTKOANCCNFV-UHFFFAOYSA-N hexahydrate;hydrochloride Chemical compound O.O.O.O.O.O.Cl VOAPTKOANCCNFV-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 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 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
Abstract
The invention provides a preparation method of indoline compounds, which is characterized in that aniline substituted by N-arylsulfonyl-2-beta, gamma-unsaturated olefin is subjected to cyclization rearrangement reaction by a visible light and metal complex catalysis method, so that the indoline compounds are prepared. The indoline compound prepared by the invention has a specific structure, and the preparation method adopts an environment-friendly catalysis method without additives such as transition metal, oxidant and the like, so that the reaction condition is mild, the operation is simple and efficient, and the applicability of the substrate is wide. The invention also provides an indoline compound and application thereof.
Description
Technical Field
The invention belongs to the technical field of nitrogen-containing heterocyclic compounds, and particularly relates to an indoline compound and a preparation method thereof.
Background
With the development of nitrogen radical chemistry, the nitrogen radical cascade is considered to be one of the most powerful tools with potential for constructing a variety of functionalized N-heterocycles. Free radical carboamination of olefins has also proven to be an attractive, straightforward process to obtain a variety of dihydropyrazole and benzothiazine fused structures. Many related compounds with an aromatic ring fused thiazine structure are found to show wide biological activity, for example, the benzazolpidem-I and derivatives thereof have good calpain-I inhibitory activity, the benzazolpidem-II is a novel nuclear factor NF-KB inhibitor, and the brinzolamide-III is also determined to be an effective drug for treating glaucoma.
Currently, the synthesis of pyrrole ring fused thiazine mainly comprises the following methods: in 2004 Chemler developedWith Cu (OAc) 2 Catalytic intramolecular nitrogen radical oxidative cyclization to give the corresponding tetracyclic compound:
in 2007, Chemler used copper as the catalyst and oxidant to give enantioselective pyrrolidine fused benzothiazine compounds:
however, in both methods, copper is used as a catalyst and an oxidant, and the using amount is large; and the reaction time is long, or the reaction temperature is high, so that the substrate limitation is large. Therefore, the development of a more green process route for synthesizing indoline compounds, which solves the above defects in the prior art, has become the focus of wide attention of many leading scholars in the field, and is of great significance.
Disclosure of Invention
In view of the above, the present invention provides an indoline compound and a preparation method thereof, wherein the indoline compound has a specific structure, and the preparation method has the advantages of simple process and high yield.
The invention provides an indoline compound which has a structure shown in a formula I:
in the formula I, R 1 Selected from alkyl or substituted alkyl, H, halogen atom, carbonyl or substituted carbonyl, aryl or substituted aryl;
R 2 selected from H, halogen atoms, alkyl or substituted alkyl, aryl or substituted aryl, carbonyl or substituted carbonyl groups;
R 3 selected from H, alkyl or substituted alkyl, and R 4 Looping;
R 4 selected from H, alkyl or substituted alkyl, and R 3 Looping.
In the present invention, said R 1 Or R 2 The alkyl in (1) is preferably independently selected from alkyl with 1-5 carbon atoms, more preferably independently selected from alkyl with 1-3 carbon atoms, and most preferably independently selected from methyl; the substituted alkyl groups are preferably independently selected from alkoxy or haloalkyl; the alkoxy is preferably independently selected from alkoxy with 1-5 carbon atoms, more preferably independently selected from alkoxy with 1-3 carbon atoms, and most preferably independently selected from methoxy; the halogenated alkyl is preferably independently selected from halogenated alkyl with 1-5 carbon atoms, more preferably independently selected from halogenated alkyl with 1-3 carbon atoms, and more preferably independently selected from halogenated methyl; the halogens in the haloalkyl are preferably independently selected from F; most preferably the haloalkyl is independently selected from-CF 3 。
In the present invention, said R 1 Or R 2 The halogen atom in (A) is preferably independently selected from Br, I, F or Cl.
In the present invention, said R 1 Or R 2 The substituted carbonyl groups in (a) are preferably independently selected from alkoxy substituted carbonyl groups; the number of carbon atoms in the alkoxy substituted carbonyl group is preferably independently 2-5, more preferably independently 2-3; most preferably, the substituted carbonyl groups are independently selected from methoxycarbonyl and ethoxycarbonyl, most preferably independently selected from 4-ethoxycarbonyl.
In the present invention, said R 1 Or R 2 The aryl groups in (a) are preferably independently selected from phenyl; the substituted aryl group is preferably independently selected from the group consisting of halogen substituted aryl, alkyl substituted aryl, substituted alkyl substituted aryl; the halogen in the halogen-substituted aryl is preferably independently selected from fluorine, bromine, iodine or chlorine; the aryl groups of the halogen-substituted aryl groups are preferably independently selected from phenyl; the alkyl in the alkyl-substituted aryl is preferably independently selected from alkyl with 1-5 carbon atoms, more preferably independently selected from alkyl with 1-3 carbon atoms, and most preferably independently selected from methyl; the aryl groups in the alkyl-substituted aryl groups are preferably independently selected from phenyl; said substituted alkylThe substituted alkyl group in the aryl group substituted with a group is preferably independently selected from a halogen-substituted alkyl group or an alkoxy group; the halogen in the halogen-substituted alkyl group is preferably independently selected from F; the number of carbon atoms of the alkyl in the halogen substituted alkyl is preferably independently selected from 1 to 5, more preferably independently selected from 1 to 3, and most preferably independently selected from 1; the number of carbon atoms in the alkoxy group is preferably independently selected from 1 to 5, more preferably independently selected from 1 to 3, and most preferably independently selected from 1; the aryl group of the substituted alkyl-substituted aryl group is preferably independently selected from phenyl.
In the present invention, said R 1 Or R 2 The substituted aryl groups in (1) are preferably independently selected from 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-tolyl, 4-chlorophenyl, 5-chlorophenyl or 5-bromophenyl.
In the present invention, said R 3 Or R 4 The alkyl group in (2) is preferably independently selected from alkyl groups having 1 to 5 carbon atoms, more preferably independently selected from alkyl groups having 1 to 3 carbon atoms, and most preferably independently selected from methyl groups.
In the present invention, said R 3 And R 4 The ring formation is preferably a cycloalkyl group having 4 to 6 carbon atoms, and more preferably a cyclopentyl group or a cyclobutyl group.
In the present invention, the structure of formula I is preferably selected from one of the following structures:
in the present invention, all the terminal groups not given in the above structural formulae are methyl groups.
The invention provides a preparation method of indoline compounds, which comprises the following steps:
carrying out photocatalytic reaction on a compound with a structure shown in a formula VI and alkali in a solvent under the action of a catalyst to obtain a compound with a structure shown in a formula I;
in the formula VI, R 1 、R 2 、R 3 And R 4 Are identical to those of formula I.
In the present invention, the catalyst is preferably selected from the group consisting of tris (2,2 '-bipyridyl) ruthenium bis (hexafluorophosphate) salt, cyclometallated iridium complex, ruthenium terpyridyl chloride hexahydrate, (4,4' -di-tert-butyl-2, 2 '-bipyridyl) bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, [4,4' -di-tert-butyl-2, 2 '-bipyridyl ] bis [3, 5-difluoro-2- (5-trifluoromethyl-2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, bis [2- (2, 5-difluorophenyl) -5-trifluoromethylpyridine ] iridium bis (hexafluorophosphate) salt, bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bipyridyl ] iridium bis (hexafluorophosphate) salt and [2, one or more of 2' -bipyridyl bis [4,4' -di-tert-butyl-2, 2' -bipyridyl ] iridium (III) hexafluorophosphate.
In the present invention, the alkali is preferably one or more selected from potassium phosphate, potassium phosphate tri-crystal water, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium pivalate, potassium carbonate, sodium phosphate and tetramethylguanidine.
In the present invention, the solvent used for the photocatalytic reaction is referred to as a second solvent; the second solvent is preferably one or more selected from benzotrifluoride, acetonitrile, toluene, fluorobenzene, chlorobenzene, dichloromethane, 1, 4-dioxane, acetone and mixed solvents; the mixed solvent includes: trifluorotoluene and tert-butanol; the volume ratio of the trifluorotoluene to the tertiary butanol is preferably (0.8-1.2): 1, more preferably 1: 1.
in the present invention, the molar ratio of the compound of formula VI to the base is preferably 1: (1-2), more preferably 1: (1.3 to 1.7), most preferably 1: 1.5; the molar ratio of the compound of formula VI to the catalyst is preferably 1: (0.01 to 0.05), more preferably 1: (0.02 to 0.04), most preferably 1: 0.03.
In the present invention, the photocatalytic reaction is preferably carried out under a closed and protective atmosphere; the protective atmosphere is preferably selected from nitrogen and/or inert gases; the light during the photocatalytic reaction is preferably selected from blue light and/or green light; the power of the light is preferably 20-25W, more preferably 21-24W, and most preferably 22-23W; the temperature of the photocatalytic reaction is preferably 30-60 ℃, more preferably 40-50 ℃, and most preferably 45 ℃; the time of the photocatalytic reaction is preferably 6 to 15 hours, more preferably 8 to 12 hours, and most preferably 10 hours.
In the invention, research on the technological conditions of the photocatalytic reaction shows that the yield of products prepared by adopting different catalysts, alkalis and solvents is different, and the product is prepared by adopting [ Ir (ppy) 2 (dtbbpy)]PF 6 As a catalyst, K 3 PO 4 As a base, PhMe is used as a solvent to prepare the indoline compound, so that the indoline compound has higher yield.
In the present invention, it is preferable that the photocatalytic reaction further includes:
and (3) decompressing the obtained reaction product, removing the solvent, and carrying out column chromatography purification on the residue to obtain the compound with the structure shown in the formula I.
In the present invention, the preparation method of the compound having the structure of formula VI preferably comprises:
reacting a compound with a structure shown in a formula V, arylsulfonyl chloride, pyridine and dichloromethane to obtain a compound with a structure shown in a formula VI;
in the formula V, R 2 、R 3 And R 4 Are identical to those of formula I.
In the present invention, the arylsulfonyl chloride has a structural formula of:
wherein R is 1 And R in the formula I 1 The selection ranges of (a) and (b) are consistent.
In the present invention, the molar ratio of the compound having the structure of formula V, arylsulfonyl chloride, and pyridine is preferably 1: (1.2-2.5): (3.0 to 5.0), more preferably 1: (1.5-2.0): (3.5 to 4.5), most preferably 1: (1.6-1.8): 4; the concentration of the compound with the structure of the formula V in dichloromethane is preferably 2-4 mol/L, more preferably 2.5-3.5 mol/L, and most preferably 3 mol/L.
In the present invention, the reaction is preferably carried out under conditions of a closed and protective atmosphere; the temperature of the reaction is preferably room temperature.
In the present invention, the reaction preferably further comprises, after completion of the reaction:
and washing, extracting, combining organic layers, washing, drying, filtering, concentrating and carrying out column chromatography on the obtained reaction product to obtain the compound with the structure shown in the formula VI.
In the present invention, the washing is preferably carried out using a hydrochloric acid solution; the mass concentration of the hydrochloric acid solution is preferably 8-12%, and more preferably 10%; the extraction is preferably carried out by adopting ethyl acetate; the combined organic layers are preferably intended to be washed with brine; the drying is preferably carried out by adopting anhydrous sodium sulfate; the column chromatography is preferably Flash column chromatography, and petroleum ether and ethyl acetate are preferably adopted in the column chromatography process; the volume ratio of the petroleum ether to the ethyl acetate is preferably (13-17): 1, more preferably (14 to 16): 1, most preferably 15: 1.
in the present invention, the preparation method of the compound with the structure of formula V preferably comprises:
carrying out rearrangement reaction on the compound with the structure shown in the formula IV and p-toluenesulfonic acid in acetonitrile to obtain a compound with the structure shown in the formula V;
in the formula IV, R 2 、R 3 And R 4 Is identical to that in formula I;
end groups not specified being ═ CH 2 。
In the present invention, the p-toluenesulfonic acid is preferably p-toluenesulfonic acid crystal water; the acetonitrile is preferably an acetonitrile aqueous solution, and the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is preferably (35-45): (3.5-4.5), more preferably (38-42): (3.8-4.2), and most preferably 40: 4.
in the invention, the molar ratio of the compound with the structure IV to the p-toluenesulfonic acid is preferably (1-1.2): (0.1 to 0.3), more preferably 1.1: 0.2; the concentration of the compound with the structure shown in the formula IV in acetonitrile is preferably 2-4 mol/L, and more preferably 3 mol/L. In the present invention, the rearrangement reaction is preferably carried out under a closed and protective atmosphere; the temperature of the rearrangement reaction is preferably 70-90 ℃, more preferably 75-85 ℃, and most preferably 80 ℃; the time for the rearrangement reaction is preferably overnight.
In the present invention, it is preferable that the rearrangement reaction further comprises:
and cooling, washing, extracting, combining organic layers, washing, drying, filtering and spin-drying the obtained reaction product to obtain the compound with the structure shown in the formula V.
In the present invention, the cooling is preferably to room temperature; the washing is preferably washing with water; the extraction is preferably performed by using ethyl acetate; the combined organic layer wash is preferably washed with brine; the drying is preferably carried out by using anhydrous Na 2 SO 4 And (5) drying.
In the present invention, the preparation method of the compound with the structure of formula IV preferably comprises:
carrying out mixed reaction on a compound with a structure shown in a formula II, a compound with a structure shown in a formula III and tetrakis (triphenylphosphine) palladium in a solvent to obtain a compound with a structure shown in a formula IV;
in the formula II, R 2 Is identical to that in formula I;
in the formula III, R 3 And R 4 Is identical to that in formula I;
end groups not specified being ═ CH 2 。
In the present invention, the molar ratio of the compound of formula II to the compound of formula III is preferably 1: (1 to 1.5), more preferably 1: (1.1 to 1.4), most preferably 1: (1.2-1.3).
In the present invention, the molar ratio of the compound having the structure of formula II to tetrakis (triphenylphosphine) palladium is preferably 1: (0.02-0.05), more preferably 1 (0.03-0.04).
In the invention, a solvent adopted in the mixed reaction process is marked as a first solvent; the first solvent is preferably one or more selected from tetrahydrofuran and N, N-dimethylformamide.
In the present invention, the mixing reaction is preferably carried out under a closed and protective atmosphere; the mixing reaction time is preferably 12-24 hours, more preferably 15-20 hours, and most preferably 16-18 hours; the temperature of the mixing reaction is preferably 25-80 ℃, more preferably 30-70 ℃, more preferably 40-60 ℃ and most preferably 50 ℃; the mixing reaction is preferably carried out under stirring.
In the present invention, it is preferable that the mixing reaction further comprises:
and washing, extracting, combining organic layers, washing, drying, filtering, concentrating and purifying the obtained reaction product to obtain the compound with the structure shown in the formula IV.
In the present invention, the washing is preferably performed with a saturated ammonium chloride solution; the extraction is preferably carried out by using ethyl acetate; the combined organic layer is preferably washed with brine; the drying is preferably anhydrous sodium sulfate drying; the purification method is preferably performed by using a lightning chromatography, and the eluent in the lightning chromatography process preferably comprises petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is preferably (55-65): 1, more preferably (58-62): 1, most preferably 60: 1.
in the invention, the synthetic route of the compound with the structure of formula I is as follows:
the present invention provides an inhibitor comprising: the indoline compound according to the technical scheme.
In the present invention, the inhibitor is preferably selected from calpain-I inhibitors and/or NF-KB inhibitors.
The invention provides a medicament for treating glaucoma, which comprises the following components: the indoline compound according to the technical scheme.
The indoline compound provided by the invention has a specific structure, and the product obtained under the catalysis of visible light is thiazine ring fused cyclohexadiene, has enantioselectivity, and can be further oxidized into a benzene ring. The preparation method of the indoline compound provided by the invention has the advantages of high yield, large substrate range, low reaction temperature and short time, and the metal complex only needs a catalytic amount of a few thousandth. The indoline compound prepared by the method adopts visible light catalysis, reduces the use of transition metal catalysis and oxidant-free, and is efficient and environment-friendly; moreover, the conditions are mild, and the target product is easy to obtain.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The compound with the structure shown in the formula 1 is prepared according to the following process route:
the specific process is as follows:
aniline (1.82mL,20mmol), tert-butyl- (2-methylbutyl-3-en-2-yl) carbonate (5.02 g,27mmol) and tetrakis (triphenylphosphine) palladium (462.4mg,2 mol%) were added to a solution of tetrahydrofuran (40mL) and N, N-dimethylformamide (2mL, volume ratio 20: 1), and the reaction was carried out under an inert atmosphere at 60 ℃ with stirring for 20 h;
the resulting reaction product was cooled and washed with saturated ammonium chloride solution (20mL), the aqueous layer was extracted with ethyl acetate (50mL × 2), the combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated; purification by flash chromatography (eluent petroleum ether: ethyl acetate 60:1) gave purified IV1 as a pale yellow solid.
The IV1 obtained above (2.45g,15.2mmol) was dissolved in acetonitrile: adding p-toluenesulfonic acid/crystal water (289.7mg,1.52mmol,0.1equiv) to a water (40mL:4mL) solution, and heating at 80 ℃ overnight under inert protection to perform reaction;
the resulting reaction product was cooled to room temperature, washed with water (40mL), the aqueous layer was extracted with ethyl acetate (20 mL. times.2), and the combined organic layers were washed with brine (30mL), anhydrous Na 2 SO 4 Drying, filtration and spin-drying gave the crude product V1 which was used directly in the next step without further purification.
Adding the obtained V1 to pyridine (5equiv) at room temperature under inert gas, and adding p-toluenesulfonyl chloride (1.5equiv) to react for 6 h;
the resulting reaction product was added to dichloromethane (50mL), washed with 10% hydrochloric acid solution (100mL), the aqueous layer was extracted with ethyl acetate (30mL × 2), the combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated; flash column chromatography (petroleum ether: ethyl acetate: 15:1) afforded VI1 as a white solid.
Compound VI1(0.2mmol,1.0equiv.), [ ir (ppy)2(dtbbpy) ] PF6(3.83mg,0.004 mmol,2 mol%) and tripotassium phosphate (34.7mg,0.16mmol,0.8equiv.) were added to a 10ml oven-dried lenk tube equipped with a magnetic stir bar; sealing, protecting with argon, adding toluene (2.5mL), maintaining the reaction temperature at 45 ℃, and irradiating for 6 hours under a 22W blue LED to perform reaction;
after the reaction is finished, the solvent is removed under reduced pressure, and the residue is purified by column chromatography to obtain a white solid.
The product prepared in the embodiment 1 of the invention is subjected to nuclear magnetic resonance, infrared spectroscopy, high resolution mass spectrometry and melting point detection, and the detection result is as follows:
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝8.4Hz,1H),7.18–7.11(m,2H), 6.94(t,J＝7.4Hz,1H),6.89(t,J＝3.3Hz,1H),5.50(d,J＝1.2Hz,1H),4.26(t,J ＝9.6Hz,1H),3.33(s,1H),3.12(dd,J＝15.5,9.0Hz,1H),3.01–2.86(m,1H), 2.85–2.65(m,2H),1.78(s,3H),1.10(s,3H),0.78(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ142.81,135.65,132.81,130.78,128.54, 127.80,124.83,122.80,117.42,113.41,71.91,46.42,40.55,30.96,30.68,23.00, 22.76,14.28；
FT-IR(thin film,KBr):ν(cm -1 ):2971,2912,1601,1477,1315,1236,1147, 969,919,761,678,622；
HRMS(ESI)[M+Na] + Calculated for C 18 H 21 NO 2 S 338.1185,found 338.1189。
from the above detection results, the target compound of formula 1 is prepared by the method provided in example 1 of the present invention:
(11aR,12aS)-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][1,2]t hiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 134-138 ℃ (detected by a melting point instrument); the yield thereof was found to be 84%.
Example 2
The compound of formula 2 was prepared according to the procedure of example 1 using different starting materials (substituted by a single methyl group at the para position on the phenyl ring side).
The product prepared in example 2 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝8.4Hz,1H),7.18–7.11(m,2H), 6.94(t,J＝7.4Hz,1H),6.89(t,J＝3.3Hz,1H),5.50(d,J＝1.2Hz,1H),4.26(t,J ＝9.6Hz,1H),3.33(s,1H),3.12(dd,J＝15.5,9.0Hz,1H),3.01–2.86(m,1H), 2.85–2.65(m,2H),1.78(s,3H),1.10(s,3H),0.78(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ142.81,135.65,132.81,130.78,128.54, 127.80,124.83,122.80,117.42,113.41,71.91,46.42,40.55,30.96,30.68,23.00, 22.76,14.28；
FT-IR(thin film,KBr):ν(cm -1 ):2971,2912,1601,1477,1315,1236,1147, 969,919,761,678,622；
HRMS(ESI)[M+Na] + Calculated for C 18 H 21 NO 2 S 338.1185,found 338.1189。
from the above detection results, the target compound of formula 2 is prepared by the method provided in example 2 of the present invention:
(11aR,12aS)-2,9,12,12-tetramethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][ 1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 132-135 ℃; the yield thereof was found to be 88%.
Example 3
The compound of formula 3 was prepared according to the procedure of example 1 using different starting materials (substituted by F, a halogen element, on the phenyl ring side).
The product prepared in example 3 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.47(dd,J＝8.6,4.5Hz,1H),6.90–6.79(m, 3H),5.49(s,1H),4.25(t,J＝9.6Hz,1H),3.31(s,1H),3.08(dd,J＝15.8,8.9Hz, 1H),2.98–2.64(m,3H),1.77(s,3.05H),1.08(s,3.10H),0.77(s,3.06H).
13C NMR(151MHz,CDCl 3 )δ159.01(d,J＝240.8Hz),138.78,135.47, 132.87,131.05,130.58,130.53,117.29,114.14,114.05,113.99,112.36,112.20, 77.26,77.05,76.84,72.40,46.40,40.51,30.95,30.65,22.98,22.68,14.29；
FT-IR(thin film,KBr):ν(cm -1 ):2954,2923,2854,1475,1443,1306, 1217,1171,1148,964,913,872,676,629；
HRMS(ESI)[M+H]+Calculated for C 18 H 20 FNO 2 S 334.1272,found 334.1276。
from the above detection results, the target compound of formula 3 is prepared by the method provided in example 3 of the present invention:
(11aR,12aS)-9-fluoro-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[ 5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 127-133 ℃; the yield thereof was found to be 76%.
Example 4
The compound of formula 4 was prepared according to the method of example 1 using different starting materials (substituted by halogen element Cl at para-position on one side of benzene ring).
The product prepared in example 4 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(600MHz,CDCl 3 )δ7.45(d,J＝8.3Hz,1H),7.09(d,J＝8.1Hz, 2.09H),6.87(dd,J＝4.8,2.0Hz,1.08H),5.48(d,J＝1.0Hz,1H),4.25(t,J＝9.5 Hz,1H),3.31(d,J＝1.4Hz,1H),3.08(dd,J＝15.8,9.1Hz,1H),2.96–2.63(m, 4H),1.77(s,3H),1.07(s,3H),0.75(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ141.49,135.43,132.91,131.09,130.56, 127.76,127.68,125.05,117.28,114.14,72.09,46.38,40.65,30.95,30.46,22.97, 22.63,14.21；
FT-IR(thin film,KBr):ν(cm -1 ):2970,2916,2873,1467,1319,1230,1176, 1148,995,961,828,718,679,624；
HRMS(ESI)[M+H] + Calculated for C 18 H 20 ClNO 2 S 350.0976,found 350.0979。
from the above detection results, the target compound of formula 4 is prepared by the method provided in embodiment 4 of the present invention:
(11aR,12aS)-9-chloro-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[ 5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 125-129 ℃; the yield thereof was found to be 74%.
Example 5
The compound of formula 5 was prepared according to the procedure of example 1 using different starting materials (substituted by a halogen element Br at the para position on the phenyl ring side).
The product prepared in example 5 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.52–7.30(m,1H),7.26–7.22(m,2H), 6.91–6.83(m,1H),5.48(d,J＝1.5Hz,1H),4.26(t,J＝9.5Hz,1H),3.44–3.27 (m,1H),3.10(dd,J＝15.8,9.1Hz,1H),2.98–2.58(m,3H),1.77(s,3H),1.08(s, 3H),0.75(s,3H)；
13C NMR(151MHz,CDCl 3 )δ142.00,135.39,132.93,131.13,130.94, 130.62,127.91,117.27,115.16,114.65,71.99,46.36,40.67,30.95,30.41,23.01, 22.64,14.22；
FT-IR(thin film,KBr):ν(cm -1 ):2970,2908,2873,1595,1466,1318,1229, 1176,1147,960,825,733,714,679,621；
HRMS(ESI)[M+H]+Calculated for C 18 H 20 BrNO 2 S 394.0471,found 394.0471。
from the above detection results, the target compound of formula 5 is prepared by the method provided in example 5 of the present invention:
(11aR,12aS)-9-bromo-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[ 5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 135-138 ℃; the yield thereof was found to be 81%.
Example 6
The compound of formula 6 was prepared according to the procedure of example 1 using different starting materials (substituted by halogen element I at the para position on the phenyl ring side).
The product prepared in example 7 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.46–7.40(m,1.98H),7.34–7.28(m, 1.09H),6.93–6.80(m,1.08H),5.55–5.44(m,1H),4.25(t,J＝9.4Hz,1H),3.31 (d,J＝3.7Hz,1H),3.10(dd,J＝15.9,9.1Hz,1H),2.98–2.68(m,3H),1.77(s, 3H),1.07(s,3H),0.74(s,3H)；
13 C NMR(101MHz,CDCl 3 )δ142.82,136.67,135.48,133.72,132.98, 131.32,131.12,117.33,115.25,85.28,71.86,46.40,40.72,30.99,30.29,23.02, 22.67,14.23；
FT-IR(thin film,KBr):ν(cm -1 ):2970,2902,1465,1318,1230,1148,960, 824,712,679,620；
HRMS(ESI)[M+H] + Calculated for C 18 H 20 INO 2 S 442.0332,found 442.0332。
from the above detection results, the target compound of formula 6 is prepared by the method provided in example 6 of the present invention:
(11aR,12aS)-9-iodo-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5, 6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 130-136 ℃; the yield thereof was found to be 72%.
Example 7
The compound of formula 7 was prepared according to the procedure of example 1 using different starting materials (substituted by halogen element Cl at meta position on one side of the benzene ring).
The product prepared in example 7 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(600MHz,CDCl 3 )δ7.42(d,J＝8.1Hz,1H),7.08(t,J＝8.1Hz, 1H),6.91(d,J＝8.1Hz,1H),6.89–6.85(m,1H),5.48(d,J＝1.4Hz,1H),4.29(t, J＝9.5Hz,1H),3.32(d,J＝3.5Hz,1H),3.18(dd,J＝16.1,9.3Hz,1.3H),2.93– 2.69(m,3.42H),1.77(s,3.39H),1.10(s,3.23H),0.77(s,3H)；
13C NMR(151MHz,CDCl 3 )δ143.99,135.43,132.90,131.13,130.74, 129.34,127.07,122.75,117.29,111.50,71.45,46.32,40.69,30.95,30.13,22.99, 22.60,14.16；
FT-IR(thin film,KBr):ν(cm -1 ):2916,2855,1595,1448,1328,1244, 1152,1052,994,785,686,622；
HRMS(ESI)[M+Na]+Calculated for C 18 H 20 ClNO 2 S 372.0795,found 372.0793。
from the above detection results, the target compound of formula 7 is prepared by the method provided in example 7 of the present invention:
(11aR,12aS)-10-chloro-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo [5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 126-129 ℃; the yield thereof was found to be 72%.
Example 8
The compound of formula 8 was prepared according to the procedure of example 1 using different starting materials (substituted by a halogen element Br at the meta position on the phenyl ring side).
The product prepared in example 8 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝7.9Hz,1H),7.14–6.96(m,2H), 6.88(s,1H),5.49(s,1H),4.29(t,J＝9.5Hz,1H),3.33(s,1H),3.15(dd,J＝16.2, 9.3Hz,1H),2.96–2.64(m,3H),1.78(s,3H),1.11(s,3H),0.78(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ143.70,135.42,132.90,131.16,129.51, 129.22,125.61,119.62,117.29,112.02,71.08,46.31,40.69,32.17,30.95,23.00, 22.59,14.17；
FT-IR(thin film,KBr):ν(cm -1 ):2972,2919,2849,1593,1445,1323, 1244,1151,1047,980,767,684,638；
HRMS(ESI)[M+H] + Calculated for C 18 H 20 BrNO 2 S 394.0471,found 394.0473。
from the above detection results, the target compound of formula 8 is prepared by the method provided in embodiment 8 of the present invention:
(11aR,12aS)-10-bromo-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo [5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 140-144 ℃; the yield thereof was found to be 72%.
Example 9
A compound of formula 9 was prepared according to the procedure of example 1 using different starting materials (one side of the benzene ring was substituted with a naphthalene ring).
The product prepared in example 9 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.9Hz,1.02H),7.79(d,J＝8.2 Hz,1.11H),7.70(d,J＝8.9Hz,1H),7.60(d,J＝8.3Hz,1.09H),7.46(t,J＝7.5 Hz,1.09H),7.34(t,J＝7.5Hz,1.14H),6.91(t,J＝3.2Hz,0.98H),5.52(s,1H), 4.44(t,J＝9.9Hz,0.98H),3.47(dd,J＝15.5,9.5Hz,1H),3.35(d,J＝17.3Hz, 1.11H),3.16(dd,J＝15.5,10.3Hz,1.02H),2.91–2.64(m,2.03H),1.78(s,3H), 1.18(s,3.04H),0.81(s,3H)；
13C NMR(101MHz,CDCl 3 )δ132.86,130.68,130.31,130.20,128.82, 128.70,126.75,124.04,122.77,121.69,117.51,114.41,72.40,46.60,40.76,31.01, 29.42,23.04,22.82,14.38；
FT-IR(thin film,KBr):ν(cm -1 ):2965,2924,1601,1460,1316,1232,1157, 1135,973,764,673；
HRMS(ESI)[M+Na]+Calculated for C 22 H 23 NO 2 S 388.1342,found 388.1340。
from the above detection results, the target compound of formula 9 is prepared by the method provided in example 9 of the present invention:
(13aR,14aS)-2,14,14-trimethyl-13,13a,14,14a-tetrahydro-3H-benzo[f]benzo[5 ,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 135-138 ℃; the yield thereof was found to be 55%.
Example 10
A compound having a structure of formula 10 was prepared according to the method of example 1 using different starting materials (the para-position on the benzene ring side was substituted with an acetate group).
The product prepared in example 10 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.88–7.85(m,1H),7.81(d,J＝1.1Hz,1H), 7.55(d,J＝8.5Hz,0.96H),6.93–6.77(m,0.95H),5.49(d,J＝1.5Hz,1H),4.40 –4.35(m,1H),4.32(dd,J＝8.0,6.3Hz,2H),3.35(d,J＝3.7Hz,0.96H),3.18(dd, J＝15.9,9.3Hz,1.03H),3.02–2.68(m,3H),1.88–1.68(s,3H),1.37(t,J＝7.1 Hz,3.33H),1.09(s,3.02H),0.74(s,3H)；
13C NMR(151MHz,CDCl 3 )δ166.27,146.86,135.35,132.97,131.21, 130.36,128.66,126.18,124.83,117.28,112.29,71.96,60.73,46.31,40.97,30.95, 30.21,22.98,22.54,14.34,14.06；
FT-IR(thin film,KBr):ν(cm -1 ):2971,2871,1703,1607,1464,1314,1266, 1175,967,769,680,622；
HRMS(ESI)[M+H]+Calculated for C 21 H 25 NO 4 S 388.1577,found 388.1582。
from the above detection results, the target compound of formula 10 is prepared by the method provided in example 10 of the present invention:
ethyl(11aR,12aS)-2,12,12-trimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][ 1,2]thiazino[2,3-a]indole-9-carboxylate 5,5-dioxide；
the melting point m.p is 139-143 ℃; the yield thereof was found to be 60%.
Example 11
The compound of formula 11 was prepared according to the procedure of example 1 using different starting materials (no substitution on the phenyl ring side).
The product prepared in example 11 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.55(d,J＝8.7Hz,0.96H),7.14(dd,J＝7.2, 5.6Hz,2.18H),6.99–6.92(m,1.05H),6.92–6.87(m,0.94H),5.93–5.85(m, 1H),5.82–5.75(m,1H),4.28(t,1H),3.41–3.30(m,1H),3.13(dd,J＝15.5,9.0 Hz,1H),3.01–2.83(m,3H),1.10(s,3H),0.83(s,3.05H)；
13 C NMR(151MHz,CDCl 3 )δ142.83,142.79,135.65,130.67,128.46, 127.84,125.33,124.83,123.08,122.84,113.42,71.87,45.37,40.32,30.68,26.34, 22.66,14.36；
FT-IR(thin film,KBr):ν(cm -1 ):2961,2920,2851,1634,1600,1478,1314, 1234,1153,1106,967,750,711,638；
HRMS(ESI)[M+Na] + Calculated for C 17 H 19 NO 2 S 324.1029,found 324.1032。
from the above detection results, the target compound of formula 11 is prepared by the method provided in example 11 of the present invention:
(11aR,12aS)-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][1,2]thi azino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 136-141 ℃; the yield thereof was found to be 80%.
Example 12
The compound of formula 12 was prepared according to the procedure of example 1 using different starting materials (substituted on the sulfonamide side with halogen F).
The product prepared in example 13 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.53(d,J＝8.4Hz,1H),7.14(dd,J＝7.2,5.0 Hz,2.05H),6.96(dd,J＝10.9,4.0Hz,1H),6.88–6.75(m,1H),5.43–5.28(m, 1H),4.28(t,J＝9.5Hz,1H),3.66–3.49(m,1H),3.24–2.89(m,4H),1.06(s, 3.07H),0.82(s,3.16H)；
13C NMR(101MHz,CDCl 3 )δ158.90,156.36(d,J＝256.0Hz),142.53, 136.14,136.11,128.54,128.48,128.42,127.97,124.95,123.10,113.42,99.59, 99.41,71.68,47.02,46.94,40.84,30.78,27.03,26.73,22.77,14.28；
FT-IR(thin film,KBr):ν(cm -1 ):2968,2921,1720,1601,1461,1316,1232, 1177,1137,962,761,625；
HRMS(ESI)[M+H]+Calculated for C 17 H 18 FNO 2 S 320.1115,found 320.1116。
from the above detection results, the target compound of formula 12 is prepared by the method provided in example 12 of the present invention:
(11aR,12aS)-2-fluoro-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6 ][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 144-147 ℃; the yield thereof was found to be 82%.
Example 13
The compound of formula 13 was prepared according to the procedure of example 1 using different starting materials (substituted on the sulfonamide side with a halogen element, Br).
The product prepared in example 13 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝8.6Hz,1H),7.17–7.10(m, 2.2H),7.01–6.91(m,1.12H),6.84–6.65(m,1H),6.22–6.12(m,1H),4.27(t,J ＝9.5Hz,1.05H),3.54–3.40(m,1.06H),3.37–3.12(m,3.29H),2.96(dd,J＝15.6,9.8Hz,1H),1.12(s,3.1H),0.84(s,3.12H)；
13 C NMR(101MHz,CDCl 3 )δ142.52,135.17,129.56,128.36,127.99, 124.93,124.90,123.12,120.11,113.44,71.45,48.84,40.86,35.36,30.70,22.75, 14.62；
FT-IR(thin film,KBr):ν(cm -1 ):2964,2919,1675,1600,1460,1318,1231, 1163,964,762,619；
HRMS(ESI)[M+Na] + Calculated for C 17 H 18 BrNO 2 S 402.0134,found 402.0137。
from the above detection results, the target compound of formula 13 is prepared by the method provided in example 13 of the present invention:
(11aR,12aS)-2-bromo-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5, 6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 135-139 ℃; the yield thereof was found to be 85%.
Example 14
A compound of formula 14 was prepared according to the procedure of example 1 using a different starting material (substituted on the sulfonamide side with halogen I) in contrast to example 1.
The product prepared in example 14 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.1Hz,1H),7.19–7.11(m, 2.28H),6.99–6.84(m,1.15H),6.64(dd,J＝5.0,1.9Hz,1.01H),6.45(dd,J＝3.5, 1.8Hz,1H),4.26(t,J＝9.5Hz,1.06H),3.44–3.24(m,3H),3.14(dd,J＝15.6, 9.1Hz,1.16H),2.96(dd,J＝15.6,9.8Hz,1.07H),1.12(s,3H),0.85(s,3H)；
13C NMR(101MHz,CDCl 3 )δ142.54,134.90,133.18,130.09,128.33, 127.99,124.91,123.10,113.44,93.32,71.32,49.44,40.84,39.30,30.67,22.74, 14.68；
FT-IR(thin film,KBr):ν(cm -1 ):2968,2919,1667,1600,1460,1317,1231, 1163,964,761,713,619；
HRMS(ESI)[M+Na]+Calculated for C 17 H 18 INO 2 S 449.9995,found 449.9998。
from the above detection results, the target compound of formula 14 is prepared by the method provided in example 14 of the present invention:
(11aR,12aS)-2-iodo-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][ 1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 130-135 ℃; the yield thereof was found to be 77%.
Example 15
The compound of formula 15 was prepared according to the procedure of example 1 using different starting materials (substituted on the sulfonamide side with trifluoromethyl).
The product prepared in example 15 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.1Hz,1.09H),7.16(s,2.23H), 7.12–6.79(m,1.29H),6.41(s,1H),4.33(t,J＝9.3Hz,1H),3.52(s,1H),3.29– 2.90(m,4H),1.17(s,3H),0.81(s,3.06H)；
13 C NMR(151MHz,CDCl 3 )δ142.41,135.03,128.44,128.19,127.99, 127.72,127.52,127.32,127.11(dd,J＝62.2,31.2Hz),126.24,126.21,126.17, 126.14(q,J＝5.5Hz),125.64,123.84,122.03,120.23(q,J＝272.2Hz),124.92, 123.16,113.41,71.54,45.71,40.71,30.61,23.72,22.68,14.65；
FT-IR(thin film,KBr):ν(cm -1 ):2972,2917,1656,1600,1478,1460,1395, 1319,1299,1232,1165,1106,969,760,710,622；
HRMS(ESI)[M+H] + Calculated for C 18 H 18 F 3 NO 2 S 370.1073,found 370.1073。
from the above detection results, the target compound of formula 15 is prepared by the method provided in example 15 of the present invention:
(11aR,12aS)-12,12-dimethyl-2-(trifluoromethyl)-11,11a,12,12a-tetrahydro-3 H-benzo[5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 137-139 ℃; the yield thereof was found to be 71%.
Example 16
The compound of formula 16 was prepared according to the procedure of example 1 using different starting materials (substituted with methoxy on the sulfonamide side).
The product prepared in example 16 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.77–7.68(m,1.99H),7.46–7.38(m, 0.99H),7.22–7.15(m,1.02H),7.14–7.05(m,4.08H),6.70(s,0.95H),5.05– 4.89(m,1H),2.99(d,J＝7.0Hz,2.09H),1.73(d,J＝1.2Hz,3.09H),1.70(s,3H)；
13C NMR(101MHz,CDCl 3 )δ153.83,142.77,135.98,129.79,128.62, 127.88,124.88,122.89,113.43,89.77,71.89,54.36,46.81,41.14,30.85,28.80, 23.00,13.98；
FT-IR(thin film,KBr):ν(cm -1 ):2970,2902,1719,1682,1477,1318,1219, 1152,965,754,625；
HRMS(ESI)[M+Na]+Calculated for C 18 H 21 NO 2 S 354.1134,found 354.1127。
from the above detection results, the target compound of formula 16 is prepared by the method provided in example 16 of the present invention:
(11aR,12aS)-2-methoxy-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[ 5,6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 141-146 ℃; the yield thereof was found to be 75%.
Example 17
A compound of formula 17 was prepared according to the procedure of example 1 using different starting materials (substituted on the sulfonamide side with an acetate group).
The product prepared in example 17 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 ) δ 7.58-7.50 (m,1H), 7.18-7.12 (m,2.02H), 7.02-6.98 (m,0.94H), 6.98-6.92 (m,1.49H),4.33(t, J ═ 9.5Hz,1H),3.80(s, 3H), 3.58-3.50 (m,1H), 3.20-3.11 (m,3.02H),2.96(dd, J ═ 15.6,9.9Hz, 1.05H),1.20(s,3H),0.81(s, 3H); impurities: 1 H NMR(400MHz,CDCl 3 )δ8.19(d,J ＝7.6Hz,0.98H),8.08(dd,J＝8.3,1.6Hz,1.08H),8.01(d,J＝8.3Hz,1H),7.63 (d,J＝7.9Hz,0.95H),7.23(d,J＝8.0Hz,1.42H),7.09–7.04(m,1.68H),4.70(t, J＝9.8Hz,1H),4.04–3.93(m,3.32H),3.39(dd,J＝15.8,9.8Hz,1.15H),3.27– 3.20(m,1H),1.52(s,3.09H),1.32(s,3.33H)；
the mixture is as follows: 13 C NMR(151MHz,CDCl 3 )δ166.07,165.55,145.05,142.53, 141.42,140.36,134.43,134.15,133.83,130.26,128.80,128.77,128.36,128.32, 128.21,127.96,125.16,124.87,124.33,124.03,123.05,114.46,113.44,71.68, 68.15,52.70,52.11,46.80,40.77,39.78,30.90,30.63,29.68,25.92,24.66,24.19, 22.79,14.93；
FT-IR(thin film,KBr):ν(cm -1 ):2919,2850,1717,1460,1317,1263,1164, 966,754,655；
HRMS(ESI)[M+H] + Calculated for C 19 H 21 NO 4 S 360.1264,found 360.1269。
from the above detection results, the target compound of formula 17 is prepared by the method provided in example 17 of the present invention:
methyl(11aR,12aS)-12,12-dimethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6][ 1,2]thiazino[2,3-a]indole-2-carboxylate 5,5-dioxide；
the melting point m.p is 135-139 ℃; the yield thereof was found to be 70%.
Example 18
The compound of formula 18 was prepared according to the procedure of example 1 using different starting materials (substituted on the sulfonamide side with phenyl).
The product prepared in example 18 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.3Hz,1H),7.45–7.30(m, 5.17H),7.20–7.12(m,2.15H),7.07–7.02(m,1H),6.99–6.90(m,1H),6.16(d, J＝2.0Hz,1H),4.35(t,J＝9.5Hz,1H),3.56(dd,J＝11.3,7.3Hz,0.95H),3.44– 3.22(m,2.01H),3.16(dd,J＝15.6,9.1Hz,1.04H),2.98(dd,J＝15.6,10.1Hz, 1.11H),1.20(s,3H),0.86(s,3H)；
13C NMR(101MHz,CDCl 3 )δ142.79,139.99,135.62,135.34,130.67, 128.62,128.49,128.01,127.94,125.32,124.90,122.95,120.06,113.50,71.94, 46.92,41.08,30.74,28.69,22.94,14.64；
FT-IR(thin film,KBr):ν(cm -1 ):2957,2918,2872,1467,1318,1230,1176, 1148,961,828,718,679,624；
HRMS(ESI)[M+H]+Calculated for C 23 H 23 NO 2 S 378.1522,found 378.1523。
from the above detection results, the target compound of formula 18 is prepared by the method provided in example 18 of the present invention:
(11aR,12aS)-12,12-dimethyl-2-phenyl-11,11a,12,12a-tetrahydro-3H-benzo[5, 6][1,2]thiazino[2,3-a]indole 5,5-dioxide；
the melting point m.p is 132-135 ℃; the yield thereof was found to be 65%.
Example 19
A compound of formula 19 was prepared according to the procedure of example 1 using different starting materials (olefin ends substituted with a four-membered ring).
The product prepared in example 19 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(600MHz,CDCl 3 )δ7.54–7.49(m,1H),7.18(d,J＝7.3Hz, 1.05H),7.16–7.09(m,1.26H),6.98–6.92(m,1.05H),6.88(t,J＝3.0Hz,1H), 5.79(d,J＝1.3Hz,1.11H),4.32(t,J＝9.5Hz,1.09H),3.39(s,1.07H),3.31(d,J ＝9.4Hz,2.04H),2.91(dd,J＝23.4,7.0Hz,1.16H),2.86–2.73(m,1.23H),2.17 –2.08(m,1.19H),2.00–1.87(m,2.12H),1.84(s,3H),1.82–1.63(m,3.4H)；
13 C NMR(151MHz,CDCl 3 )δ142.83,135.15,133.27,130.95,128.61, 127.87,124.82,122.87,117.77,113.45,69.76,46.60,43.83,31.59,31.08,24.38, 23.14,19.96,14.27；
FT-IR(thin film,KBr):ν(cm -1 ):2960,2852,1635,1474,1311,1228,1151, 993,750,669；
HRMS(ESI)[M+H] + Calculated for C 19 H 21 NO 2 S 328.1366,found 328.1366。
from the above detection results, the target compound of formula 19 is prepared by the method provided in example 19 of the present invention:
(11aR,12aS)-2-methyl-3,11,11a,12a-tetrahydrospiro[benzo[5,6][1,2]thiazino[ 2,3-a]indole-12,1'-cyclobutane]5,5-dioxide；
the melting point m.p is 133-138 ℃; the yield thereof was found to be 56%.
Example 20
A compound of formula 20 was prepared according to the procedure of example 1 using a different starting material (olefin end substituted with five-membered ring).
The product prepared in example 20 of the present invention was tested according to the method of example 1, and the test results were:
1H NMR(400MHz,CDCl 3 )δ7.55(d,J＝8.2Hz,1H),7.14(t,J＝7.0Hz, 2H),6.94(t,J＝7.4Hz,1H),6.88(s,1H),5.49(s,1H),4.48(t,J＝9.8Hz,1H), 3.53(s,1H),3.17(dd,J＝15.3,8.6Hz,1H),3.04–2.67(m,3H),1.97–1.83(m, 1H),1.81(s,3H),1.75–1.39(m,7H)；
13C NMR(101MHz,CDCl 3 )δ142.95,136.33,132.83,130.83,128.53, 127.91,124.77,122.91,118.49,113.64,77.35,77.04,76.72,71.88,52.20,46.18, 34.53,31.86,31.12,28.10,27.46,26.59,23.07；
FT-IR(thin film,KBr):ν(cm -1 ):2956,2863,1601,1478,1317,1235,1153, 1001,963,752,677,639；
HRMS(ESI)[M+Na]+Calculated for C 20 H 23 NO 2 S 364.1342,found 364.1333。
from the above detection results, the target compound of formula 20 is prepared by the method provided in example 20 of the present invention:
(11aR,12aS)-2-methyl-3,11,11a,12a-tetrahydrospiro[benzo[5,6][1,2]thiazino[ 2,3-a]indole-12,1'-cyclopentane]5,5-dioxide；
the melting point m.p is 130-134 ℃; the yield thereof was found to be 60%.
Example 21
A compound of formula 21 was prepared according to the procedure of example 1 using different starting materials (mono-methyl substitution on the olefin chain).
The product prepared in example 21 of the present invention was tested according to the method of example 1, and the test results were:
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.1Hz,1.02H),7.16–7.05(m, 2.06H),6.97–6.89(m,1H),6.83(t,J＝2.9Hz,1H),5.49(d,J＝1.5Hz,1H),3.90 (d,J＝6.2Hz,1.04H),3.36(s,1.01H),3.29–3.19(m,1.07H),2.88–2.62(m, 2.19H),1.76(s,3.16H),1.40(d,J＝6.8Hz,3H),1.12(s,3.08H),0.67(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ141.85,135.67,133.85,132.96,129.47, 127.92,123.81,122.39,117.39,112.43,78.11,46.43,41.85,37.60,30.82,23.04, 22.21,21.93,14.56；
FT-IR(thin film,KBr):ν(cm -1 ):2968,2921,1598,1477,1460,1319,1232, 1150,997,750,688,612；
HRMS(ESI)[M+H] + Calculated for C 19 H 23 NO 2 S 330.1522,found 330.1525。
from the above detection results, the target compound of formula 21 is prepared by the method provided in example 21 of the present invention:
(11aR,12aS)-2,11,12,12-tetramethyl-11,11a,12,12a-tetrahydro-3H-benzo[5,6] [1,2]thiazino[2,3-a]indole 5,5-dioxide
the melting point m.p is 121-126 ℃; the yield thereof was found to be 52%.
The indoline compound provided by the invention has a specific structure, and the product obtained under the catalysis of visible light is thiazine ring fused cyclohexadiene, has an enantioselective product, and can be further oxidized into a benzene ring. The preparation method of the indoline compound provided by the invention has the advantages of high yield, large substrate range, low reaction temperature and short time, and the metal complex only needs a catalytic amount of a few thousandth. The indoline compound prepared by the method adopts visible light catalysis, reduces the use of transition metal catalysis and oxidant-free, and is efficient and environment-friendly; moreover, the conditions are mild, and the target product is easy to obtain.
The indoline compounds provided by the present invention, the preparation method and application thereof are described in detail, the principle and the embodiment of the present invention are illustrated by the specific examples, and the description of the examples is only for the help of understanding the method of the present invention and the core idea thereof, including the best mode, and also for the anyone skilled in the art to practice the present invention, including making and using any device or system, and implementing any method in combination. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.
While the invention has been described and illustrated with reference to specific embodiments thereof, such description and illustration are not intended to limit the invention. It will be clearly understood by those skilled in the art that various changes in form and details may be made therein without departing from the true spirit and scope of the invention as defined by the appended claims, to adapt a particular situation, material, composition of matter, substance, method or process to the objective, spirit and scope of this application. All such modifications are intended to be within the scope of the claims appended hereto. Although the methods disclosed herein have been described with reference to particular operations performed in a particular order, it should be understood that these operations may be combined, sub-divided, or reordered to form equivalent methods without departing from the teachings of the present disclosure. Accordingly, unless specifically indicated herein, the order and grouping of the operations is not a limitation of the present application.
Claims (10)
1. A preparation method of indoline compounds comprises the following steps:
carrying out photocatalytic reaction on a compound with a structure shown in a formula VI and alkali in a solvent under the action of a catalyst to obtain a compound with a structure shown in a formula I;
in the formula VI, the reaction mixture is shown in the specification,
R 1 selected from alkyl or substituted alkyl,H. A halogen atom, a carbonyl or substituted carbonyl, aryl or substituted aryl group;
R 2 selected from H, halogen atoms, alkyl or substituted alkyl, aryl or substituted aryl, carbonyl or substituted carbonyl;
R 3 selected from H, alkyl or substituted alkyl, and R 4 Looping;
R 4 selected from H, alkyl or substituted alkyl, and R 3 Looping.
2. The process of claim 1, wherein the catalyst is selected from the group consisting of tris (2,2 '-bipyridine) ruthenium bis (hexafluorophosphate) salt, cyclometallated iridium complex, terpyridine ruthenium chloride hexahydrate, (4,4' -di-tert-butyl-2, 2 '-bipyridine) bis [ (2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, [4,4' -di-tert-butyl-2, 2 '-bipyridine ] bis [3, 5-difluoro-2- (5-trifluoromethyl-2-pyridyl) phenyl ] iridium (III) hexafluorophosphate, bis [2- (2, 5-difluorophenyl) -5-trifluoromethylpyridine ] iridium bis (hexafluorophosphate) salt, bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bipyridine ] iridium bis (hexafluorophosphate) Acid) salt and one or more of [2,2' -bipyridyl ] bis [4,4' -di-tert-butyl-2, 2' -bipyridyl ] iridium (III) hexafluorophosphate.
3. The method of claim 1, wherein the base is selected from the group consisting of potassium phosphate, potassium phosphate tri-crystal water, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium pivalate, potassium carbonate, sodium phosphate, and tetramethylguanidine.
4. The process according to claim 1, wherein the solvent is selected from one or more of trifluorotoluene, acetonitrile, toluene, fluorobenzene, chlorobenzene, dichloromethane, 1,4 dioxane, acetone and trifluorotoluene/triethylamine.
5. The method of claim 1, wherein the molar ratio of the compound having the structure of formula VI to the base is 1: (1-2.0);
the molar ratio of the compound having the structure of formula VI to the catalyst is 1: (0.01-0.05).
6. The method of claim 1, wherein the photocatalytic reaction is carried out in a protective atmosphere; the protective atmosphere comprises:
nitrogen and/or inert gas.
7. The method according to claim 1, wherein the photocatalyst in the photocatalytic reaction comprises blue light and/or green light;
the temperature of the photocatalytic reaction is 30-60 ℃;
the time of the photocatalytic reaction is 6-15 h.
8. An indoline compound having the structure of formula I:
in the formula I, R 1 Selected from alkyl or substituted alkyl, H, halogen atoms, carbonyl or substituted carbonyl, aryl or substituted aryl;
R 2 selected from H, halogen atoms, alkyl or substituted alkyl, aryl or substituted aryl, carbonyl or substituted carbonyl;
R 3 selected from H, alkyl or substituted alkyl, and R 4 Looping;
R 4 selected from H, alkyl or substituted alkyl, and R 3 Looping.
9. The indoline compound of claim 8, wherein R is 1 Or R 2 The alkyl in (1) is independently selected from alkyl with 1-5 carbon atoms; substituted alkyl is independently selected from alkoxy or haloalkyl;
the R is 1 Or R 2 The aryl groups in (a) are independently selected from phenyl; the substituted aryl is independently selected fromAlkyl substituted aryl, substituted alkyl substituted aryl, halogen substituted aryl;
the substituted alkyl is independently selected from alkoxy or halogen substituted alkyl.
10. The indoline compound of claim 8, wherein R is 1 Or R 2 Wherein the substituted aryl is independently selected from 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-tolyl, 4-chlorophenyl, 5-chlorophenyl, or 5-bromophenyl;
the R is 1 Or R 2 Wherein the substituted carbonyl is independently selected from alkoxy substituted carbonyl;
the number of carbon atoms in the alkoxy-substituted carbonyl group is independently 2-5.
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