CN108409746A - A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure - Google Patents
A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure Download PDFInfo
- Publication number
- CN108409746A CN108409746A CN201810462676.0A CN201810462676A CN108409746A CN 108409746 A CN108409746 A CN 108409746A CN 201810462676 A CN201810462676 A CN 201810462676A CN 108409746 A CN108409746 A CN 108409746A
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- China
- Prior art keywords
- carbon atom
- atom number
- chiral
- group
- indoles
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- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 43
- -1 oxo spiro indole class compound Chemical class 0.000 title claims abstract description 41
- 150000002475 indoles Chemical class 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 78
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 39
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000006467 substitution reaction Methods 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000000758 substrate Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 8
- 238000006352 cycloaddition reaction Methods 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 4
- 238000013459 approach Methods 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 158
- 150000001721 carbon Chemical group 0.000 claims description 145
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 239000002585 base Substances 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 239000002808 molecular sieve Substances 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- GTBXZWADMKOZQJ-UHFFFAOYSA-N 1-phenanthrol Chemical group C1=CC2=CC=CC=C2C2=C1C(O)=CC=C2 GTBXZWADMKOZQJ-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004381 Choline salt Substances 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- OWVIRVJQDVCGQX-VSGBNLITSA-N [(4r,5r)-5-[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-diphenylmethanol Chemical group C=1C=CC=CC=1C(O)([C@H]1[C@@H](OC(O1)(C)C)C(O)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OWVIRVJQDVCGQX-VSGBNLITSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 235000019417 choline salt Nutrition 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- NVDIDFZVSGUPSX-UHFFFAOYSA-N naphthalene phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(O)=O.c1ccc2ccccc2c1 NVDIDFZVSGUPSX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 150000003248 quinolines Chemical class 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 229940086735 succinate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- BZLZKLMROPIZSR-UHFFFAOYSA-N triphenylsilicon Chemical compound C1=CC=CC=C1[Si](C=1C=CC=CC=1)C1=CC=CC=C1 BZLZKLMROPIZSR-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 150000004985 diamines Chemical class 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 150000003384 small molecules Chemical class 0.000 claims 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 19
- 238000000034 method Methods 0.000 abstract description 13
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 abstract description 11
- 238000012360 testing method Methods 0.000 abstract description 5
- 230000001766 physiological effect Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 150000002611 lead compounds 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 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 5
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
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- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- VCYBVWFTGAZHGH-UHFFFAOYSA-N 1-methylindole-2,3-dione Chemical compound C1=CC=C2N(C)C(=O)C(=O)C2=C1 VCYBVWFTGAZHGH-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- KHZOJCQBHJUJFY-UHFFFAOYSA-N 2-[4-(2-methylpyridin-4-yl)phenyl]-n-(4-pyridin-3-ylphenyl)acetamide Chemical compound C1=NC(C)=CC(C=2C=CC(CC(=O)NC=3C=CC(=CC=3)C=3C=NC=CC=3)=CC=2)=C1 KHZOJCQBHJUJFY-UHFFFAOYSA-N 0.000 description 1
- QSLLFYVBWXWUQT-UHFFFAOYSA-N 7-azaindolizine Natural products C1=NC=CN2C=CC=C21 QSLLFYVBWXWUQT-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- HOTPOFSVRBOJQP-OAQYLSRUSA-N O=C([C@]12NCC[n]3c1ccc3)N(Cc1ccccc1)c1c2cccc1 Chemical compound O=C([C@]12NCC[n]3c1ccc3)N(Cc1ccccc1)c1c2cccc1 HOTPOFSVRBOJQP-OAQYLSRUSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 150000002332 glycine derivatives Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical class C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to chemical catalysis field, a kind of chiral oxo spiro indole class compound containing pyrroles or indoles and azacycloalkyl structure and its raceme and preparation method are disclosed.This method withNIsatin after substituted isatin or phenyl ring substitution（1）WithNThe pyrroles of alkylamino substitution or indoles（2）As reaction substrate, using chiral phosphoric acid or its enantiomter or its raceme as catalyst, in solvent and additive environment, directly it is prepared via one step of catalysis [m+1] cycloaddition approach.By [5+1] or [6+1] or the method for [7+1] cycloaddition, and using chiral phosphoric acid asymmetric syntheses is realized as catalyst.Using unmodified isatin only by single step reaction, 3', 4' dihydro 2'H spiral shells [indoline 3,1' pyrrolo-es [1,2 a] pyrazine] 2 ketone compounds are obtained for the first time, which can extend to the cycloaddition process of more macrocyclic ring system.The present invention has carried out active testing to obtained compound, and has obtained the lead compound with fine physiological activity.
Description
Technical field
The invention belongs to chemical catalysis fields, are related to a kind of chiral oxo spiral shell containing pyrroles or indoles and azacycloalkyl structure
Ring Benzazole compounds and its raceme and preparation method.
Background technology
Oxo spiro indole class compound is a kind of important natural products mother nucleus structure [(a) Kitajima, M.；
Nakamura,T.；Kogure,N.；Ogawa,M.；Mitsuno,Y.；Ono,K.；Yano,S.；Aimi,N.；Takayama,
H.J.Nat.Prod.2006,69,715-718.(b)Zhao,Y.；Liu,L.；Sun,W.；Lu,J.；McEachern,D.；Li,
X.；Yu,S.；Bernard,D.；Ochsenbein,P.；Ferey,V.；Carry,J.；Deschamps,J.R.；Sun,D.；
Wang, S.J.Am.Chem.Soc.2013,135,7223-7234.], wherein it is tied by the parent nucleus to such natural products
Structure is modified and improved compound has apparent antitumor activity, and related compound comes into clinicalⅰstage experiment
And it is concerned [(a) Zhao, Y.；Aguilar,A.；Bernard,D.；Wang,S.J.Med.Chem.2015,58,1038-
1052.(b)Aguilar,A.；Lu,J.；Liu,L.；Du,D.；Bernard,D.；McEachern,D.；Przybranowski,
S.；Li,X.；Luo,R.；Wen,B.；Sun,D.；Wang,H.；Wen,J.；Wang,G.；Zhai,Y.；Guo,M.；Yang,D.；
Wang,S.J.Med.Chem.2017,60,2819-2839.].Therefore synthesis of chiral oxo spiro indole class compound and its disappear
The research that body is important in organic synthesis field is revolved, meanwhile, develop and the physiological activity for studying such compound also has to pass
Important role.
The carbon carbon that 3 are obtained by the reaction generally by isatin in advance for the synthetic method of chiral oxo spiro indole compound is double
After key with the carboxylate of particular configuration [(a) Chen, X.-H.；Wei,Q.；Luo,S.-W.；Xiao,H.；Gong,L.-
Z.J.Am.Chem.Soc.2009,131,13819-13825.(b)Awata,A.；Arai,T.Chem.Eur.J.2012,18,
8278-8282.], isocyanates (Meloche, J.L.；Ashfeld,B.L.Angew.Chem.,Int.Ed.2017,56,
The substrate reactions such as 6604-6608.), are corresponded to the product of [3+2] or [4+1] cycloaddition.And carbon-carbon double bond is built at 3-
Reaction includes Knoevenagel condensations (Demchuk, D.V.et al.Mendeleev Commun.2011,21 (4), 224-
225.) and Wittig reacts (Wittig, G；Haag, W.Chem.Ber.1955,88 (11), 1654-1666.) etc., such reaction
There are complicated for operation, separation difficulties etc.；And the ylide reagent of phosphorus is unstable in Wittig reactions, will appear in product separation big
Triphen oxygen phosphorus disturbing reaction product isolation and purification is measured, wastage of material, cost can be caused to increase in entire building-up process, reduced
Combined coefficient.
In addition, for only similar reaction, Gong Liuzhu groups used chiral phosphoric acid as catalyst success in 2009
The method for realizing the oxo spiro indole compound similar to five-ring heterocycles, but the reaction is former with aldehyde using glycine derivative
Position generates imines, then the fixation reaction pattern reacted with carbon-carbon double bond by imine intermediate so that the production that the reaction is synthesized
Object is limited only to five-ring heterocycles, and three component reactions can undoubtedly increase the regulation and control difficulty of reaction, and it is anti-that these all limit this
The application answered.
Chen,X.-H.；Wei,Q.；Luo,S.-W.；Xiao,H.；Gong,L.-Z.J.Am.Chem.Soc.2009,131,
13819-13825.
The isatin and the imines derivative obtained through tert-butyl glycinate that Takayoshi Arai groups build double bond using 3
Object reacts, and using nickel acetate as catalyst, using specific chiral imidazole phenol amine as ligand, has also obtained oxo spiro indole chemical combination
Object.But the reaction is limited to the glycinate structure of substrate, is reacted with the isatin of modified and can only obtain five-ring heterocycles structure, this
The case where aspect stays column group with Gong is similar, and this reaction needs metal catalytic, whole flow process very fine to the selection of ligand
It needs to react under protection of argon gas, whole condition is harsh, is unfavorable for practical application.
Awata,A.；Arai,T.Chem.Eur.J.2012,18,8278-8282.
Brandon L.Ashfeld groups are reacted, in vinegar using the isatin after 3 diazotising with 2- styrene isocyanates
Under sour rhodium catalysis, corresponding oxo spiro indole compound is obtained.But the reaction has the following problems：1) reaction yield is not high,
And by-product is numerous；2) achirality synthesizes；3) rhodium used in is expensive, and anhydrous and oxygen-free is needed to operate.These all make this
The application of reaction is difficult expansion.
Meloche,J.L.；Ashfeld,B.L.Angew.Chem.,Int.Ed.2017,56,6604-6608.
In conclusion only reporting [3+2] or [4 in the document case of synthesizing oxo spiro indole class compound at present
+ 1] use of the synthesis strategy of cycloaddition, CROSS REFERENCE is limited by reaction condition or substrate itself, and fails to obtain good
Good enantioselectivity or there are diastereoisomers, reports a new class of by [5+1] or [6+1] or [7+1] herein
Cycloaddition synthesizes the chiral oxo spiro indole class compound and its raceme of pyrroles or indoles and azacycloalkyl structure.
Invention content
The purpose of the present invention is to provide a kind of chiral oxo spiro indole containing pyrroles or indoles and azacycloalkyl structure
Class compound and its raceme.
Another object of the present invention is to provide a kind of chiral oxos containing pyrroles or indoles and azacycloalkyl structure
The preparation method of spiro indole class compound and its raceme.
Another object of the present invention is to provide a kind of chiral oxos containing pyrroles or indoles and azacycloalkyl structure
The optical isomer of spiro indole class compound and its raceme, pharmaceutical salts or solvate.
Another object of the present invention is to provide the described chiral oxo loop coil containing pyrroles or indoles and azacycloalkyl structure
Benzazole compounds and its raceme, optical isomer, pharmaceutical salts or solvate are being prepared for preventing or treating tumour
Application in drug.
The above-mentioned purpose of the present invention is solved by following technical method：
A kind of novel chiral oxo spiro indole class compound and its racemization containing pyrroles or indoles and azacycloalkyl structure
Body, which is characterized in that have following structure that formula, R/S- (3) are the raceme of the compound, R- (3) is the chiral photo-isomerisation of R configurations
Body, S- (3) are the chiral isomer of S configurations：
Wherein：
Substituent R1Selected from hydrogen, carbon atom number be 1-10 alkyl, carbon atom number be 3-10 cycloalkylmethylene ,-
COR4、-SO2R5, allyl, propargyl, carbon atom number be 6-14 aryl replace methylene, and with one or more
The above-mentioned group of secondary substituent group；The secondary substituent group, R4And R5It is respectively selected from halogen, nitro, hydroxyl, carbon atom number 6-
Alkoxy that alkyl that 14 aryl, carbon atom number are 1-10, carbon atom number are 1-10, trifluoromethyl；
Substituent R2For the substituted group of one or more hydrogen on aromatic rings, the group is selected from fluorine, chlorine, bromine, iodine, three
Methyl fluoride, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitre
The tool that the substituent group with furan structure that aryl that base, carbon atom number are 6-14, carbon atom number are 4-9, carbon atom number are 5-9
There is the substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary
The above-mentioned group of substituent group；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is 1-10's
Alkyl, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
Substituent R3For the substituted group of one or more hydrogen on pyrrole ring, the group is selected from fluorine, chlorine, bromine, iodine, three
Methyl fluoride, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitre
The tool that the substituent group with furan structure that aryl that base, carbon atom number are 6-14, carbon atom number are 4-9, carbon atom number are 5-9
There is the substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary
The above-mentioned group of substituent group；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is 1-10's
Alkyl, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
What the n in compound R/S- (3), R- (3), S- (3) was expressed as the alkylamino that N on pyrroles or indoles replaces contains carbon number
Mesh is 1 or 2 or 3.
A kind of chiral oxo spiro indole class compound and its racemization containing pyrroles or indoles and azacycloalkyl structure
Pyrroles or indoles (2) of the isatin (1) with the substitution of N- alkylaminos after the preparation method of body, N-substituted isatin or phenyl ring substitution
As reaction substrate, using chiral phosphoric acid or its enantiomter or its raceme as catalyst, in solvent and additive ring
It in border, is directly prepared via one step of catalysis [m+1] cycloaddition approach, wherein m is 5 or 6 or 7；
Its reaction equation is as follows：
Wherein：
Substituent R1Selected from hydrogen, carbon atom number be 1-10 alkyl, carbon atom number be 3-10 cycloalkylmethylene ,-
COR4、-SO2R5, allyl, propargyl, carbon atom number be 6-14 aryl replace methylene, and with one or more
The above-mentioned group of secondary substituent group；The secondary substituent group, R4And R5It is respectively selected from halogen, nitro, hydroxyl, carbon atom number 6-
Alkoxy that alkyl that 14 aryl, carbon atom number are 1-10, carbon atom number are 1-10, trifluoromethyl；
Substituent R2For the substituted group of one or more hydrogen on aromatic rings, the group is selected from fluorine, chlorine, bromine, iodine, three
Methyl fluoride, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitre
The tool that the substituent group with furan structure that aryl that base, carbon atom number are 6-14, carbon atom number are 4-9, carbon atom number are 5-9
There is the substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary
The above-mentioned group of substituent group；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is 1-10's
Alkyl, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
Substituent R3For the substituted group of one or more hydrogen on pyrrole ring, the group is selected from fluorine, chlorine, bromine, iodine, three
Methyl fluoride, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitre
The tool that the substituent group with furan structure that aryl that base, carbon atom number are 6-14, carbon atom number are 4-9, carbon atom number are 5-9
There is the substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary
The above-mentioned group of substituent group；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is 1-10's
Alkyl, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
What the n in compound R/S- (3), R- (3), S- (3) was expressed as the alkylamino that N on pyrroles or indoles replaces contains carbon number
Mesh is 1 or 2 or 3.
Preferably, the chiral phosphoric acid or its enantiomter or its raceme are organic molecule phosphoric acid, the hand
Property phosphoric acid is respectively：(I) dinaphthalene skeleton chiral phosphoric acid, (II) octahydro dinaphthalene skeleton chiral phosphoric acid, it is chiral that (III) joins phenanthrol skeleton
Phosphoric acid, (IV) loop coil diphenols chiral phosphoric acid, (V) have the chiral phosphoric acid of class TADDOL skeletons, (VI) binaphthalene amine chiral
The chirality that phosphoric acid, (VII) biphenyl class chiral phosphoric acid, (VIII) N- trifyl phosphamides, and (IX) ehter bond are connected is double
Phosphoric acid, (X) duplex naphthalene phosphoric acid；
Structural formula difference is as follows：
The wherein described substituent R is selected from following group range：Fluorine, chlorine, bromine, iodine, trifluoromethyl, carbon atom number are 6-14's
Aryl, trifyl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, hydroxyl, nitro, acetenyl, carbon atom number
For the alkyl of 1-10, carbon atom number be 3-10 naphthenic base, carbon atom number be 4-10 heterocycle, carbon atom number be 1-10 alkane
Oxygroup, and the above-mentioned group with one or more secondary substituent groups；The secondary substituent group is selected from the alkane of carbon atom number 1-6
The aryl of base or carbon atom number 6-14, carbon atom number are the naphthenic base of 3-10, carbon atom number is 1-10 alkoxy, halogen, three
Methyl fluoride, nitro；
Substituent R ' selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, the alkyl or carbon atom number that carbon atom number is 1-12
The aryl of 6-10, the heterocycle that carbon atom number is 4-10, and the above-mentioned group with one or more secondary substituent groups；It is described
It is the naphthenic base of 3-10, carbon that secondary substituent group, which is selected from the alkyl of carbon atom number 1-6 or the aryl of carbon atom number 6-14, carbon atom number,
Atomicity is alkoxy, halogen, trifluoromethyl, nitro, the hydroxyl of 1-10；
Substituent R " is selected from methyl, trifluoromethyl, azo group, trifyl ,-CH2R6、-CHR6R7Carbon atom number is
The heterocycle that alkynyl that the alkenyl of 2-4, carbon atom number are 2-4, the aryl of carbon atom number 6-10, carbon atom number are 4-10, and
Above-mentioned group with one or more secondary substituent groups；The secondary substituent group is selected from the alkyl or carbon original of carbon atom number 1-6
The aryl of subnumber 6-14, alkoxy, halogen, trifluoromethyl, nitro, the hydroxyl that carbon atom number is 1-10；The R6It is derived from carbon original
The aryl and carbon atom number of subnumber 6-14 is the heterocycle of 4-10；The R7It is derived from amino, methylamino；
Preferably, the chiral oxo spiro indole class compound containing pyrroles or indoles and azacycloalkyl structure and its disappear
The preparation method for revolving body, includes the following steps：
Isatin (1) after the isatin of N- substitutions or phenyl ring substitution and the pyrroles of N- alkylaminos substitution or mixing for indoles (2)
It closes in solution, chiral phosphoric acid or its enantiomter or its raceme and additive is added；0 is reacted under the conditions of 0~50 DEG C
~48 hours, you can generate chiral spiro oxidized indole compounds and its raceme respectively；
The pyrroles's or indoles (2) of the isatin of wherein N- substitutions or isatin (1) and the substitution of N- alkylaminos after phenyl ring substitution
Molar ratio is 1:1~5, catalyst amount be N- substitution isatin or phenyl ring substitution after isatin (1) substance amount 1%~
20%.
Preferably, the additive isOrMolecular sieve, cyclodextrin, inorganic acid, inorganic base or organic amine and its
One or more of derivative.
Preferably, the solvent is dichloromethane, monochloro methane, chloroform, carbon tetrachloride, dichloroethanes, tetrahydrochysene furan
It mutters, ether, ethyl acetate, toluene, benzene, dimethylbenzene, ethylene glycol, polyethylene glycol, glycol dimethyl ether, glycol monoethyl ether, first
Base tertbutyl ether, methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, N, N- dimethylacetamides
The mixture of one or more of amine, or in which one or more and the mixed solutions of water.
A kind of chiral oxo spiro indole class compound and its racemization containing pyrroles or indoles and azacycloalkyl structure
Optical isomer, pharmaceutical salts or the solvate of body.
Preferably, the pharmaceutical salts are the salt with acid-addition salts or with alkali formation；The solvate is hydrate or packet
Containing other recrystallisation solvents.
Preferably, it is described with acid-addition salts include hydrochloride, sulfate, phosphate, hydrobromate, acetate, oxalates,
Sal limonis, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactate and horse
Carry out hydrochlorate；The salt formed with alkali includes lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, diethanolamine salt, choline salt or alkyl phenyl amine
Salt.
A kind of chiral oxo spiro indole class compound and its racemization containing pyrroles or indoles and azacycloalkyl structure
Body, optical isomer, pharmaceutical salts or solvate are being prepared for preventing or treating the application in the drug of tumour.
Compared with prior art, the present invention has the advantages that：
Method provided by the present invention will realize the method for [5+1] or [6+1] or [7+1] cycloaddition and use chiral phosphorus
Acid realizes that asymmetric syntheses obtains 3', 4'- bis- for the first time using unmodified isatin only by single step reaction as catalyst
Hydrogen -2'H- spiral shells [indoline -3,1'- pyrrolo- [1,2-a] pyrazine] -2- ketone compounds, the reaction can extend to bigger
The cycloaddition process of member ring systems.
So far, the relevant report that there are no synthesis the type compound, the invention reside in developed a kind of novel contain
The chiral oxo spiro indole class compound and its raceme and its synthetic method of pyrroles or indoles and azacycloalkyl structure, simultaneously
The biological activity test (being shown in Table 4 activity datas) of anti-tumor aspect has been carried out to such obtained compound, and has been had
The lead compound of fine physiological activity.
Specific implementation mode
The present invention can be explained further and illustrate in conjunction with following specific examples, but specific embodiment is not to the present invention
There is any type of restriction.Test method without specific conditions in lower example embodiment, usually according to this field normal condition
Or the condition suggested according to manufacturer.Any unsubstantiality that those skilled in the art is done on the basis of the present invention
Variation and replacement belong to scope of the present invention.
Embodiment 1：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To the dichloromethane solution of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol)
In (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution
It directly purifies to obtain target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrroles by column chromatography
And [1,2-a] pyrazine] -2- ketone:55.7mg yield：85%, enantiomeric excess value (ee values)：88%, yellow solid, [α]25 D
=-82.13 (c=0.88, CH2Cl2), mp：119-121℃；1H NMR(400MHz,CDCl3)δ7.38–7.30(m,4H),
7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03 (td, J=7.5,1.0Hz, 1H), 6.75 (d, J=
7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=3.6,2.7Hz, 1H), 5.53 (dd, J=3.6,
1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz, 1H), 4.30 (ddd, J=13.0,8.8,
4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)13C NMR(101MHz,CDCl3)δ
177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,124.6,123.3,120.3,
109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated for C21H19N3O[M+H]+:
330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 2：(-) -1- methyl -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
This molecular structure is as follows：
To the dichloromethane solution of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N-methyl-isatin (0.2mmol)
In (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution
It directly purifies to obtain target product (-) -1- methyl -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrroles by column chromatography
And [1,2-a] pyrazine] -2- ketone, yellow solid, 34.3mg, yield：68%, enantiomeric excess value (ee values)：68%, [α]25 D
=-89.52 (c=0.83, CH2Cl2), mp：122.7-125.4℃.[α]25 D=-89.52 (c=0.83, CH2Cl2).1HNMR
(400MHz,CDCl3) δ 7.33 (tt, J=7.7,1.0Hz, 1H), 7.24 (s, 1H), 7.05 (t, J=7.5Hz, 1H), 6.86
(d, J=7.8Hz, 1H), 6.64 (t, J=2.2Hz, 1H), 6.07 (t, J=3.2Hz, 1H), 5.47 (dd, J=3.7,1.6Hz,
1H), 4.20 (dtd, J=11.3,8.0,7.1,4.2Hz, 1H), 4.12 (dt, J=8.5,3.8Hz, 2H), 3.26 (dt, J=
12.7,4.1Hz,1H),3.19(s,3H).13C NMR(101MHz,CDCl3)δ177.4,143.5,133.0,129.4,125.4,
124.6,123.2,120.3,108.2,108.0,104.6,61.2,45.1,39.2,26.3.HRMS(ESI)calculated
for C15H15N3O[M+H]+:254.1288,found:254.1276.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), mobile phase is just
Hexane/isopropyl alcohol=90/10, flow velocity 1.0mL/min, absorbing wavelength λ=254nm, retention time tR(major)=
22.25min retention time tR(minor)=32.80min.
Embodiment 3：(-) -1- isopropyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
This molecular structure is as follows：
To the dichloromethane solution of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- isopropyls isatin (0.2mmol)
In (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution
It directly purifies to obtain target product (-) -1- isopropyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrroles by column chromatography
Cough up simultaneously [1,2-a] pyrazine] -2- ketone, yellow solid, 54.2mg, yield：97%, enantiomeric excess value (ee values)：74%, [α]25 D
=-80.15 (c=0.85, CH2Cl2), mp：144-147℃.[α]25 D=-80.15 (c=0.85, CH2Cl2).1H NMR
(400MHz,CDCl3) δ 7.34-7.29 (m, 1H), 7.27 (s, 1H), 7.05 (d, J=7.8Hz, 2H), 6.69-6.60 (m,
1H), 6.09 (t, J=3.2Hz, 1H), 5.48 (dd, J=3.7,1.7Hz, 1H), 4.58 (p, J=7.0Hz, 1H), 4.21 (td,
J=8.5,4.7Hz, 1H), 4.18-4.08 (m, 2H), 3.30 (dt, J=12.3,4.2Hz, 1H), 1.52 (dd, J=7.0,
1.6Hz,6H).13C NMR(101MHz,CDCl3)δ177.2,142.1,133.8,129.0,125.8,124.8,122.7,
120.1,109.8,108.0,104.2,61.0,45.2,43.8,39.5,19.3,19.2.HRMS(ESI)calculated for
C17H19N3O[M+H]+:282.1601,found:282.1594.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), mobile phase is just
Hexane/isopropyl alcohol=90/10, flow velocity 1.0mL/min, absorbing wavelength λ=254nm, retention time tR(major)=
11.72min retention time tR(minor)=18.66min.
Embodiment 4：(-) -1- benzyls -1', 5', 6', 7'- tetrahydrochysene spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] [1,
4] diaza] -2- ketone synthesis：
This molecular structure is as follows：
To in the dichloromethane solution (2mL) of N- Propylaminos pyrroles (0.24mmol) and N- benzyls isatin (0.2mmol), add
Chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution directly passes through column
Chromatographic purifying obtains (-) -1- benzyls -1', 5', 6', 7'- tetrahydrochysene spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] [1,4] two
Azepine] -2- ketone, yellow oily, yield 69%, enantiomeric excess value (ee values)：23%, [α]25 D=-49.6 (c=0.96,
CH2Cl2),1H NMR(400MHz,CDCl3) δ 7.45 (dd, J=7.4,1.2Hz, 1H), 7.34-7.21 (m, 6H), 7.10 (td,
J=7.6,1.1Hz, 1H), 6.72 (d, J=7.8Hz, 1H), 6.66 (t, J=2.3Hz, 1H), 5.91 (dd, J=3.7,
2.7Hz, 1H), 5.53 (dd, J=3.7,1.9Hz, 1H), 5.12 (ddd, J=13.8,10.6,3.3Hz, 1H), 4.87 (d, J=
4.2Hz, 2H), 4.21-4.11 (m, 1H), 3.91 (ddd, J=13.5,9.3,3.9Hz, 1H), 3.17 (dt, J=13.9,
4.5Hz,1H),2.18–2.06(m,2H).13C NMR(101MHz,CDCl3)δ175.3,142.0,135.7,132.7,131.0,
129.1,128.8,127.5,127.0,125.0,124.9,122.9,110.8,109.3,105.6,64.3,49.9,43.7,
43.4,31.8,29.7.HRMS(ESI)calculated forC22H21N3O[M+H]+:344.1757,found:344.1747.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), mobile phase is just
Hexane/isopropyl alcohol=90/10, flow velocity 1.0mL/min, absorbing wavelength λ=254nm, retention time tR(major)=
15.67min retention time tR(minor)=18.00min.
Embodiment 5：(-) -1- benzyls -5- fluoro- 3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a]
Pyrazine] -2- ketone synthesis：
This molecular structure is as follows：
To the dichloromethane of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyl -5- fluoro indigo reds (0.2mmol)
In solution (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Instead
Liquid is answered directly to purify to obtain target product (-) -1- benzyls -5- fluoro- 3', 4'- dihydro -2'H- spiral shell [indoline-by column chromatography
3,1'- pyrrolo-es [1,2-a] pyrazine] -2- ketone synthesis, yellow oily liquid, 55mg, yield：79%, enantiomeric excess value
(ee values)：61%, [α]25 D=-64.8 (c=0.96, CH2Cl2)。[α]25 D=-80.15 (c=0.85, CH2Cl2).1H NMR
(400MHz,CDCl3) δ 7.40-7.29 (m, 5H), 7.05 (dd, J=7.7,2.6Hz, 1H), 6.91 (td, J=8.8,2.7Hz,
1H), 6.70 (dd, J=2.7,1.7Hz, 1H), 6.67 (dd, J=8.6,4.1Hz, 1H), 6.14 (dd, J=3.6,2.7Hz,
1H), 5.55 (dd, J=3.6,1.6Hz, 1H), 5.03 (d, J=15.7Hz, 1H), 4.75 (d, J=15.7Hz, 1H), 4.26
(ddd, J=12.8,8.6,4.5Hz, 1H), 4.21-4.13 (m, 2H), 3.31 (dt, J=12.7,4.2Hz, 1H)13C NMR
(101MHz,CDCl3)δ160.7,158.3,138.4,138.4,135.5,134.8,134.8,128.9,127.8,127.2,
124.9,120.5,115.7,115.5,112.9,112.7,109.9,109.9,108.2,104.7,61.6,61.5,45.1,
43.8,39.5.19F NMR(377MHz,CDCl3)δ-119.5.HRMS(ESI)calculated for C21H18FN3O[M+H]+:
348.1507,found:348.1506.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), mobile phase is just
Hexane/isopropyl alcohol=88/12, flow velocity 1.0mL/min, absorbing wavelength λ=254nm, retention time tR(major)=
16.24min retention time tR(minor)=19.73min.
Embodiment 6：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shells [indoline -3,1'- piperazines simultaneously [1,2-a] Yin
Diindyl] -2- ketone synthesis：
The structural formula of this is as follows：
To the dichloromethane solution of N- (1H- indoles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol)
In (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution
It directly purifies to obtain target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- piperazines by column chromatography
And [1,2-a] indoles] -2- ketone:55.1mg yield：73%, enantiomeric excess value (ee values)：80%, yellow oily liquid, [α
]25 D=-90.05 (c=0.82, CH2Cl2)；1H NMR(400MHz,CDCl3) δ 7.52 (d, J=7.8Hz, 1H), 7.44-7.35
(m, 5H), 7.35-7.24 (m, 4H), 7.17-7.11 (m, 1H), 7.09-7.03 (m, 1H), 6.83 (d, J=7.7Hz, 1H),
5.92 (s, 1H), 5.07 (d, J=15.6Hz, 1H), 4.81 (d, J=15.6Hz, 1H), 4.47 (ddd, J=13.3,9.5,
4.3Hz, 1H), 4.39 (dt, J=11.4,3.9Hz, 1H), 4.25-4.12 (m, 1H), 3.46 (ddd, J=12.9,4.6,
3.5Hz,1H).13C NMR(101MHz,CDCl3)δ176.9,142.7,136.7,135.7,133.2,132.7,129.6,
128.9,127.7,127.3,124.9,123.4,121.5,120.6,120.2,109.4,109.1,98.3,61.5,43.7,
42.2,38.8.HRMS(ESI)calculated for C25H21N3O[M+H]+:380.1757,found:380.1745.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=87/13,1.0mL/min, λ=254nm, tR(major)=22.65min, tR(minor)=30.59min.
Embodiment 7：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To in the ether (2mL) of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol), add
Chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution directly passes through column
Chromatographic purifying obtains target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a]
Pyrazine] -2- ketone:45.9mg yield：70%, enantiomeric excess value (ee values)：78%, yellow solid；1HNMR(400MHz,
CDCl3) δ 7.38-7.30 (m, 4H), 7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03 (td, J=
7.5,1.0Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=3.6,
2.7Hz, 1H), 5.53 (dd, J=3.6,1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz, 1H),
4.30 (ddd, J=13.0,8.8,4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)13C
NMR(101MHz,CDCl3)δ177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,
124.6,123.3,120.3,109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated
for C21H19N3O[M+H]+:330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 8：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To in the toluene (2mL) of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol), add
Chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution directly passes through column
Chromatographic purifying obtains target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a]
Pyrazine] -2- ketone:52.4mg yield：80%, enantiomeric excess value (ee values)：80%, yellow solid；1HNMR(400MHz,
CDCl3) δ 7.38-7.30 (m, 4H), 7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03 (td, J=
7.5,1.0Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=3.6,
2.7Hz, 1H), 5.53 (dd, J=3.6,1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz, 1H),
4.30 (ddd, J=13.0,8.8,4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)13C
NMR(101MHz,CDCl3)δ177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,
124.6,123.3,120.3,109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated
for C21H19N3O[M+H]+:330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 9：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To the 1,2- dichloroethanes of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol)
In (2mL), be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution
It directly purifies to obtain target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrroles by column chromatography
And [1,2-a] pyrazine] -2- ketone:51.1mg yield：78%, enantiomeric excess value (ee values)：75%, yellow solid；1H NMR
(400MHz,CDCl3) δ 7.38-7.30 (m, 4H), 7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03
(td, J=7.5,1.0Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=
3.6,2.7Hz, 1H), 5.53 (dd, J=3.6,1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz,
1H), 4.30 (ddd, J=13.0,8.8,4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)
.13C NMR(101MHz,CDCl3)δ177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,
124.6,123.3,120.3,109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated
for C21H19N3O[M+H]+:330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 10：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To the tetrahydrofuran (2mL) of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol)
In, be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution is direct
It purifies to obtain target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es by column chromatography
[1,2-a] pyrazine] -2- ketone:49.1mg yield：75%, enantiomeric excess value (ee values)：79%, yellow solid；1H NMR
(400MHz,CDCl3) δ 7.38-7.30 (m, 4H), 7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03
(td, J=7.5,1.0Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=
3.6,2.7Hz, 1H), 5.53 (dd, J=3.6,1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz,
1H), 4.30 (ddd, J=13.0,8.8,4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)
.13C NMR(101MHz,CDCl3)δ177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,
124.6,123.3,120.3,109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated
for C21H19N3O[M+H]+:330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 11：(-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es [1,2-a] pyrroles
Piperazine] -2- ketone synthesis：
The structural formula of this is as follows：
To the chloroform (2mL) of 2- (1H- pyrroles -1- bases) ethamine (0.24mmol) and N- benzyls isatin (0.2mmol)
In, be added chiral phosphoric acid catalyst IV -12 (10mol%) andMolecular sieve reacts overnight at 25 DEG C.Reaction solution is direct
It purifies to obtain target product (-) -1- benzyls -3', 4'- dihydro -2'H- spiral shell [indoline -3,1'- pyrrolo-es by column chromatography
[1,2-a] pyrazine] -2- ketone:55.7mg yield：85%, enantiomeric excess value (ee values)：83%, yellow solid；1H NMR
(400MHz,CDCl3) δ 7.38-7.30 (m, 4H), 7.30-7.26 (m, 2H), 7.22 (td, J=7.8,1.3Hz, 1H), 7.03
(td, J=7.5,1.0Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.69 (dd, J=2.7,1.7Hz, 1H), 6.13 (dd, J=
3.6,2.7Hz, 1H), 5.53 (dd, J=3.6,1.6Hz, 1H), 5.04 (d, J=15.7Hz, 1H), 4.77 (d, J=15.7Hz,
1H), 4.30 (ddd, J=13.0,8.8,4.6Hz, 1H), 4.24-4.12 (m, 2H), 3.33 (dt, J=12.8,4.1Hz, 1H)
.13C NMR(101MHz,CDCl3)δ177.6,142.6,135.9,133.2,129.3,128.8,127.7,127.2,125.6,
124.6,123.3,120.3,109.3,108.1,104.6,61.3,45.2,43.6,39.4.HRMS(ESI)calculated
for C21H19N3O[M+H]+:330.1601,found:330.1597.
Enantiomeric excess value (ee values) is measured by the following conditions：Daicel Chiralpak OD-H (25cm), n-hexane/
Isopropanol=90/10,1.0mL/min, λ=254nm, tR(major)=22.70min, tR(minor)=27.98min.
Embodiment 13~30
With reference to the preparation method of embodiment 1, the present invention also prepares part asymmetric syntheses product, structure, yield and
Enantiomeric excess Value DataaAs shown in table 1：
Table 1
a1 (0.2mmol), 2 (1.2equiv), IV -12 (10mol%) andMS, DCM (2mL), 25 DEG C,
overnight。
Embodiment 31
The present embodiment is synthesized, the catalyst of use is as shown in table 2, obtains with reference to the processing step and condition of embodiment 1
It is as shown in table 3 to obtain product, yield and ee values.
Table 2
Table 3
Show that the method provided through the invention can simple, efficient synthesis of chiral oxo by the example of above-mentioned offer
Spiro indole class compound and its raceme, this method have at low cost, easy to operate, mild condition, be swift in response, yield and
Enantioselectivity high advantage when asymmetry catalysis.
Experimental example 1：Anti tumor activity in vitro is tested
Chirality oxo spiro indole class compound of the present invention or its raceme are as preparation treating cancer medicinal usage
Pharmacological research.The compound of all tests is prepared into hydrochloride form before the test, with clinically common antineoplastic
Object-cis-platinum is as positive control medicine.
Liver cancer cell lines (HepG2), Human Laryngeal Cancer Cell (Hep-2), breast cancer cell line (MCF-7), gastric cancer are selected respectively
Cell line (BGC-823), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer cell line (PC-3) etc.
Cell line is tested using mtt assay.The specific method is as follows:The good, cell in exponential phase by growth conditions respectively
Strain is with 5 × 104The concentration of a/mL is inoculated in 96 orifice plates, and 160 μ L are inoculated with per hole, and 96 orifice plates are then placed in 37 DEG C, contain 5%CO2
Incubator in cultivate 24 hours, abandon old liquid, change fresh medium, the oxoquinoline derivatives of sterilization treatment are added, continue to train
After supporting 48 hours, culture solution is discarded, adds RPMI-1640 culture solutions of the 20uL containing 5mg/mLMTT per hole, continues culture 4 hours, it is small
After the heart removes supernatant, the DMSO of 200 μ L is added per hole, oscillation about 10min dissolving precipitations then detect OD values, wave with microplate reader
Long 490nm.The cell survival rate under each sample concentration is found out with following formula：Survival rate %=sample sets mean OD value/control group
Mean OD value × 100%.It is mapped to drug concentration logarithm with cell survival rate, the IC of each sample is found out by graphing method50Value, knot
Fruit is shown in Table 4.
Oxo spiro indole analog derivative extracorporeal anti-tumor result (IC of the present invention50,μMa,b,c)
Table 4
a IC50Value indicates to inhibit the 50% required drug concentration of growth of tumour cell.
bTumor cell line includes liver cancer cell lines (HepG2), human laryngeal cancer cell line (Hep-2), breast cancer cell line
(MCF-7), gastric carcinoma cell lines (BGC-823), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer is thin
Born of the same parents are (PC-3).
cEach numerical value represents the average value of parallel test result three times in table.
Claims (10)
1. a kind of novel chiral oxo spiro indole class compound and its raceme containing pyrroles or indoles and azacycloalkyl structure,
It is characterized in that, have following structure formula,R/S(3) it is the raceme of the compound,R(3) it isRThe chiral isomer of configuration,S(3) it isSThe chiral isomer of configuration
Wherein：
Substituent R1Selected from hydrogen, carbon atom number be 1-10 alkyl, carbon atom number be 3-10 cycloalkylmethylene ,-COR4、-
SO2R5, the methylene that replaces of allyl, propargyl, the aryl that carbon atom number is 6-14, and taken with one or more secondary
The above-mentioned group of Dai Ji；The secondary substituent group, R4And R5It is respectively selected from halogen, nitro, hydroxyl, the virtue that carbon atom number is 6-14
Alkoxy that alkyl that base, carbon atom number are 1-10, carbon atom number are 1-10, trifluoromethyl；
Substituent R2For the substituted group of one or more hydrogen on aromatic rings, the group is selected from fluorine, chlorine, bromine, iodine, fluoroform
Base, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitro, carbon
The substituent group with furan structure that aryl that atomicity is 6-14, carbon atom number are 4-9, carbon atom number are 5-9 with pyrrole
The substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary substitutions
The above-mentioned group of base；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is the alkane of 1-10
Base, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
Substituent R3For the substituted group of one or more hydrogen on pyrrole ring, the group is selected from fluorine, chlorine, bromine, iodine, fluoroform
Base, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitro, carbon
The substituent group with furan structure that aryl that atomicity is 6-14, carbon atom number are 4-9, carbon atom number are 5-9 with pyrrole
The substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary substitutions
The above-mentioned group of base；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is the alkane of 1-10
Base, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
CompoundR/S-(3)、R-(3)、S(3) what the n in was expressed as the alkylamino that N on pyrroles or indoles replaces contains carbon number,
It is 1 or 2 or 3.
2. a kind of chiral oxo spiro indole class compound containing pyrroles or indoles and azacycloalkyl structure described in claim 1 and
The preparation method of its raceme, which is characterized in that
WithNIsatin after isatin or the phenyl ring substitution of substitution（1）WithNThe pyrroles of alkylamino substitution or indoles（2）As reaction
Substrate, using chiral phosphoric acid or its enantiomter or its raceme as catalyst, in solvent and additive environment, via
One step of catalysis [m+1] cycloaddition approach is directly prepared, and wherein m is 5 or 6 or 7；
Its reaction equation is as follows：
Wherein：
Substituent R1Selected from hydrogen, carbon atom number be 1-10 alkyl, carbon atom number be 3-10 cycloalkylmethylene ,-COR4、-
SO2R5, the methylene that replaces of allyl, propargyl, the aryl that carbon atom number is 6-14, and taken with one or more secondary
The above-mentioned group of Dai Ji；The secondary substituent group, R4And R5It is respectively selected from halogen, nitro, hydroxyl, the virtue that carbon atom number is 6-14
Alkoxy that alkyl that base, carbon atom number are 1-10, carbon atom number are 1-10, trifluoromethyl；
Substituent R2For the substituted group of one or more hydrogen on aromatic rings, the group is selected from fluorine, chlorine, bromine, iodine, fluoroform
Base, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitro, carbon
The substituent group with furan structure that aryl that atomicity is 6-14, carbon atom number are 4-9, carbon atom number are 5-9 with pyrrole
The substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary substitutions
The above-mentioned group of base；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is the alkane of 1-10
Base, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；
Substituent R3For the substituted group of one or more hydrogen on pyrrole ring, the group is selected from fluorine, chlorine, bromine, iodine, fluoroform
Base, alkoxy that naphthenic base that alkyl that carbon atom number is 1-10, carbon atom number are 3-10, carbon atom number are 1-10, nitro, carbon
The substituent group with furan structure that aryl that atomicity is 6-14, carbon atom number are 4-9, carbon atom number are 5-9 with pyrrole
The substituent group of pyridine structure, the substituent group with thiophene-structure that carbon atom number is 4-9, and with one or more secondary substitutions
The above-mentioned group of base；The secondary substituent group is selected from halogen, trifluoromethyl, hydroxyl, nitro, and carbon atom number is the alkane of 1-10
Base, carbon atom number are the alkoxy of 1-10, and carbon atom number is the aryl of 6-14；；
CompoundR/S-(3)、R-(3)、S(3) what the n in was expressed as the alkylamino that N on pyrroles or indoles replaces contains carbon number,
It is 1 or 2 or 3.
3. chiral oxo spiro indole class compound according to claim 2 containing pyrroles or indoles and azacycloalkyl structure and
The preparation method of its raceme, which is characterized in that the chiral phosphoric acid or its enantiomter or its raceme are organic small
Molecule phosphoric acid, the chiral phosphoric acid are respectively：（I）Dinaphthalene skeleton chiral phosphoric acid,（II）Octahydro dinaphthalene skeleton chiral phosphoric acid,
(III) join phenanthrol skeleton chiral phosphoric acid, (IV) loop coil diphenols chiral phosphoric acid, (V) has the chiral phosphoric acid of class TADDOL skeletons,
(VI) dinaphthalene Diamines chiral phosphoric acid, (VII) biphenyl class chiral phosphoric acid, (VIII) N- trifyl phosphamides, and
(IX) the connected chiral bisphosphine acid of ehter bond, (X) duplex naphthalene phosphoric acid；
Structural formula difference is as follows：
Wherein：
The wherein described substituent R is selected from following group range, fluorine, chlorine, bromine, iodine, trifluoromethyl, the virtue that carbon atom number is 6-14
Base, trifyl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, hydroxyl, nitro, acetenyl, carbon atom number are
The alcoxyl that heterocycle that naphthenic base that the alkyl of 1-10, carbon atom number are 3-10, carbon atom number are 4-10, carbon atom number are 1-10
Base, and the above-mentioned group with one or more secondary substituent groups；The secondary substituent group is selected from the alkyl of carbon atom number 1-6
Or the aryl of carbon atom number 6-14, carbon atom number be 3-10 naphthenic base, carbon atom number be 1-10 alkoxy, halogen, trifluoro
Methyl, nitro；
Substituent R ' selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, the alkyl or carbon atom number 6-10 that carbon atom number is 1-12
Aryl, the heterocycle that carbon atom number is 4-10, and the above-mentioned group with one or more secondary substituent groups；The secondary
It is the naphthenic base of 3-10, carbon atom that substituent group, which is selected from the alkyl of carbon atom number 1-6 or the aryl of carbon atom number 6-14, carbon atom number,
Number is alkoxy, halogen, trifluoromethyl, nitro, the hydroxyl of 1-10；
Substituent R ' ' selected from methyl, trifluoromethyl, azo group, trifyl ,-CH2R6、-CHR6 R7Carbon atom number is 2-4
Alkenyl, carbon atom number be 2-4 alkynyl, the aryl of carbon atom number 6-10, carbon atom number be 4-10 heterocycle, and have
The above-mentioned group of one or more secondary substituent groups；The secondary substituent group is selected from the alkyl or carbon atom number of carbon atom number 1-6
The aryl of 6-14, alkoxy, halogen, trifluoromethyl, nitro, the hydroxyl that carbon atom number is 1-10；The R6It is derived from carbon atom number
The aryl and carbon atom number of 6-14 is the heterocycle of 4-10；The R7It is derived from amino, methylamino.
4. chiral oxo spiro indole class compound according to claim 2 containing pyrroles or indoles and azacycloalkyl structure and
The preparation method of its raceme, which is characterized in that include the following steps：
NIsatin after isatin or the phenyl ring substitution of substitution（1）WithNThe pyrroles of alkylamino substitution or indoles（2）Mixing it is molten
In liquid, chiral phosphoric acid or its enantiomter or its raceme and additive is added；Reaction 0 ~ 48 is small under the conditions of 0 ~ 50 DEG C
When, you can chiral oxo spiro indole class compound and its raceme are generated respectively；
WhereinNIsatin after isatin or the phenyl ring substitution of substitution（1）WithNThe pyrroles of alkylamino substitution or indoles（2）Mole
Ratio is 1:1 ~ 5, catalyst amount isNIsatin after isatin or the phenyl ring substitution of substitution（1）1% ~ 20 % of the amount of substance.
5. chiral oxo spiro indole class compound according to claim 2 containing pyrroles or indoles and azacycloalkyl structure and
The preparation method of its raceme, which is characterized in that the additive is 3 or 4 molecular sieves, cyclodextrin, inorganic acid, inorganic base
Or one kind in organic amine and its derivative.
6. chiral oxo spiro indole class compound according to claim 2 containing pyrroles or indoles and azacycloalkyl structure and
The preparation method of its raceme, which is characterized in that
The solvent is dichloromethane, monochloro methane, chloroform, carbon tetrachloride, dichloroethanes, tetrahydrofuran, ether, acetic acid
Ethyl ester, toluene, benzene, dimethylbenzene, ethylene glycol, polyethylene glycol, glycol dimethyl ether, glycol monoethyl ether, methyl tertiary butyl ether(MTBE), first
One kind in alcohol, ethyl alcohol, isopropanol, the tert-butyl alcohol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or
Several mixtures, or in which one or more and the mixed solutions of water.
7. a kind of chiral oxo spiro indole class compound containing pyrroles or indoles and azacycloalkyl structure described in claim 1 and
Optical isomer, pharmaceutical salts or the solvate of its raceme.
8. chiral oxo spiro indole class compound according to claim 7 containing pyrroles or indoles and azacycloalkyl structure and
Optical isomer, pharmaceutical salts or the solvate of its raceme, which is characterized in that the pharmaceutical salts be and acid-addition salts or and alkali
The salt of formation；
The solvate is hydrate or includes other recrystallisation solvents.
9. chiral oxo spiro indole class compound according to claim 8 containing pyrroles or indoles and azacycloalkyl structure and
Optical isomer, pharmaceutical salts or the solvate of its raceme, which is characterized in that described and acid-addition salts include hydrochloride, sulphur
Hydrochlorate, phosphate, hydrobromate, acetate, oxalates, sal limonis, gluconate, succinate, tartrate, to toluene
Sulfonate, mesylate, benzoate, lactate and maleate；The salt formed with alkali includes lithium salts, sodium salt, sylvite, calcium
Salt, magnesium salts, diethanolamine salt, choline salt or alkyl phenyl amine salt.
10. according to the chiral oxo loop coil containing pyrroles or indoles and azacycloalkyl structure described in any one of claim 1 or 7 ~ 9
Benzazole compounds and its raceme, optical isomer, pharmaceutical salts or solvate are being prepared for preventing or treating tumour
Application in drug.
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| CN115010565A (en) * | 2021-03-05 | 2022-09-06 | 中国科学院大连化学物理研究所 | Synthesis method of spiro chiral indolinone containing indole skeleton |
| CN115403588A (en) * | 2022-08-04 | 2022-11-29 | 青岛农业大学 | Oxoindolspirodibenz [ b, f ] oxooctanes and preparation method thereof |
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| CN113321657A (en) * | 2021-02-01 | 2021-08-31 | 南京工业大学 | Fluoro/fluoroalkyl 1, 3-dione compounds and method for synthesizing chiral compounds having fluoro/alkyl fluoro quaternary carbon centers |
| CN115010565A (en) * | 2021-03-05 | 2022-09-06 | 中国科学院大连化学物理研究所 | Synthesis method of spiro chiral indolinone containing indole skeleton |
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