CN104774171A - 3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof - Google Patents
3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof Download PDFInfo
- Publication number
- CN104774171A CN104774171A CN201410018057.4A CN201410018057A CN104774171A CN 104774171 A CN104774171 A CN 104774171A CN 201410018057 A CN201410018057 A CN 201410018057A CN 104774171 A CN104774171 A CN 104774171A
- Authority
- CN
- China
- Prior art keywords
- oxoindole
- hydroxymethyl
- formaldehyde
- ethyl acetate
- formate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- WXCVOKOPENHWHK-UHFFFAOYSA-N 3-hydroxy-3-(hydroxymethyl)-1h-indol-2-one Chemical class C1=CC=C2C(CO)(O)C(=O)NC2=C1 WXCVOKOPENHWHK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- HPUOSBAFCGTELP-UHFFFAOYSA-N 3-amino-3-(hydroxymethyl)-1H-indol-2-one Chemical compound C1=CC=C2C(N)(CO)C(=O)NC2=C1 HPUOSBAFCGTELP-UHFFFAOYSA-N 0.000 title claims abstract description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 162
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims abstract description 44
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims abstract description 37
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 258
- 238000006243 chemical reaction Methods 0.000 claims description 78
- 238000003756 stirring Methods 0.000 claims description 34
- 238000004440 column chromatography Methods 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- GURJQHUTWUWLQT-UHFFFAOYSA-N (3Z)-3-diazo-1H-indol-2-one Chemical compound C1=CC=C2C(=[N+]=[N-])C(=O)NC2=C1 GURJQHUTWUWLQT-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 230000010261 cell growth Effects 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001448 anilines Chemical class 0.000 claims description 3
- 239000003966 growth inhibitor Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JUWOBCNAWKDBSM-UHFFFAOYSA-N 3-diazonio-1h-indol-2-olate Chemical compound C1=CC=C2C([N+]#N)=C([O-])NC2=C1 JUWOBCNAWKDBSM-UHFFFAOYSA-N 0.000 claims 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 229930014626 natural product Natural products 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012954 diazonium Substances 0.000 abstract 2
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- 239000012043 crude product Substances 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 238000002347 injection Methods 0.000 description 36
- 239000007924 injection Substances 0.000 description 36
- 239000000047 product Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 31
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- 239000003208 petroleum Substances 0.000 description 28
- 238000002390 rotary evaporation Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 239000000523 sample Substances 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 18
- TUVQJSJIEZDXNX-UHFFFAOYSA-N 1-benzyl-3-diazonioindol-2-olate Chemical compound C12=CC=CC=C2C(=[N+]=[N-])C(=O)N1CC1=CC=CC=C1 TUVQJSJIEZDXNX-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 8
- -1 compound 3-hydroxy-3-hydroxymethyl oxoindole derivative Chemical class 0.000 description 7
- SQMODZDTYDHABH-UHFFFAOYSA-N 1-benzyl-3-diazonio-5-methylindol-2-olate Chemical compound C(C1=CC=CC=C1)N1C(C(C2=CC(=CC=C12)C)=[N+]=[N-])=O SQMODZDTYDHABH-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XIHXDEAXDVHWNA-UHFFFAOYSA-N 1-acetyl-3-diazonioindol-2-olate Chemical compound C1=CC=C2N(C(=O)C)C([O-])=C([N+]#N)C2=C1 XIHXDEAXDVHWNA-UHFFFAOYSA-N 0.000 description 3
- KOURBIFKJIEMRK-UHFFFAOYSA-N 3-amino-1,3-dihydroindol-2-one Chemical compound C1=CC=C2C(N)C(=O)NC2=C1 KOURBIFKJIEMRK-UHFFFAOYSA-N 0.000 description 3
- SGZFJWQQBHYNNF-UHFFFAOYSA-N 3-hydroxyindolin-2-one Chemical group C1=CC=C2C(O)C(=O)NC2=C1 SGZFJWQQBHYNNF-UHFFFAOYSA-N 0.000 description 3
- 0 C/C(/*#CC=C1C2=N*)=C\C=C1\N(*)C2=O Chemical compound C/C(/*#CC=C1C2=N*)=C\C=C1\N(*)C2=O 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000006452 multicomponent reaction Methods 0.000 description 3
- CEMPEZGRVVKUQG-UHFFFAOYSA-N 1-benzyl-5-bromo-3-diazoindol-2-one Chemical compound C(C1=CC=CC=C1)N1C(C(C2=CC(=CC=C12)Br)=[N+]=[N-])=O CEMPEZGRVVKUQG-UHFFFAOYSA-N 0.000 description 2
- KOLPMNSDISYEBU-WJOKGBTCSA-N 2-[(3r)-1-(2,2-diethoxyethyl)-3-[(4-methylphenyl)carbamoylamino]-2-oxoindol-3-yl]-n-(4-methylphenyl)acetamide Chemical compound C([C@]1(NC(=O)NC=2C=CC(C)=CC=2)C(=O)N(C2=CC=CC=C21)CC(OCC)OCC)C(=O)NC1=CC=C(C)C=C1 KOLPMNSDISYEBU-WJOKGBTCSA-N 0.000 description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 2
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 2
- 150000008049 diazo compounds Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- NJXZWIIMWNEOGJ-WEWKHQNJSA-N (2s,4r)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-4-hydroxy-n,n-dimethylpyrrolidine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@@H](O)C2)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O NJXZWIIMWNEOGJ-WEWKHQNJSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- PWCXGMXWGWEWDI-UHFFFAOYSA-N 1-benzyl-5-chloro-3-diazonioindol-2-olate Chemical compound [O-]C1=C([N+]#N)C2=CC(Cl)=CC=C2N1CC1=CC=CC=C1 PWCXGMXWGWEWDI-UHFFFAOYSA-N 0.000 description 1
- DYSRXWYRUJCNFI-UHFFFAOYSA-N 2,4-dibromoaniline Chemical compound NC1=CC=C(Br)C=C1Br DYSRXWYRUJCNFI-UHFFFAOYSA-N 0.000 description 1
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- DPUCWQUWEJBKPK-UHFFFAOYSA-N 3-aminoindol-2-one Chemical class C1=CC=C2C(=N)C(=O)NC2=C1 DPUCWQUWEJBKPK-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- BDVJDCNYDDTQAY-UHFFFAOYSA-N 3-diazonio-1-methylindol-2-olate Chemical compound C1=CC=C2N(C)C([O-])=C([N+]#N)C2=C1 BDVJDCNYDDTQAY-UHFFFAOYSA-N 0.000 description 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- AFLLJVZHYVUNNX-STQMWFEESA-N CPC-1 Natural products CO[C@]12CCN(C)[C@H]1N(C)c1ccccc21 AFLLJVZHYVUNNX-STQMWFEESA-N 0.000 description 1
- AJBXXVPBMQMBGJ-UHFFFAOYSA-N Cc(cc1C2(CO)Nc(c(C)ccc3)c3Cl)ccc1N(Cc1ccccc1)C2=O Chemical compound Cc(cc1C2(CO)Nc(c(C)ccc3)c3Cl)ccc1N(Cc1ccccc1)C2=O AJBXXVPBMQMBGJ-UHFFFAOYSA-N 0.000 description 1
- FOQSFYULONWJOS-UHFFFAOYSA-N Cc(cccc1Cl)c1NC(CO)(c1ccccc1N1Cc2ccccc2)C1=O Chemical compound Cc(cccc1Cl)c1NC(CO)(c1ccccc1N1Cc2ccccc2)C1=O FOQSFYULONWJOS-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 101100007537 Cryphonectria parasitica CPC-1 gene Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- BDUHCSBCVGXTJM-IZLXSDGUSA-N Nutlin-3 Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@H](C=2C=CC(Cl)=CC=2)[C@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 BDUHCSBCVGXTJM-IZLXSDGUSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- NGSUYOQYYVLKJJ-NAZRFLCCSA-N complestatin B Chemical compound N([C@@H]1CC2(O)C(=O)NC=3C2=CC=C(C=3)C=2C=C3C=C(C=2O)OC2=CC=C(C=C2)C[C@H](N(C([C@@H](C=2C=C(Cl)C(O)=C(Cl)C=2)NC(=O)[C@@H]3NC(=O)[C@@H](C=2C=C(Cl)C(O)=C(Cl)C=2)NC1=O)=O)C)C(=O)N[C@@H](C(O)=O)C=1C=CC(O)=CC=1)C(=O)C(=O)C1=CC(Cl)=C(O)C(Cl)=C1 NGSUYOQYYVLKJJ-NAZRFLCCSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229930186529 maremycin Natural products 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NGSUYOQYYVLKJJ-UHFFFAOYSA-N neuroprotectin B Natural products O=C1NC(C=2C=C(Cl)C(O)=C(Cl)C=2)C(=O)NC2C(=O)NC(C=3C=C(Cl)C(O)=C(Cl)C=3)C(=O)N(C)C(C(=O)NC(C(O)=O)C=3C=CC(O)=CC=3)CC(C=C3)=CC=C3OC(C=3O)=CC2=CC=3C(C=2)=CC=C3C=2NC(=O)C3(O)CC1NC(=O)C(=O)C1=CC(Cl)=C(O)C(Cl)=C1 NGSUYOQYYVLKJJ-UHFFFAOYSA-N 0.000 description 1
- 108010067847 neuroprotectin B Proteins 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229930194774 paratunamide Natural products 0.000 description 1
- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical compound [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses preparation methods of 3-amino-3-hydroxymethyl oxoindole and a 3-hydroxyl-3-hydroxymethyl oxoindole derivative; with 3-diazonium oxoindole, aniline and formaldehyde or 3-diazonium oxoindole, water and formaldehyde as raw materials, with rhodium acetate as a catalyst and an organic solvent as a solvent, and through a one-step reaction, the product 3-amino-3-hydroxymethyl oxoindole and the 3-hydroxyl-3-hydroxymethyl oxoindole derivative are obtained. The preparation methods have the advantages of high-efficiency atomic economy, high selectivity and the like, and the operation is simple, safe and reliable. The 3-amino-3-hydroxymethyl oxoindole and the 3-hydroxyl-3-hydroxymethyl oxoindole derivative have anti-cancer activity and contain important natural product and active pharmaceutical molecular intermediate skeletons, and have broad application prospects in the field of medicine and chemical industry.
Description
Technical Field
The invention belongs to the technical field of drug synthesis chemical industry, and particularly relates to a preparation method of 3-amino-3-hydroxymethyl oxoindole and 3-hydroxy-3-hydroxymethyl oxoindole derivatives.
Background
Many natural products and active compounds contain 3-aminooxindole and 3-hydroxyoxindole structures, so that the preparation of 3-aminooxindole and 3-hydroxyoxindole derivatives is of great significance. For example: chem.2012, 77, 3589-3594 points out that the 3-aminooxoindole derivative AG-041R is able to stimulate chondrocyte proliferation and cartilage-specific extracellular matrix synthesis in vitro without altering the characteristics of the cells that do not alter their differentiation. Journal of world chinese digestion 2006, 14 (13): 1262-1266 report that AG-041R has the activity of inhibiting the proliferation of MKN-45 cells. Chem.2012, 77, 3589-3594 also reports that the 3-aminooxindole derivative SSR-149415 can be used for the treatment of anxiety and depression. Curr, bioact, compact, 2009, 5, 20 reports that 3-hydroxyoxindole derivatives, convolutamidines, arnudophine, donaxatridine, maremycins, paratunamide, cellontin K, TMC-95AD, neuroprotectin B, flusterinol a and B, 3-hydroxy welidolinones and pyrolidinoid-type alkoids, CPC-1 is a natural compound with biological activities of anti-oxidation, anti-cancer, anti-aids, etc.
Therefore, the efficient synthesis of the compounds has important theoretical and economic values. However, the 3-amino-3-hydroxymethyl oxoindole derivative provided by the patent has a special structure, so that the compound is difficult to synthesize by a traditional method, and no report of the compound exists at present; the 3-hydroxy-3-hydroxymethyl oxoindole derivative provided by the patent is a brand new compound, and although part of the 3-hydroxy-3-hydroxymethyl oxoindole derivative can be derived from the document nat. Med.2009, 15, 750-756, the reaction conditions of the method are harsh, and the operation is complex. Therefore, it is very important and urgent to explore and develop a synthesis method with low cost, high yield, mild reaction conditions, good selectivity, wide substrate applicability, simple post-treatment and safe operation.
Disclosure of Invention
The invention provides 3-amino-3-hydroxymethyl oxoindole, 3-hydroxy-3-hydroxymethyl oxoindole derivatives and a preparation method thereof. The preparation method has the advantages of high efficiency, atom economy, high selectivity, high yield, simple and safe operation and the like. The 3-amino-3-hydroxymethyl oxoindole and 3-hydroxy-3-hydroxymethyl oxoindole derivatives prepared by the invention can be used as intermediates for drug discovery or other applications.
The invention provides a compound 3-amino-3-hydroxymethyl oxoindole with an innovative structure, which has a structure shown in a formula (A),
wherein,
R1including alkyl, H, halogen, formate;
R2including alkyl, halogen, benzyl, formate, acyl;
R3including alkyl, halogen, formate, acyl.
The invention provides a preparation method of 3-amino-3-hydroxymethyl oxoindole, which comprises the steps of taking 3-diazooxoindole, aniline and formaldehyde or 3-diazooxoindole, water and formaldehyde as raw materials, taking rhodium acetate as a catalyst, taking an organic solvent as a solvent, dissolving aniline, formaldehyde aqueous solution and rhodium acetate in the organic solvent, adding the 3-diazooxoindole under stirring, and carrying out one-step reaction to obtain the 3-amino-3-hydroxymethyl oxoindole and 3-hydroxy-3-hydroxymethyl oxoindole derivatives; wherein the aniline comprises aniline and substituted aniline;
the preparation method is shown as a reaction formula (I):
wherein,
R1including alkyl, H, halogen, formate, etc.;
R2including alkyl, halo, benzyl, formate, acyl, and the like;
R3including alkyl, halogen, formate, acyl, and the like.
Wherein, the molar ratio of the raw material to the catalyst in the method is 3-diazo oxoindole: aniline: formaldehyde: rhodium acetate is 0.1: 1.0: 0.01-2: 1.0: 10.0: 0.10.
The invention also provides a compound 3-hydroxy-3-hydroxymethyl oxoindole derivative with an innovative structure, which has a structure shown in a formula (B),
wherein,
R4including alkyl, H, halogen, formate;
R5including alkyl, halogen, benzyl, formate, acyl.
The invention also provides a preparation method of the 3-hydroxy-3-hydroxymethyl oxoindole derivative, which comprises the steps of taking 3-diazooxoindole, water and formaldehyde as raw materials, taking rhodium acetate as a catalyst, taking an organic solvent as a solvent, dissolving the formaldehyde aqueous solution and the rhodium acetate in the organic solvent, adding the 3-diazooxoindole under stirring, and carrying out one-step reaction to obtain the 3-hydroxy-3-hydroxymethyl oxoindole derivative;
the preparation method is shown as a reaction formula (II):
wherein,
R4including alkyl, H, halogen, formate, etc.;
R5including alkyl, halogen, benzyl, formate, acyl, and the like.
Wherein the molar ratio of the raw material to the catalyst is 3-diazo oxoindole: water: formaldehyde: rhodium acetate is 0.1: 3.0: 1.0: 0.01-2: 1.0: 10.0: 0.10.
In the preparation method of the invention, the method comprises the following steps: and respectively dissolving the aniline, the formaldehyde aqueous solution or the formaldehyde aqueous solution and rhodium acetate in the organic solvent, adding a solution obtained by dissolving the diazo compound in the organic solvent under stirring, and respectively obtaining a product of 3-amino-3-hydroxymethyl oxoindole or 3-hydroxy-3-hydroxymethyl oxoindole derivative through reaction.
In the preparation method, the product 3-amino-3-hydroxymethyl oxoindole or 3-hydroxy-3-hydroxymethyl oxoindole derivative is separated and purified by column chromatography or other modes respectively.
In the preparation method, the organic solvent comprises tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, toluene, ethyl acetate, dichloromethane and other solvents.
In the preparation method, the 3-diazo-2-oxindole comprises 3-diazo-2-oxindole, various benzene substituted 3-diazo-2-oxindoles and various N substituted 3-diazo-2-oxindoles.
In the preparation method, the aniline comprises aniline and substituted aniline. The water and aldehydes are limited to water and formaldehyde.
The products obtained by the preparation method are 3-amino-3-hydroxymethyl oxoindole shown in formula (A) and 3-hydroxy-3-hydroxymethyl oxoindole derivatives shown in formula (B), and the derivatives are compounds with innovative structures.
In the 3-amino-3-hydroxymethyl oxoindole and the 3-hydroxy-3-hydroxymethyl oxoindole derivative, the 3-position is a quaternary carbon center and the 3-position is connected with a hydroxymethyl group.
The preparation method comprises the following synthetic processes: 3-diazo indole oxide, aniline and formaldehyde or 3-diazo indole oxide, water and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, a one-step reaction is carried out, the solvent is removed to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain the product. The method comprises the following specific steps: dissolving aldehyde and aniline in an organic solvent, dropwise adding a solution formed by dissolving a diazo compound in the organic solvent into a reaction system within 1 hour under stirring, and reacting for 1 hour after the dropwise adding is finished. After the reaction is finished, the organic solvent is removed under reduced pressure to obtain a crude product, and the crude product is purified by column chromatography to obtain a product.
The invention also provides application of the 3-amino-3-hydroxymethyl oxoindole in preparation of a colon cancer cell growth inhibitor.
The invention also provides application of the 3-hydroxy-3-hydroxymethyl oxoindole derivative in preparation of a colon cancer cell growth inhibitor.
The invention has the beneficial effects that 3-amino-3-hydroxymethyl oxoindole and 3-hydroxy-3-hydroxymethyl oxoindole derivatives are designed and synthesized, diazo, aniline, formaldehyde or 3-diazooxoindole, water and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, and a product is obtained through one-step reaction. The invention firstly proposes that a 3-amino-3-hydroxymethyl oxoindole and a 3-hydroxy-3-hydroxymethyl oxoindole derivative are constructed through one-step reaction, and a product is obtained through one-step three-component reaction. Due to the characteristics of high flexibility, high selectivity, high atom economy, high exploration energy, high yield, simple and safe operation and the like of the multi-component reaction, the multi-component reaction becomes a hot point of research more and more along with the gradual development of the atom economy concept in recent years. The application of the multicomponent reaction in the field of drug synthesis has wide prospects. The 3-amino-3-hydroxymethyl oxoindole and 3-hydroxy-3-hydroxymethyl oxoindole derivatives are important natural product frameworks or active drug intermediates, and the compounds also have anticancer activity and wide application prospects in the field of pharmaceutical chemicals.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
The reaction process of the preparation method of the invention is as follows:
wherein R is1Including alkyl, H, halogen, formate, etc.; r2Including alkyl, halo, benzyl, formate, acyl, and the like; r3Including alkyl, halogen, formic acidEsters, acyl groups, and the like; r4Including alkyl, H, halogen, formate; r5Including alkyl, halogen, benzyl, formate, acyl.
Example 1:
a solution prepared by dissolving 2, 6-dichloroaniline (0.1mmol), formaldehyde (0.6mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 1, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 94 percent of
1H NMR(400MHz，CDCl3)7.40-7.27(m，5H)，7.15(td，1H)，7.09(d，2H)，6.78(dt，3H)，6.69-6.59(m，1H)，5.27(s，1H)，5.04(d，1H)，4.82(d，1H)，3.97(t，1H)，3.87(dd，1H)，3.15(dd，1H)；
13C NMR(100MHz，CDCl3)178.10，142.99，139.96，135.51，129.69，129.39，128.82，128.13，127.86，127.82，125.84，124.12，123.71，122.35，109.56，69.82，66.45，44.10。
Example 2:
aniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) are dissolved in 1mL ethyl acetate to form a reaction system, the temperature is kept at 60 ℃, and a solution formed by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL ethyl acetate is added into the reaction system for 1 hour by using an automatic sample injection pump. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 2, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 42 percent of
1H NMR(400MHz，CDCl3)7.40-7.16(m，8H)，7.06(t，1H)，6.95(t，2H)，6.84(d，1H)，6.70(t，1H)，6.27(d，2H)，5.18(s，1H)，5.11(d，1H)，4.76(d，1H)，3.92(t，1H)，3.75-3.64(m，1H)，3.12(d，1H)；
13C NMR(100MHz，CDCl3)178.04，145.56，141.88，129.57，129.13，128.84，127.88，127.62，124.03，123.55，119.59，115.53，110.07，68.08，64.95，44.09。
Example 3:
4-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) were dissolved in 1mL of ethyl acetate to prepare a reaction system, and a solution prepared by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate was added to the reaction system for 1 hour by using an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 3, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 89 percent
1H NMR(400MHz，CDCl3)7.60(dd，4H)，7.26-7.22(m，1H)，7.22-7.16(m，2H)，7.06(t，1H)，6.88(t，2H)，6.84(d，1H)，6.24-6.12(m，2H)，5.24(s，1H)，5.09(d，1H)，4.73(d，1H)，3.97-3.82(m，1H)，3.75-3.66(m，1H)，3.46(d，1H)；
13C NMR(100MHz，CDCl3)177.73，144.18，141.87，135.24，129.75，128.98，128.88，128.01，127.61，127.60，124.40，124.05，123.65，116.95，110.15，67.94，65.20，44.12。
Example 4:
4-bromoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) are dissolved in 1mL of ethyl acetate to form a reaction system, the temperature is maintained at 60 ℃, and a solution formed by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate is added into the reaction system for 1 hour by using an automatic sample injection pump. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 4, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 86 percent.
1H NMR(400MHz，CDCl3)7.23(d，4H)，7.18(d，1H)，7.14(d，2H)，6.99(t，1H)，6.94(d，2H)，6.78(d，1H)，6.05(d，2H)，5.18(s，1H)，5.02(d，1H)，4.67(d，1H)，3.83(s，1H)，3.63(d，1H)，3.25(s，1H)；
13C NMR(100MHz，CDCl3)177.69，144.63，141.81，135.21，131.89，129.79，128.90，128.04，127.64，127.16，124.02，123.68，117.25，111.60，110.18，67.93，65.00，44.13。
Example 5:
4-iodoaniline (0.10mmo1), formaldehyde (0.60mmo1) and rhodium acetate (0.001mmo1) were dissolved in 1mL of ethyl acetate to prepare a reaction system, and a solution prepared by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate was added to the reaction system for 1 hour by means of an autosampler at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 5, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 88 percent
1H NMR(400MHz，CDCl3)7.21(d，4H)，7.17(dd，3H)，7.11(d，2H)，6.98(t，1H)，6.78(d，1H)，5.94(d，2H)，5.18(s，1H)，5.02(d，1H)，4.68(d，1H)，3.82(s，1H)，3.63(d，1H)，3.25(d，1H)；
13C NMR(100MHz，CDCl3)177.69，145.28，141.75，137.77，135.22，129.78，128.92，128.05，127.67，127.13，124.00，123.69，117.57，110.19，81.03，67.95，64.85，44.16。
Example 6:
4-nitroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) are dissolved in 1mL of ethyl acetate to form a reaction system, the temperature is kept at 60 ℃, and a solution formed by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate is added into the reaction system for 1 hour by using an automatic sample injection pump. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 6, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 94 percent of
1H NMR(400MHz，CDCl3)7.80(d，J＝9.0Hz，2H)，7.40-7.28(m，6H)，7.26(s，1H)，7.07(t，J＝7.5Hz，1H)，6.97(d，J＝7.9Hz，1H)，6.14(d，J＝9.0Hz，2H)，6.03(s，1H)，5.11(d，J＝15.3Hz，1H)，4.85(d，J＝15.3Hz，1H)，3.92(d，J＝11.5Hz，1H)，3.78(d，J＝11.6Hz，1H)，3.51(s，1H)；
13C NMR(100MHz，CDCl3)176.51，151.05，141.62，139.55，135.09，160.25，129.03，128.92，128.35，127.84，127.12，125.95，125.89，123.96，123.84，113.22，110.48，67.90，64.20，44.41。
Example 7:
3-nitroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) are dissolved in 1mL of ethyl acetate to form a reaction system, the temperature is kept at 60 ℃, and a solution formed by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate is added into the reaction system for 1 hour by using an automatic sample injection pump. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 7, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 95 percent
1H NMR(400MHz，CDCl3)7.40(d，1H)，7.28-7.13(m，8H)，6.98(dt，3H)，6.86(d，1H)，6.43(d，1H)，5.64(s，1H)，4.96(d，1H)，4.86(d，1H)，3.87(t，1H)，3.69(d，1H)，3.41(s，1H)；
13C NMR(100MHz，CDCl3)177.29，149.01，146.54，141.82，135.14，160.18，129.72，128.97，128.06，127.48，126.33，123.90，120.56，113.69，110.52，108.83，67.93，64.71，44.32。
Example 8:
2-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) were dissolved in 1mL of ethyl acetate to prepare a reaction system, and a solution prepared by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate was added to the reaction system for 1 hour by using an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 8, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 84 percent
1H NMR(400MHz，CDCl3)7.28-7.12(m，8H)，6.98(t，1H)，6.82(d，1H)，6.55(dt，2H)，5.81(s，1H)，5.62(d，1H)，5.06(d，1H)，4.72(d，1H)，3.91(t，1H)，3.66(d，1H)，3.01(d，1H)；
13C NMR(100MHz，CDCl3)177.39，141.72，135.37，129.76，129.44，128.89，128.03，127.83，127.50，127.09，123.95，123.70，120.89，119.18，113.15，110.13，68.18，64.49，44.24。
Example 9:
3-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) were dissolved in 1mL of ethyl acetate to prepare a reaction system, and a solution prepared by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate was added to the reaction system for 1 hour by using an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 9, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 82 percent of
1H NMR(400MHz，CDCl3)7.31-7.11(m，8H)，6.99(t，1H)，6.75(t，2H)，6.57(d，1H)，6.21(s，1H)，6.01(d，1H)，5.26(s，1H)，5.06(d，1H)，4.70(d，1H)，3.86-3.75(m，1H)，3.62(d，1H)，3.24(s，1H)；
13C NMR(100MHz，CDCl3)177.59，146.83，141.74，135.18，134.75，160.14，129.84，129.02，127.93，127.45，127.03，123.93，123.73，119.60，115.02，113.14，110.28，68.07，64.74，44.23。
Example 10:
a solution prepared by dissolving 2, 4-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 10, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 98 percent of
1H NMR(400MHz，CDCl3)7.19(dd，8H)，6.98(t，1H)，6.83(d，1H)，6.51(d，1H)，5.77(s，1H)，5.50(d，1H)，5.04(d，1H)，4.70(d，1H)，3.88(t，1H)，3.66(d，1H)，3.11(s，1H)；
13C NMR(100MHz，CDCl3)177.07，141.69，140.53，135.28，129.95，129.07，128.94，128.16，127.86，127.46，126.70，123.96，123.80，123.25，121.42，113.81，110.23，68.04，64.58，44.27。
Example 11:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 11, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 94 percent of
1H NMR(400MHz，CDCl3)7.32-7.14(m，7H)，7.07(d，1H)，7.00(t，1H)，6.78(d，1H)，6.50(d，1H)，5.88(s，1H)，5.67(s，1H)，5.09(d，1H)，4.73(d，1H)，3.88(t，1H)，3.66(d，1H)，3.11(d，1H)；
13C NMR(100MHz，CDCl3)176.85，142.59，141.74，135.05，160.15，160.09，129.21，127.94，127.25，126.22，123.90，123.87，119.12，118.95，112.91，110.44，68.20，64.38，44.41。
Example 12:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 12, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 64 percent
1H NMR(400MHz，CDCl3)8.89(s，1H)，7.80(d，1H)，7.27(dd，6H)，7.19(d，1H)，7.01(t，1H)，6.93(d，1H)，6.61(dd，1H)，5.63(dd，1H)，5.09(d，1H)，4.77(d，1H)，3.92(t，1H)，3.76(d，1H)，2.91(d，1H)；
13C NMR(100MHz，CDCl3)175.93，153.32，141.48，139.89，135.26，133.02，160.20，129.00，128.31，128.05，126.31，124.17，124.14-123.80，116.24112.80，112.54，110.41，68.15，64.58，44.42。
Example 13.
Dissolving 2-iodoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, maintaining the temperature at 60 ℃, and adding a solution prepared by dissolving 1-benzyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate by using an automatic sample injection pump into the reaction system for 1 hour. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 13, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 76 percent of
1H NMR(400MHz，CDCl3)7.66(dd，J＝7.8，1.3Hz，1H)，7.34-7.27(m，7H)，7.07(t，J＝7.4Hz，1H)，6.90(d，J＝7.8Hz，1H)，6.72(dd，J＝11.3，4.2Hz，1H)，6.45-6.34(m，1H)，5.72(s， 1H)，5.64(dd，J＝8.1，1.1Hz，1H)，5.13(d，J＝15.3Hz，1H)，4.81(d，J＝15.3Hz，1H)，4.00(t，J＝11.4Hz，1H)，3.72(dd，J＝11.5，2.5Hz，1H)，2.95(dd，J＝11.3，2.5Hz，1H)；
13C NMR(100MHz，CDCl3)177.26，145.04，141.79，139.39，135.39，129.74，129.14，128.89，128.03，127.84，126.92，123.94，123.69，120.44，112.51，110.10，87.14，68.26，65.01，44.24。
Example 14:
a solution prepared by dissolving 2-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo-5-methyl-2-oxoindole (0.10mmol) in 1mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 14, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 73 percent
1H NMR(400MHz，CDCl3)7.36-7.27(m，5H)，7.24(dd，1H)，7.12(s，1H)，7.07(d，1H)，6.78(d，1H)，6.66(td，1H)，6.60(td，1H)，5.87(s，1H)，5.71(dd，1H)，5.12(d，1H)，4.78(d，1H)，3.97(d，1H)，3.72(d，1H)，3.05(s，1H)，2.27(s，3H)；
13C NMR(100MHz，CDCl3)177.32，141.78，139.27，135.48，133.46，160.06，129.41，128.85，127.90(d，J＝14.2Hz)，127.51，127.04，124.63，120.83，119.09，113.14，109.91，68.23，64.44，44.24，21.05。
Example 15:
4-iodoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) are dissolved in 1mL of ethyl acetate to form a reaction system, the temperature is maintained at 60 ℃, and a solution formed by dissolving 1-benzyl-3-diazo-5-methyl-2-oxindole (0.10mmol) in 1mL of ethyl acetate is added into the reaction system for 1 hour by using an automatic sample injection pump. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 15, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 29 percent
1H NMR(400MHz，CDCl3)7.35-7.28(m，3H)，7.25-7.18(m，4H)，7.11(s，1H)，7.06(d，1H)，6.75(d，1H)，6.09-5.95(m，2H)，5.20(s，1H)，5.09(d，1H)，4.74(d，1H)，3.89(d，1H)，3.67(d，1H)，3.02(s，1H)，2.28(s，3H)；
13C NMR(100MHz，CDCl3)177.56，145.36，139.32，137.78，135.33，133.45，160.10，128.86，127.99，127.69，127.02，124.65，117.47，109.97，68.00，64.65，44.16，21.07.
Example 16:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo-5-methyl-2-oxindole (0.10mmol) in 1mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 16, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 84 percent
1H NMR(400MHz，CDCl3)7.38-7.23(m，5H)，6.94(dd，1H)，6.77(t，1H)，6.66(d，1H)，6.44(d，1H)，5.25(s，1H)，5.00(d，1H)，4.80(d，1H)，3.95(t，1H)，3.85(d，1H)，3.19(d，1H)，2.08(s，3H).
13C NMR(100MHz，CDCl3)177.95，140.54，140.00，135.61，131.95，129.65，129.62，128.78(s)，128.09，127.80，126.02，124.90，123.62，109.26，69.82，66.53，44.09，20.91。
Example 17:
a solution prepared by dissolving 2, 4, 6-dibromoaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an autoinjector pump to dissolve 1-benzyl-3-diazo-5-methyl-2-oxoindole (0.10mmol) in 1mL of ethyl acetate. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 17, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 80 percent of
NMR(400MHz，CDCl3)7.48(s，2H)，7.40-7.35(m，2H)，7.29(dt，3H)，6.98(d，1H)，6.71(d，1H)，6.34(s，1H)，5.27(s，1H)，5.00(d，1H)，4.79(d，1H)，3.99(t，1H)，3.80(d，1H)，3.26(s，1H)，2.11(s，3H)；
13C NMR(100MHz，CDCl3)177.88，141.94，140.69，135.39，134.21，132.11，129.86，128.80，128.03，127.93，125.18，121.04，115.81，109.37，70.01，66.38，44.12，21.03；
Example 18:
dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, maintaining the temperature at 60 ℃, and adding a solution formed by dissolving 1-benzyl-3-diazo-5-bromo-2-oxindole (0.10mmol) in 1mL of ethyl acetate by using an automatic sample injection pump into the reaction system for 1 hour. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 18, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 89 percent
1H NMR(400MHz，CDCl3)7.47-7.24(m，12H)，7.15(d，J＝8.0Hz，2H)，6.91-6.75(m，2H)，6.64(d，J＝8.3Hz，1H)，5.18(s，1H)，5.01(d，J＝15.5Hz，1H)，4.80(d，J＝15.4Hz，1H)，4.02-3.78(m，2H)，2.93(dd，J＝10.2，3.5Hz，1H)；
13C NMR(100MHz，CDCl3)177.29，141.99，139.43，135.01，132.22，129.66，128.90，128.31，128.02，127.72，127.36，124.15，115.08，110.95，69.44，66.62，44.19。
Example 19:
dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keeping the temperature at 60 ℃, and adding a solution formed by dissolving 1-benzyl-3-diazo-7-chloro-2-oxindole (0.10mmol) in 1mL of ethyl acetate by using an automatic sample injection pump into the reaction system for 1 hour. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 19, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 93 percent
1H NMR(400MHz，CDCl3)7.39-7.15(m，12H)，7.15-7.08(m，5H)，6.77(dt，J＝15.7，8.0Hz，4H)，6.59(d，J＝7.3Hz，2H)，5.43(d，J＝15.9Hz，2H)，5.29(d，J＝15.9Hz，2H)，5.22(s，2H)，4.01-3.77(m，4H)，3.14(s，2H)；
13C NMR(100MHz，CDCl3)178.55，139.57，139.05，137.17，132.04，129.50，129.12，128.56，128.26，127.41，127.19，123.85，123.26，122.73，115.76，69.81，65.97，45.09。
Example 20:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo-4-chloro-2-oxindole (0.10mmol) in 1mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 20, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 74 percent
1H NMR(400MHz，CDCl3)7.36-7.27(m，5H)，7.13(t，J＝8.1Hz，1H)，7.09(d，J＝8.0Hz，2H)，6.83(d，J＝8.2Hz，1H)，6.74(t，J＝8.0Hz，1H)，6.70(d，J＝7.8Hz，1H)，5.50(s，1H)，4.99(d，J＝15.5Hz，1H)，4.81(d，J＝15.5Hz，1H)，4.43(t，J＝11.0Hz，1H)，3.98-3.85(m，1H)，3.18-2.99(m，1H)；
13C NMR(100MHz，CDCl3)176.98，145.00，140.07，135.01，131.50，130.74，128.88，128.36，127.99，127.73，127.24，124.05，123.67，122.46，108.12，67.29，66.72，44.30
Example 21:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-methyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give a crude product, compound 21, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 78 percent of
1H NMR(400MHz，CDCl3)7.26(d，J＝6.5Hz，1H)，7.11(d，J＝8.0Hz，2H)，6.86-6.73(m，3H)，6.68(d，J＝7.3Hz，1H)，5.22(s，1H)，3.92(t，J＝10.8Hz，1H)，3.83(dd，J＝11.3，3.2Hz，1H)，3.24(s，3H)，3.15(d，J＝9.0Hz，1H)；
13C NMR(100MHz，CDCl3)178.16，143.79，140.04，129.61，129.50，128.18，125.89，124.08，123.68，122.35，108.62，69.49，66.45，26.27.
Example 22:
a solution prepared by dissolving 2, 6-dichloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate was added to a reaction system for 1 hour by using an automatic sample pump to dissolve 1-acetyl-3-diazo-2-oxindole (0.10mmol) in 1mL of ethyl acetate, while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 22, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-1: 1) to give the pure product. Yield: 89 percent
1H NMR(400MHz，CDCl3)8.23(d，1H)，7.60(t，1H)，7.13(d，2H)，6.98(t，1H)，6.81(t，1H)，6.74(d，1H)，5.12(s，1H)，3.92(s，2H)，2.73(s，3H)，2.62(d，1H)；
13C NMR(100MHz，CDCl3)178.52，170.75，140.25，139.02，129.93，129.70，128.34，125.24，124.86，124.13，123.71，116.91，69.57，66.59，26.68.
Example 23:
a solution prepared by dissolving 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) in 2mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo 5-methyl-2-oxindole (0.20mmol) in 4mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 23, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 73 percent
1H NMR(400MHz，CDCl3)7.34-7.16(m，6H)，7.00(d，J＝7.9Hz，1H)，6.58(d，J＝7.9Hz，1H)，4.91(d，J＝15.7Hz，1H)，4.76(d，J＝15.7Hz，1H)，4.48(s，1H)，3.88(q，J＝11.8Hz，2H)，3.36(s，1H)，2.28(s，3H).
13C NMR(100MHz，CDCl3)177.80，140.22)，135.28，133.14，130.25，128.85，127.76(d，J＝10.8Hz)，127.13，125.21，109.49，75.80，66.99，43.73，21.00
Example 24:
a solution prepared by dissolving 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) in 2mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo 5-bromo-2-oxindole (0.20mmol) in 4mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 24, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 54 percent
1H NMR(400MHz，CDCl3)7.47(s，1H)，7.21(ddd，J＝21.5，15.1，7.8Hz，6H)，6.49(d，J＝8.3Hz，1H)，4.85(d，J＝15.8Hz，1H)，4.69(d，J＝15.8Hz，1H)，4.42(s，1H)，3.81(s，2H)，3.22(s，1H).
13C NMR(100MHz，CDCl3)177.25，141.63，134.65，132.84，129.91，128.99，127.96，127.85，127.08，116.24，111.21，75.80，66.79，43.85.
Example 25:
a solution prepared by dissolving 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) in 2mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo 4-chloro-2-oxindole (0.20mmol) in 2mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 25, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 74 percent
1H NMR(400MHz，MeOD)8.78(d，J＝7.2Hz，2H)，8.68(dt，J＝23.3，6.9Hz，3H)，8.59(t，J＝8.0Hz，1H)，8.43(d，J＝8.2Hz，1H)，8.10(d，J＝7.8Hz，1H)，6.44(d，J＝16.0Hz，1H)，6.25(s，1H)，5.82(d，J＝10.1Hz，1H)，5.41(d，J＝10.1Hz，1H).
13C NMR(100MHz，MeOD)179.19，146.88，136.77，132.76，131.97，129.74，128.60，128.19，127.23，125.12，109.33，79.03，64.02，44.53.
Example 26:
a solution prepared by dissolving 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) in 2mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-benzyl-3-diazo 5-chloro-2-oxindole (0.20mmol) in 4mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 26, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 55 percent of
1H NMR(400MHz，MeOD)8.86(s，1H)，8.81-8.69(m，4H)，8.65(dd，J＝15.5，7.8Hz，2H)，8.15(d，J＝8.3Hz，1H)，6.41(d，J＝15.9Hz，1H)，6.32-6.19(m，5H)，5.31(s，2H).
13C NMR(100MHz，MeOD)179.12，143.27，136.81，133.34，130.31，129.77，129.44，128.65，128.25，125.82，111.79，77.89，66.85，44.44.
Example 27:
a solution of 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) dissolved in 2mL of ethyl acetate was added to the reaction system for 1 hour by dissolving 1-acetyl-3-diazo-2-oxindole (0.20mmol) in 2mL of ethyl acetate with an autosampler at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give a crude product, compound 27, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 46 percent
1H NMR(400MHz，MeOD)7.43-7.19(m，6H)，7.07(dd，J＝7.9，1.2Hz，1H)，6.76(s，1H)，4.99(d，J＝16.0Hz，1H)，4.86(d，J＝9.4Hz，1H)，3.89(s，2H).
13C NMR(100MHz，MeOD)179.50，146.04，136.73，136.19，129.97，129.83，128.72，128.23，126.53，123.82，111.07，77.51，66.83，44.41.
Example 28:
a solution prepared by dissolving 37% aqueous formaldehyde (98mg, containing 3.4mmol of water and 1.2mmol of formaldehyde) and rhodium acetate (0.004mmol) in 2mL of ethyl acetate was added to a reaction system for 1 hour by dissolving 1-acetyl-3-diazo-2-oxindole (0.20mmol) in 2mL of ethyl acetate with an automatic sample pump while maintaining the temperature at 60 ℃. After the injection, the reaction was continued for 1 hour with stirring at 60 ℃. The solvent was removed by rotary evaporation under reduced pressure to give the crude product, compound 28, whose structure is shown above. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give the pure product. Yield: 73 percent
1H NMR(400MHz，MeOD)7.40(d，J＝7.3Hz，1H)，7.26(t，J＝6.2Hz，4H)，7.21(dd，J＝8.3，3.7Hz，2H)，7.07(t，J＝7.7Hz，1H)，5.32(q，J＝16.5Hz，2H)，3.91(q，J＝10.4Hz，2H).
13C NMR(100MHz，MeOD)180.19，140.65，138.78，134.66，132.98，129.54，128.04，127.27，125.34，124.19，116.55，77.21，67.12，45.79.
Example 29: experiment on antitumor Activity
Taking human colon cancer HCT116 cells in logarithmic growth phase, digesting with pancreatin, resuspending the cells, counting with a cell counting plate, and inoculating the cells with the density of 2 multiplied by 103Culturing in 96-well culture plate at 37 deg.C under 5% CO2The incubator was used for overnight culture. Adding medicines with different concentration gradients, incubating for 72h, adding 20ul MTS solution into each well, incubating for 2 hr, measuring 490nm (L1) light absorption value by using SpectraMAX340, referencing to 690nm (L2) wavelength, (L1-L2) value is plotted against different inhibitor concentrations, and fitting to obtain IC50
Representative compounds 1, 3-6, 23-27 obtained in examples 1, 3-6 and 23-27 above were dissolved in DMSO and further diluted in the medium. The final concentration of DMSO is not more than 0.1% (v/v). Nutlin-3 was used as a control, which contained HCT116 cells and DMSO, but no compound, and a blank contained DMSO, but no cells. Within one set of experiments, the results for each experimental condition were averaged over 3 replicate wells. From all controlsBlank values were subtracted from the values of the samples and values. For each sample, the mean cell growth was expressed as a percentage of the mean growth of control cells, and IC was calculated using SigmaPlot10.050(the concentration of drug required to reduce cell growth to 50% of the control sample). Most of the tested compounds showed higher effect of cell growth of p53WTHCT116 compared to p53knockoutHCT 116. The corresponding test results are shown in table 1. Compared with a reference substance, the compound of the invention has higher cell growth effect of p53WTHCT116, has no obvious activity on the p53knockoutWTHCT116, has good selectivity, has potential anticancer activity prospect and further develops space for structural modification and activity test.
TABLE 1 inhibition data of HCT116 colon cancer cells by compounds 1, 3-6, 23-27
Claims (10)
1. A3-amino-3-hydroxymethyl oxoindole is characterized in that the structure is shown in formula (A),
wherein,
R1including alkyl, H, halogen, formate;
R2including alkyl, halogen, benzyl, formate, acyl;
R3including alkyl, halogen, formate, acyl.
2. A preparation method of 3-amino-3-hydroxymethyl oxoindole is characterized in that 3-diazooxoindole, aniline and formaldehyde are used, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, the aniline, formaldehyde aqueous solution and rhodium acetate are dissolved in the organic solvent, the 3-diazooxoindole is added under stirring, and the 3-amino-3-hydroxymethyl oxoindole is obtained through one-step reaction; wherein the aniline comprises aniline and substituted aniline;
the preparation method is shown as a reaction formula (I):
wherein,
R1including alkyl, H, halogen, formate;
R2including alkyl, halogen, benzyl, formate, acyl;
R3including alkyl, halogen, formate, acyl.
3. The process of claim 2, wherein the molar ratio of starting material to catalyst in the process is 3-diazooxindole, aniline, formaldehyde, rhodium acetate = 0.1: 1.0: 0.01-2: 1.0: 10.0: 0.10.
4. A3-hydroxy-3-hydroxymethyl oxoindole derivative is characterized in that the structure is shown as a formula (B),
wherein,
R4including alkyl, H, halogen, formate;
R5including alkyl, halogen, benzyl, formate, acyl.
5. A preparation method of a 3-hydroxy-3-hydroxymethyl oxoindole derivative, which is characterized in that 3-diazooxoindole, water and formaldehyde are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, the formaldehyde aqueous solution and rhodium acetate are dissolved in the organic solvent, the 3-diazooxoindole is added under stirring, and the 3-hydroxy-3-hydroxymethyl oxoindole derivative is obtained through one-step reaction;
the preparation method is shown as a reaction formula (II):
wherein,
R4including alkyl, H, halogen, formate;
R5including alkyl, halogen, benzyl, formate, acyl.
6. The method of claim 5, wherein the 3-diazooxindole, water, formaldehyde, rhodium acetate = 0.1: 3.0: 1.0: 0.01-2: 1.0: 10.0: 0.10.
7. The method according to claim 2 or 5, wherein the product obtained by the method is separated and purified by column chromatography.
8. The method according to claim 2 or 5, wherein the organic solvent comprises tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, toluene, ethyl acetate, and dichloromethane.
9. Use of 3-amino-3-hydroxymethyloxindole according to claim 1 for the preparation of an inhibitor of colon cancer cell growth.
10. Use of the 3-hydroxy-3-hydroxymethyloxoindole derivative according to claim 4 for the preparation of a colon cancer cell growth inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410018057.4A CN104774171B (en) | 2014-01-15 | 2014-01-15 | The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410018057.4A CN104774171B (en) | 2014-01-15 | 2014-01-15 | The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104774171A true CN104774171A (en) | 2015-07-15 |
| CN104774171B CN104774171B (en) | 2017-06-16 |
Family
ID=53615976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410018057.4A Active CN104774171B (en) | 2014-01-15 | 2014-01-15 | The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104774171B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801466A (en) * | 2016-04-26 | 2016-07-27 | 华东师范大学 | Beta-alkoxy-beta-quaternary carbon center-alpha-amino acid derivative and synthetic method and application thereof |
| CN106631976A (en) * | 2016-10-31 | 2017-05-10 | 华东师范大学 | 3-amino-3-hydroxymethyloxindole derivative as well as preparation method and application thereof |
| CN110551057A (en) * | 2018-05-31 | 2019-12-10 | 华东师范大学 | Chiral 3, 3-disubstituted oxindole derivative and synthesis method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445211A (en) * | 2002-03-20 | 2003-10-01 | 中国医学科学院药物研究所 | New amide ramification of sweetsop as well as its preparing method, its medication composition and usage |
| CN101415712A (en) * | 2006-02-07 | 2009-04-22 | 阿斯利康(瑞典)有限公司 | Use of spiro [imidazolidin-4, 3'-indole]2,2',5'(1H) trione in the treatment of diseases related to vanilloid receptor 1 |
-
2014
- 2014-01-15 CN CN201410018057.4A patent/CN104774171B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445211A (en) * | 2002-03-20 | 2003-10-01 | 中国医学科学院药物研究所 | New amide ramification of sweetsop as well as its preparing method, its medication composition and usage |
| CN101415712A (en) * | 2006-02-07 | 2009-04-22 | 阿斯利康(瑞典)有限公司 | Use of spiro [imidazolidin-4, 3'-indole]2,2',5'(1H) trione in the treatment of diseases related to vanilloid receptor 1 |
Non-Patent Citations (2)
| Title |
|---|
| QI-XIANG GUO，等: "Enantioselective and Solvent-Controlled Diastereoselective Mannich Reaction of Isatin Imines with Hydroxyacetone: Synthesis of 3-Substituted 3-Aminooxindoles", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| T. RAJASEKARAN，等: "Dual Behavior of Isatin-Based Cyclic Ketimines with Dicarbomethoxy Carbene: Expedient Synthesis of Highly Functionalized Spirooxindolyl Oxazolidines and Pyrrolines", 《ORG. LETT.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801466A (en) * | 2016-04-26 | 2016-07-27 | 华东师范大学 | Beta-alkoxy-beta-quaternary carbon center-alpha-amino acid derivative and synthetic method and application thereof |
| CN105801466B (en) * | 2016-04-26 | 2018-12-14 | 华东师范大学 | A kind of β-alkoxy-β-quaternary carbon center-alpha-amino acid derivatives and its synthetic method and application |
| CN106631976A (en) * | 2016-10-31 | 2017-05-10 | 华东师范大学 | 3-amino-3-hydroxymethyloxindole derivative as well as preparation method and application thereof |
| CN110551057A (en) * | 2018-05-31 | 2019-12-10 | 华东师范大学 | Chiral 3, 3-disubstituted oxindole derivative and synthesis method and application thereof |
| CN110551057B (en) * | 2018-05-31 | 2023-02-07 | 华东师范大学 | Chiral 3,3-disubstituted oxindole derivative and synthesis method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104774171B (en) | 2017-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108117507B (en) | Synthesis method and application of azaspiro cyclohexadienone | |
| CN102491931B (en) | 3-substituted indolone derivative and preparation method and application thereof | |
| CN112645809B (en) | Novel coronavirus 3CL protease inhibitor based on menadione structure | |
| CN104774171B (en) | The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application | |
| Khodairy et al. | Eco-friendly and efficiently synthesis, anti-inflammatory activity of 4-tosyloxyphenylpyrans via multi-component reaction under ultrasonic irradiation and room temperature conditions | |
| CN104402793A (en) | 3-substituted oxindole derivatives, and synthetic method and application thereof | |
| CN114292249A (en) | Cannabidiol-2-piperazinoate and application thereof | |
| CN111334070B (en) | 532nm excited rhodamine fluorescent dye and preparation method thereof | |
| CN109776384B (en) | 3-aryl-3' -amino di-quaternary carbon bis-oxoindole compound and synthesis method and application thereof | |
| CN100478333C (en) | Chiral and non-chiral diimidazolinylbenzene compounds and synthesis method | |
| CN104086525B (en) | A kind of there is anti-microbial activity spiral shell [tetralone-tetramethylene sulfide] derivative and synthetic method and application | |
| CN114292241B (en) | Cannabidiol-2-dioxopiperazinoate and application thereof | |
| CN114349695B (en) | Cannabidiol-2-nicotinate and application thereof | |
| CN106967095B (en) | A kind of method that catalysis prepares benzothiazole quinazoline derivant | |
| CN102070510B (en) | 3-hydroxyindole derivatives and synthesis method and use thereof | |
| CN111196791B (en) | Chiral gamma-butyrolactone derivative and synthesis method and application thereof | |
| CN110092769A (en) | A kind of chromene derivative and its synthetic method and application | |
| CN109320488B (en) | Water phase one-pot synthesis method of 3-hydroxyflavone and derivatives thereof | |
| CN103554005A (en) | Novel simple synthesis method of L-5-hydroxytryptophan | |
| CN107721895B (en) | Novel penta-substituted 2, 3-dihydropyrrole derivative and preparation method and application thereof | |
| CN102718818B (en) | Nitrogenous troxerutin derivative, preparation method thereof and application | |
| CN103467356B (en) | Tetrahydroindole compound, and preparation method and application thereof | |
| CN113861202B (en) | Large-scale preparation process of pterosin | |
| CN114292224B (en) | Cannabidiol-2- (N-acetyl) piperidine acid ester and application thereof | |
| CN114315680B (en) | Cannabidiol-2-pyrrolidine acid ester and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190118 Address after: 528437 Zone C, 13th Floor, No. 1 Health Road, Torch Development Zone, Zhongshan City, Guangzhou City, Guangdong Province Patentee after: Guangdong and Bo Pharmaceutical Co., Ltd. Address before: 200062 Zhongshan North Road, Putuo District, Shanghai, No. 3663 Patentee before: East China Normal University |