CN106316922B - One kind replacing oxoindole derivative and its synthetic method and application containing C-3 entirely - Google Patents
One kind replacing oxoindole derivative and its synthetic method and application containing C-3 entirely Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title abstract description 6
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical class C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 title abstract 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 150000007530 organic bases Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 claims description 28
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 150000008049 diazo compounds Chemical class 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 10
- 206010009944 Colon cancer Diseases 0.000 abstract description 9
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003426 co-catalyst Substances 0.000 abstract description 2
- 150000001989 diazonium salts Chemical class 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000007791 liquid phase Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 238000010587 phase diagram Methods 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- -1 amide compound Chemical class 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 239000012046 mixed solvent Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- MRBZKCMQZBKXMZ-HMKLVTIHSA-N chembl459275 Chemical compound C1=CC=C2C([C@@]34C5=CC=CC=C5N[C@@H]3N3C(=O)[C@@]5(C)SS[C@@]3([C@H]4O)C(=O)N5C)=CNC2=C1 MRBZKCMQZBKXMZ-HMKLVTIHSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- MRBZKCMQZBKXMZ-UHFFFAOYSA-N gliocladine C Natural products C1=CC=C2C(C34C5=CC=CC=C5NC3N3C(=O)C5(C)SSC3(C4O)C(=O)N5C)=CNC2=C1 MRBZKCMQZBKXMZ-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- XXUNFCYRICIBKD-UHFFFAOYSA-K C1=CCCCCCC1.[Ir](Cl)(Cl)Cl Chemical class C1=CCCCCCC1.[Ir](Cl)(Cl)Cl XXUNFCYRICIBKD-UHFFFAOYSA-K 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
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- 230000009982 effect on human Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005303 weighing 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
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses one kind to replace oxoindole derivative and its synthetic method containing C-3 entirely, using diazonium compound, MBH carbonate as raw material, using chiral organic base and allyl palladium chloride as co-catalyst, in organic solvent, the C-3 that contains is obtained by single step reaction replace oxoindole derivative entirely.Synthetic method of the present invention has high atom economy, highly selective advantage, and reaction condition is mild, safety easy to operate.What the present invention was prepared replaces oxoindole derivative to can be used as important chemical industry and medicine intermediate entirely containing C-3, and has bioactivity, suitable for preparing drugs against colon cancer.
Description
Technical Field
The invention relates to the field of synthetic medicine chemical industry, and mainly relates to a C-3-containing fully-substituted oxindole derivative, a rapid and high-selectivity chemical synthesis method and application thereof.
Background
The oxindole derivative is an indispensable important skeleton structural unit of natural products and synthetic important medicaments, contains the skeleton structure in the structures of various marine organisms and fungal metabolites, and has biological activities such as antibiosis, antitumor, anticancer, enzyme inhibition and the like, so the research on the synthetic method is always a hot topic in the field of research on natural products and the field of medicinal chemistry. In recent years, chemists have also found a variety of methods for synthesizing oxindole derivatives, such as that when OVman synthesizes gliocladine C (Gliocladine C), the structural skeleton of oxindole is obtained by using Fu catalysis (Angew. chem. int. Ed.,2003,42,3921-3924), (J.Am. chem. Soc.,2011,133, 6549-6552); the construction of the structural skeleton is completed by Stephenson using a photosensitive catalyst Ru (Angew. chem. int. Ed.,2011,50, 9655-9659). Later, new synthesis methods are discovered successively, but the new synthesis methods and routes have the defects of long steps, high cost, long time consumption, low yield, complex operation and post-treatment and the like, are difficult to apply on a large scale in the aspect of industrialization, and have limited economic value. Therefore, the above methods are not suitable for the application of C-3-containing fully substituted oxindole derivatives in organic synthesis and industrial synthesis thereof.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a C-3 fully-substituted oxindole derivative and a synthesis method thereof, the method has short preparation route, simple operation and high efficiency, and the C-3 fully-substituted oxindole derivative is a C-3 fully-substituted quaternary carbon chiral center compound. The method takes diazo compound, 2- ((1 '-aryl) (1' -tert-butyloxycarbonyloxy)) methacrylate (MBH carbonate) as raw materials, chiral organic base and allyl palladium chloride [ Pd (allyl) Cl ]]2Under the co-catalysis, the C-3-containing fully substituted oxindole derivative is prepared. Compared with the reported synthetic method, the method takes cheap and easily-obtained compounds as raw materials, has the characteristics of mild reaction conditions, short reaction route, quick reaction, low cost, less waste, simple operation, high atom economy and the like, and has wide application prospect in the field of drug synthesis.
The C-3-containing fully-substituted oxindole derivative provided by the invention is shown as a formula (I),
wherein,
ar is aryl selected from phenyl, halogen substituted phenyl, nitro substituted phenyl, C1-C10 alkyl substituted phenyl;
R1is a benzene ring substituent selected from hydrogen, halogen, C1-C10 alkyl, nitro and methoxy;
R2is C1-C10 alkyl, benzyl;
R3is C1-C10 alkyl, benzyl;
R4alkyl at position C1-C10.
Preferably, the first and second electrodes are formed of a metal,
ar is aryl selected from phenyl, 4-bromophenyl, 4-methylphenyl, 3-chlorophenyl, 4-nitrophenyl, 4-fluorophenyl;
R1is a benzene ring substituent selected from hydrogen, 4-chlorine, 4-bromine, 4-methyl, 4-nitro, 4-fluorine and 4-methoxy;
R2is alkyl selected from methyl, ethyl, benzyl;
R3is alkyl selected from methyl, ethyl, benzyl;
R4the alkyl group is selected from methyl and tertiary butyl.
It is further preferred that the first and second liquid crystal compositions,
ar is aryl selected from phenyl, 4-bromophenyl, 4-nitrophenyl, 4-fluorophenyl;
R1is a benzene ring substituent selected from hydrogen and 4-bromine;
R2is alkyl selected from methyl;
R3is alkyl selected from methyl;
R4the alkyl group is selected from methyl and tertiary butyl.
The invention provides a synthesis method of a C-3-containing fully-substituted oxindole derivative, which is characterized in that a diazo compound shown in a formula (1) and 2- ((1 '-aryl) (1' -tert-butyloxycarbonyloxy)) methacrylate (MBH carbonate) shown in a formula (2) are used as raw materials, and the C-3-containing fully-substituted oxindole derivative shown in a formula (I) is prepared through one-step reaction in an organic solvent under the co-catalysis of chiral organic base and a metal catalyst.
Specifically, the method comprises the following steps: dissolving 2- ((1 '-aryl) (1' -tert-butyloxycarbonyloxy)) methacrylate (MBH carbonate) shown in a formula (2), chiral organic alkali and a metal catalyst in an organic solvent to prepare a mixed solution; dissolving a diazo compound shown in a formula (1) in an organic solvent to prepare a diazo compound solution; adding a diazo compound solution into the mixed solution; the C-3-containing fully substituted oxindole derivative with high enantioselectivity and diastereoselectivity shown in a formula (I) is obtained through reaction and purification, and the synthetic reaction is shown in a formula (II):
wherein,
ar is aryl selected from phenyl, halogen substituted phenyl, nitro substituted phenyl, C1-C10 alkyl substituted phenyl;
R1is a benzene ring substituent selected from hydrogen, halogen, C1-C10 alkyl, nitro and methoxy;
R2is C1-C10 alkyl, benzyl;
R3is C1-C10 alkyl, benzyl;
R4alkyl at position C1-C10.
Preferably, the first and second electrodes are formed of a metal,
ar is aryl selected from phenyl, 4-bromophenyl, 4-methylphenyl, 3-chlorophenyl, 4-nitrophenyl, 4-fluorophenyl;
R1is a benzene ring substituent selected from hydrogen, 4-chlorine, 4-bromine, 4-methyl, 4-nitro, 4-fluorine and 4-methoxy;
R2is alkyl selected from methyl, ethyl, benzyl;
R3is alkyl selected from methyl, ethyl, benzyl;
R4the alkyl group is selected from methyl and tertiary butyl.
It is further preferred that the first and second liquid crystal compositions,
ar is aryl selected from phenyl, 4-bromophenyl, 4-nitrophenyl, 4-fluorophenyl;
R1is a benzene ring substituent selected from hydrogen and 4-bromine;
R2is alkyl selected from methyl;
R3is alkyl selected from methyl;
R4the alkyl group is selected from methyl and tertiary butyl.
In the method, the charging amount molar ratio of the MBH carbonate, the diazo compound shown in the formula (1), the chiral organic base and the metal catalyst is MBH carbonate: a diazo compound represented by the formula (1): chiral organic base: a metal catalyst of 1.0:0.8 to 1.5:0.15 to 0.30:0.01 to 0.08, preferably, MBH carbonate: a diazo compound represented by the formula (1): chiral organic base: the molar ratio of the metal catalyst is as follows: 1.0:1.5:0.25:0.05.
In the method, the ratio of the dosage of the organic solvent to the dosage of the MBH carbonate is 5-10 mL to 1 mmol. Preferably, the ratio of the amount of organic solvent to the amount of MBH carbonate is 10mL to 1 mmol.
In the method, the reaction temperature is-20-120 ℃. Preferably, the reaction temperature is 20 ℃.
In the method, the reaction time is 24-120 h. Preferably, the reaction time is 36-48 h.
In the method of the present invention, the diazonium compound comprises an N-alkyl-N-aryldiazonium amide compound.
In the method of the present invention, the organic solvent comprises dichloromethane, chloroform, toluene, 1, 2-dichloroethane, toluene and isopropyl acetate. Preferably, the organic solvent is a mixed solution of isopropyl acetate and toluene mixed at a volume of 1: 1.
In the process of the invention, the metal catalyst used is selected from the group consisting of allylpalladium chloride ([ Pd (Allyl) Cl)]2) Cyclooctene iridium chloride dimer ([ Ir (coe) Cl)]2) Palladium dichloride (PdCl)2) Tetratriphenylphosphine palladium (Pd (PPh)3)4) Palladium acetate (Pd (OAc)2) And [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl2). Preferably, the metal catalyst is selected from allylpalladium chloride [ Pd (allyl) Cl]2. The chiral organic base and the metal catalyst are co-catalysts.
In the method, the organic base is chiral organic base selected from chiral β -ICD (formula (III)), 4-dimethylaminopyridine (formula (IV)), and chiral 3- ((2-substituted cyclopentylamino) formyl) -4-cyclopentylamino pyridine (formula (V)), preferably, the organic base is chiral β -ICD.
In a specific embodiment, the method for synthesizing the C-3-containing fully substituted oxindole derivative comprises the following steps of weighing raw materials according to the molar ratio of MBH carbonate to N-alkyl-N-aryl diazoamide to chirality β -ICD to allyl palladium chloride being 1.0:1.5:0.25:0.05 (based on the using amount of the MBH carbonate), dissolving the MBH carbonate, the chirality β -ICD and the allyl palladium chloride in an organic solvent to prepare a mixed solution, dissolving an N-alkyl-N-aryl diazoamide compound in an organic solvent to prepare a diazoamide compound solution, adding the diazoamide compound solution into the mixed solution by using an injection pump at room temperature, stirring violently, continuing to stir the diazoamide solution at room temperature for 36-48 hours after dropwise adding the diazoamide compound solution, till the diazoamide compound is completely consumed, and performing column chromatography on a crude product to obtain a pure product, namely the C-3-containing fully substituted oxindole derivative shown in formula (I), wherein the petroleum ether is ethyl acetate being 15: 1-5: 1 as an eluent.
The invention also provides the C-3-containing fully-substituted oxindole derivative in the formula (I) prepared by the synthesis method.
The invention also provides application of the C-3-containing fully-substituted oxindole derivative in the formula (I) in preparation of anti-tumor drugs.
The invention also provides application of the C-3-containing fully-substituted oxindole derivative shown in the formula (I) in preparation of anti-colon cancer drugs.
The invention also provides application of the C-3-containing fully-substituted oxindole derivative shown in the formula (I) in preparation of a medicine for resisting colon cancer HCT116 cells.
The C-3-containing fully-substituted oxindole derivative is an important chemical and pharmaceutical intermediate, is widely applied to the field of pharmaceutical chemicals, and has a great application prospect. The synthetic method of the invention takes cheap and easily available compounds as raw materials, and has the advantages of mild reaction conditions, few reaction steps, fast reaction, low cost, less generated waste, simple and safe operation, high atom economy, high selectivity and the like.
Drawings
FIG. 1 shows the product obtained in example 11H NMR scheme.
FIG. 2 shows the product obtained in example 113Schematic C NMR.
FIG. 3 is a liquid phase diagram of the racemic product obtained in example 1.
FIG. 4 is a liquid phase diagram of the chiral product obtained in example 1.
FIG. 5 shows the product obtained in example 21H NMR scheme.
FIG. 6 shows the product obtained in example 213Schematic C NMR.
FIG. 7 shows the product obtained in example 31H NMR scheme.
FIG. 8 shows the product obtained in example 313Schematic C NMR.
FIG. 9 is a liquid phase diagram of the racemic product obtained in example 3.
FIG. 10 is a liquid phase diagram of the chiral product obtained in example 3.
FIG. 11 shows the product obtained in example 41H NMR scheme.
FIG. 12 shows the results obtained in example 413Schematic C NMR.
FIG. 13 is a liquid phase diagram of the racemic product obtained in example 4.
FIG. 14 is a liquid phase diagram of the chiral product obtained in example 4.
FIG. 15 shows the product obtained in example 51H NMR scheme.
FIG. 16 shows the results of example 513Schematic C NMR.
FIG. 17 shows the results of example 519F NMR scheme.
FIG. 18 is a liquid phase diagram of the racemic product obtained in example 5.
FIG. 19 is a liquid phase diagram of the chiral product obtained in example 5.
FIG. 20 shows the results of the experiment in which the product obtained in example 1 inhibited HCT116 cells.
FIG. 21 shows the results of the experiment in which the product obtained in example 3 inhibited HCT116 cells.
FIG. 22 shows the results of the experiment in which the product obtained in example 4 inhibited HCT116 cells.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, and 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 procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The preparation method for synthesizing the C-3-containing fully-substituted oxindole derivative comprises the steps of dissolving MBH carbonate and β -ICD in an organic solvent to prepare a mixed solution, dissolving a diazoamide compound in the organic solvent to prepare a diazoamide compound solution, adding the diazoamide compound solution into the mixed solution by using an injection pump, and after the injection is finished for 36-48 hours, carrying out column chromatography on a crude product (petroleum ether and ethyl acetate are 15: 1-5: 1 are used as eluent) to obtain a pure product, so that the C-3-containing fully-substituted oxindole derivative with high enantioselectivity and high diastereoselectivity is obtained.
The synthesis reaction process is as follows:
wherein,
ar is aryl selected from phenyl, 4-bromophenyl, 4-methylphenyl, 3-chlorophenyl, 4-nitrophenyl, 4-fluorophenyl;
R1is a benzene ring substituent selected from hydrogen, 4-chlorine, 4-bromine, 4-methyl, 4-nitro, 4-fluorine and 4-methoxy;
R2is alkyl selected from methyl, ethyl, benzyl;
R3is alkyl selected from methyl, ethyl, benzyl;
R4the alkyl group is selected from methyl and tertiary butyl.
Example 1
MBH carbonate (0.2mmol), β -ICD (0.25mmol) and allylpalladium chloride (0.05mmol) were dissolved in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a mixed solution a, and stirred at room temperature for 10 minutes, then N-alkyl-N-aryldiazoamide (0.3mmol) was dissolved in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a solution B, and then solution B was dissolved in 20 mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a solution BoUnder C, the mixed solution A was added by a syringe pump over 1 hour. Stirring for 36-48 hours, purifying the reaction mixture by column chromatography to obtain a pure product, wherein the structure of the pure product is shown as a formula (a), and the pure product is tert-butyl-2- ((R) - (4-bromophenyl) - (R) -1, 3-dimethyl-2-oxoindole-3-substituted) methyl) propaneThe yield of the alkenoic acid ester is 64 percent, the dr value is equal to 95:5, and the ee value is more than 99 percent. Process for producing compound represented by formula (a)1The H NMR is shown in FIG. 1, which13The C NMR is shown in FIG. 2, the liquid phase diagram of the racemic product is shown in FIG. 3, and the liquid phase diagram of the chiral product is shown in FIG. 4.
1H NMR(400MHz,CDCl3)δ7.37(d,J＝8.0Hz,1H),7.26(m,2H),7.18(d,1H),6.92(s,1H),6.64(d,J＝8.1Hz,1H),6.19(s,1H),5.35(s,1H),4.55(s,1H),3.11(s,3H),1.37(s,3H),1.31(s,9H).13C NMR(100MHz,CDCl3)δ179.11,165.69,142.20,141.22,137.09,134.84,130.77,130.37,127.80,127.70,127.34,124.71,114.89,109.30,80.96,51.34,50.83,27.82,26.24,24.97.HRMS(ESI):Calcd.for C24H26BrNO3Na[M+Na]+478.0994, Found 478.0979 HPLC (chiral IA, wavelength equal to 254 nm, n-hexane/ethanol 20: 1, flow rate 1.0 ml/min), tmajor6.86 min, tminor6.22 minutes.
Example 2
Dissolving MBH carbonate (0.2mmol), β -ICD (0.25mmol) and allyl palladium chloride (0.05mmol) in a mixed solvent of 1mL of i-PrOAc: DCM ═ 1:1 to prepare a mixed solution A, stirring at room temperature for 10 minutes, dissolving N-alkyl-N-aryl diazoamide (0.3mmol) in a mixed solvent of 1mL of i-PrOAc: DCM ═ 1:1 to prepare a solution B, adding the solution B into the mixed solution A at 20 ℃ by using an injection pump, stirring for 36-48 hours, and purifying the reaction mixture by column chromatography to obtain a pure product, wherein the pure product is a compound shown as a formula (B) and is methyl-2- ((R) - ((R) -5-bromo-1, 3-dimethyl-2-oxindole-3-substituted) (phenyl) methyl) acrylate, the yield is 75%, and the dr value is equal to 91:9, and the ee value race value is equal to that of the compound shown as the formula (B)1The H NMR is shown in FIG. 5, which13The C NMR chart is shown in FIG. 6.
1H NMR(400MHz,CDCl3)δ7.31(m,6H),6.90(s,1H),6.30(s,1H),5.54(s,1H),4.63(s,1H),3.64(s,3H),3.09(s,3H),1.38(s,3H).13C NMR(100MHz,CDCl3)δ179.07,166.90,142.27,139.62,136.38,134.71,130.90,130.31,127.81,127.55,126.20,114.89,109.32,52.20,51.16,51.13,26.23,24.59.HRMS(ESI):Calcd.for C21H20BrNO3Na[M+Na]+:436.0524,Found:436.0502.
Example 3
Dissolving MBH carbonate (0.2mmol), β -ICD (0.25mmol) and allyl palladium chloride (0.05mmol) in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a mixed solution A, stirring at room temperature for 10 minutes, dissolving N-alkyl N-aryl diazoamide (0.3mmol) in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a solution B, adding the solution B into the mixed solution A at 20 ℃ by using an injection pump, stirring for 36-48 hours, and purifying the reaction mixture by column chromatography to obtain a pure product, wherein the pure product is represented by the formula (c) and is tert-butyl-2- ((R) - ((R) -1, 3-dimethyl-2-oxoindole-3-substituted) (phenyl) methyl) acrylate, the yield is 64%, the dr value is greater than 95:5, and the ee value is equal to 84%1The H NMR is shown in FIG. 7, which13The C NMR is shown in FIG. 8, the liquid phase diagram of the racemic product is shown in FIG. 9, and the liquid phase diagram of the chiral product is shown in FIG. 10.
1H NMR(400MHz,CDCl3)δ7.38–7.05(m,6H),6.96(t,J＝7.5Hz,1H),6.79(t,J＝8.2Hz,2H),6.15(s,1H),5.29(s,1H),4.56(s,1H),3.15(s,3H),1.37(s,3H),1.29(s,9H).13C NMR(100MHz,CDCl3)δ179.74,165.82,143.16,141.47,137.61,132.66,130.55,127.96,127.56,127.05,124.61,124.58,122.18,107.97,80.80,51.30,50.55,27.81,26.19,25.27.HRMS(ESI):Calcd.for C24H27NO3Na[M+Na]+400.1889, Found:400.1891 HPLC (chiral IA, wavelength equal to 254 nm, n-hexane/ethanol equal to 20: 1, flow rate equal to 1.0 ml/min), tmajor7.98 min, tminor6.64 min.
Example 4
Dissolving MBH carbonate (0.2mmol), β -ICD (0.25mmol) and allyl palladium chloride (0.05mmol) in a mixed solvent of 1mL of i-PrOAc: DCM ═ 1:1 to prepare a mixed solution A, stirring at room temperature for 10 minutes, dissolving N-alkyl-N-aryl diazoamide (0.3mmol) in a mixed solvent of 1mL of i-PrOAc: DCM ═ 1:1 to prepare a solution B, adding the solution B into the mixed solution A at 20 ℃ by using an injection pump within 1 hour, stirring for 36-48 hours, and purifying the reaction mixture by column chromatography to obtain a pure product, wherein the structure of the pure product is shown as a formula (d) and is tert-butyl-2- ((R) - ((R) -1, 3-dimethyl-2-oxindole-3-substituted) (4-nitrophenyl) methyl) acrylate, the yield is 61%, the dr value is 81:19, and the ee value is 38%1The H NMR is shown in FIG. 11, which13The C NMR is shown in FIG. 12, the liquid phase diagram of the racemic product is shown in FIG. 13, and the liquid phase diagram of the chiral product is shown in FIG. 14.
1H NMR(400MHz,CDCl3)δ8.08(d,J＝8.6Hz,2H),7.31(d,J＝8.6Hz,2H),7.29–7.24(t,1H),7.02(t,J＝7.5Hz,1H),6.88(d,J＝7.3Hz,1H),6.75(d,J＝7.8Hz,1H),6.34(s,1H),5.82(s,1H),4.66(s,1H),3.10(s,3H),1.42(s,3H),1.34(s,9H).13C NMR(100MHz,CDCl3)δ178.85,165.43,147.00,145.85,142.95,139.94,132.19,130.98,128.50,126.87,123.81,122.71,122.57,108.28,81.38,51.51,50.71,27.89,26.22,24.44.HRMS(ESI):Calcd.for C24H26N2O5Na[M+Na]+445.1739, Found 445.1746.HPLC (chiral IA, wavelength equal to 254 nm, n-hexane/ethanol 20: 1, flow rate 1.0 ml/min), tmajor30.55 min, tminor15.60 minutes.
Example 5
Dissolving MBH carbonate (0.2mmol), β -ICD (0.25mmol) and allyl palladium chloride (0.05mmol) in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a mixed solution A, stirring at room temperature for 10 minutes, dissolving N-alkyl-N-aryl diazoamide (0.3mmol) in 1mL of a mixed solvent of i-PrOAc: DCM ═ 1:1 to prepare a solution B, adding the solution B into the mixed solution A at 20 ℃ by using an injection pump, stirring for 36-48 hours, purifying the reaction mixture by column chromatography to obtain a pure product, wherein the pure product is represented by the formula (e) and is tert-butyl-2- ((R) - ((R) -1, 3-dimethyl-2-oxoindole-3-substituted) (4-fluorophenyl) methyl) acrylate, the yield is 70%, the dr value is greater than 95:5, and the ee value is equal to 79%1The H NMR is shown in FIG. 15, which13The schematic diagram of C NMR is shown in FIG. 16,19the F NMR is shown in figure 17, the liquid phase diagram of the racemic product is shown in figure 18, and the liquid phase diagram of the chiral product is shown in figure 19.
1H NMR(400MHz,CDCl3)δ7.26(t,J＝9.3,6.1Hz,1H),7.13(dd,J＝8.2,5.6Hz,1H),6.98(t,J＝7.6Hz,1H),6.93(t,J＝8.6Hz,2H),6.82(d,J＝7.4Hz,1H),6.77(d,J＝7.8Hz,1H),6.19(s,1H),5.44(s,1H),4.54(s,1H),3.13(s,3H),1.37(s,3H),1.32(s,9H).13C NMR(100MHz,CDCl3)δ179.52,165.72,163.20,160.76,143.12,141.23,133.41,133.38,132.61,131.89,131.81,128.09,125.03,124.27,122.28,114.50,114.29,108.05,80.95,50.70,50.68,27.85,26.17,24.90.19F NMR(376MHz,CDCl3)δ-115.78,-115.79,-115.80,-115.80,-115.81,-115.82,-115.83,-115.84,-115.85.HRMS(ESI):Calcd.for C24H26FNO3Na[M+Na]+418.1794, Found:418.1807 HPLC (chiral IA, wavelength equal to 254 nm, n-hexane/ethanol 20: 1, flow rate 1.0 ml/min), tmajor6.95 min, tminor5.74 min.
Example 6 antitumor Activity assay
1) Tumor inhibition rate test
In this example, the biological activity of the compound of the present invention was tested by the CCK8 method, and the inhibition of tumor cells was investigated using the compound of the present invention (prepared in example 1, example 2, example 3, example 4, and example 5). The cell lines specifically used in this example are: HCT116 (human colon cancer cells). The density of the cell seed plate is 3000/hole; the administration concentration is as follows: the invention contains 30.0 mu Mol/L of C-3 fully-substituted oxindole derivative; the action time of the medicine is as follows: 72 hours; positive control: PTX, concentration: 100nMol/L, and the inhibition rate is 95%.
Table one: data on the inhibition of HCT116 (human colon cancer cells) by C-3-containing fully-substituted oxindole derivative
Experimental results show that the C-3-containing fully-substituted oxindole derivative has a good inhibition effect on human colon cancer cells. Thus, further activity tests were performed for example 1, example 3 and example 4.
2)IC50Value testing
Human colon cancer HCT116 cells were seeded in McCoy, s medium (10% serum, 1% penicillin-streptomycin)). Standing at 37 deg.C for 5% CO2In the incubator, the cells are subcultured every 2-3 days, and cells in logarithmic growth phase are taken out in the experiment. Determination of IC by CCK-8 method50The value is obtained.
Cells in logarithmic growth phase are taken, the cell suspension is adjusted to 2 ten thousand per ml by prepared fresh McCoy, s culture solution, and 100ul (2 thousand cells per well) of cell suspension is inoculated to a 96-well culture plate. Placing in 5% CO2After incubation culture for 12h in an incubator at 37 ℃, replacing fresh cell culture solution, adding DMSO (dimethyl sulfoxide) into each hole for isometric dilution of concentration gradient drugs, incubating with cells for 72h, replacing fresh cell culture solution, adding 10ul of CCK-8 solution into each hole, continuing incubation for 2-4 h, terminating culture, and detecting absorbance at 450nm by using a multifunctional microplate reader (Molecular Devices M5).
The test compounds a, c, d prepared in example 1, example 3 and example 4 were dissolved in DMSO and further diluted in culture broth. The final concentration of DMSO is not more than 0.1% (v/v). Control groups contained HCT116 cells and equal volume of DMSO but no compound, blank groups contained equal volume of DMSO but no cells. Within one experiment, 3 replicates were set for each experimental condition (final statistics are not mean, are error bar). Blank values were subtracted from all control and sample values. For each sample, the average cell growth was expressed as a percentage of the average control cell growth, and IC was calculated using GraphPad Prim650(the concentration of drug required to reduce cell growth to 50% of the control). The detection result is as follows: as shown in FIG. 20, IC of Compound a50A value of 4.643 μ M; as shown in FIG. 21, IC of Compound c50A value of 4.290 μ M; as shown in FIG. 22, IC of Compound d50The value was 3.800. mu.M.
In conclusion, the experimental results show that the C-3-containing fully-substituted oxindole derivative has a remarkable inhibiting effect on human colon cancer cells, and provides a wide development space for developing medicaments for treating colon cancer.
Claims (4)
1. A synthesis method of a C-3-containing fully-substituted oxindole derivative is characterized in that a diazo compound shown in a formula (1) and 2- ((1 '-aryl) (1' -tert-butoxycarbonyloxy)) methacrylate shown in a formula (2) are used as raw materials, and the C-3-containing fully-substituted oxindole derivative shown in a formula (I) is prepared through one-step reaction in an organic solvent under the co-catalysis of chiral organic base and a metal catalyst, wherein the chiral organic base is β -ICD, the metal catalyst is allyl palladium chloride, and the reaction is shown in a formula (II):
wherein Ar is aryl selected from phenyl, halogen substituted phenyl, nitro substituted phenyl, C1-C10 alkyl substituted phenyl;
R1is a benzene ring substituent selected from hydrogen, halogen, C1-C10 alkyl, nitro and methoxy;
R2is C1-C10 alkyl, benzyl;
R3is C1-C10 alkyl, benzyl;
R4is C1-C10 alkyl.
2. The synthesis method according to claim 1, wherein the reaction temperature is-20 to 120 ℃; the reaction time is 24-120 h.
3. The method of claim 1, wherein the molar ratio of 2- ((1 '-aryl) (1' -tert-butoxycarbonyloxy)) methacrylate to diazo compound, β -ICD, and allylpalladium chloride is 2- ((1 '-aryl) (1' -tert-butoxycarbonyloxy)) methacrylate to diazo compound, β -ICD allylpalladium chloride is 1.0:0.8 to 1.5:0.15 to 0.30:0.01 to 0.08, and the ratio of the amount of organic solvent to 2- ((1 '-aryl) (1' -tert-butoxycarbonyloxy)) methacrylate is 5mL to 10mL to 1 mmol.
4. The method of synthesis according to claim 1, wherein the organic solvent is selected from the group consisting of dichloromethane, trichloromethane, toluene, 1, 2-dichloroethane, toluene and isopropyl acetate.
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