CN103554120B - Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound - Google Patents
Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- JXDYKVIHCLTXOP-UHFFFAOYSA-N Pseudoisatin Natural products C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 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 12
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- -1 oxindole polycyclic compound Chemical class 0.000 claims description 26
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 17
- 150000001299 aldehydes Chemical class 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- QBCDBWLSKXWSCZ-UHFFFAOYSA-N 2,3-dioxoindole-1-diazonium Chemical compound N1(C(=O)C(=O)C2=CC=CC=C12)[N+]#N QBCDBWLSKXWSCZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- 230000002572 peristaltic effect Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims description 2
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 claims description 2
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 claims description 2
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 2
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 2
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 2
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- HYMGGYWJUFNMHA-UHFFFAOYSA-N CC=1C=C2C(C(N(C2=CC1)[N+]#N)=O)=O Chemical group CC=1C=C2C(C(N(C2=CC1)[N+]#N)=O)=O HYMGGYWJUFNMHA-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- 108090000461 Aurora Kinase A Proteins 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 abstract description 2
- 238000006043 Intramolecular Michael addition reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 125000000843 phenylene group Chemical class C1(=C(C=CC=C1)*)* 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 102000003989 Aurora kinases Human genes 0.000 description 7
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- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 2
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
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- 239000003208 petroleum Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- PTXVSDKCUJCCLC-UHFFFAOYSA-N 1-hydroxyindole Chemical compound C1=CC=C2N(O)C=CC2=C1 PTXVSDKCUJCCLC-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- 102100032306 Aurora kinase B Human genes 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 241001598984 Bromius obscurus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 230000024321 chromosome segregation Effects 0.000 description 1
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- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
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- 230000035484 reaction time Effects 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound as shown in a formula (I). The preparation method comprises the following steps: performing (3+2) cycloaddition on isatin diazo, aldehyde and ortho-nitro-substituted phenylene under the catalysis of rhodium acetate to construct an intermediate containing a 3, 3-spiro (2-tetrahydrofuranyl)-oxindole structure, adding a base, and then performing intramolecular Michael addition to further perform ring-closure synthesis of a target product. According to the preparation method, raw materials are available, and five cyclic structures are constructed by adopting one-pot method. The preparation method is short in preparation route, simple to operate, mild in reaction conditions and high in yield, and has high atom economy and no environment pollution. The product prepared according to the method can be used for providing various compound frameworks, and has the property of inhibiting the activity of AURKA.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical synthetic chemistry, and relates to a preparation method of a 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound.
Background
The naked ring skeleton of the oxindole is an important structural monomer and exists in a plurality of natural products and pharmaceutical active intermediates (Angew. chem., int. Ed.2007,46, 8748-. Among them, the naked ring structure of oxindole and tetrahydrofuran is not only an intermediate fragment of many natural products but also has excellent biological activity, for example, Ia-b below is a progesterone receptor inhibitor, Ic is used for treating hypertension, IIa-b is used for treating skin itch and cancer, etc. (PCTInt. Appl. Patent2,000,066,167,2000; U.S. Patent4,226,860A, 1980; PCTInt. Appl. Patent2,006,110,917,2006).
The 3, 3-spiro (2-tetrahydrofuran) oxindole compound (J.org.chem.2004,69,5631-5637) was first constructed by Rh catalyzed multicomponent reaction of diazoamide in 2004 by Muthassamy, and the Schreiber group also attempted to construct the 3, 3-spiro (2-tetrahydrofuran) oxindole compound (J.Am.chem.Soc.2007,129,1020-1021) by a method of isatin cyclization in the presence of a Lewis acid-induced silicon reagent. However, the methods have the defects of low substrate universality, harsh reaction conditions and the like. Therefore, the development of a new synthesis method of the indole oxide and tetrahydrofuran naked ring structure has important significance.
Disclosure of Invention
The invention overcomes the defects in the prior art and provides a preparation method of a 3, 3-spiro (2-tetrahydrofuran) oxindole compound. The method comprises the steps of forming carbonyl ylide by isatin diazo and aldehyde under the catalysis of rhodium acetate, carrying out 1, 3-dipolar cycloaddition reaction with an ortho-substituted phenylnitroene and other homophilic bodies to form a 3, 3-spiro (2-tetrahydrofuran) oxoindole structural intermediate 4, adding alkali, and further closing the ring through intramolecular Michael addition reaction to construct a polycyclic compound 5 containing 3, 3-spiro (2-tetrahydrofuran) oxoindole (the reaction process is shown as a formula (III)). The invention efficiently and quickly constructs the polycyclic compound of the 3, 3-spiro (2-tetrahydrofuran) oxoindole from simple and easily obtained raw materials by one step, and biological activity tests show that the compound has good inhibitory activity on aurora kinase A (AURKA), thereby providing a new method for treating tumors. .
The invention provides a preparation method of a 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound shown as a formula (I), which is characterized in that isatin diazo, aldehyde and phenyl nitroene are catalyzed by rhodium acetate and subjected to alkali addition reaction to synthesize the 3, 3-spiro (2-tetrahydrofuran) oxindole compound.
In the formula (I), R1Is hydrogen, 5-methyl; 5-fluoro, 6-chloro, etc., R2Methyl, acetyl, benzyl, etc.; r3Is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, 2-furyl, etc.; r45-chloro, 5-bromo, hydrogen, and the like.
The reaction formula of the preparation method is shown as the formula (II):
in the formula (II), R1Is hydrogen, 5-methyl; 5-fluoro, 6-chloro, etc., R2Methyl, acetyl, benzyl, etc.; r3Is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, 2-furyl, etc.; r45-chloro, 5-bromo, hydrogen, and the like.
Wherein the mol ratio of the isatin diazo to the aldehyde to the nitroene to the rhodium acetate to the alkali is 1.5: 1.0: 0.02: 0.2.
Wherein the isatin diazo is 5-methyl isatin diazo, 5-fluoro isatin diazo, 6-chloro isatin diazo, nitro methyl isatin diazo, nitro acetyl isatin diazo, nitro benzyl isatin diazo, etc.
Wherein the aldehyde is benzaldehyde, p-bromobenzaldehyde, m-bromobenzaldehyde, p-methoxybenzaldehyde, o-fluorobenzaldehyde, 2-furaldehyde, 2-thiophenecarbaldehyde, cinnamaldehyde and the like.
Wherein R of the ortho-substituted phenylnitroalkene (shown as the following formula 3)4Is 5-chloro, 5-bromo, hydrogen, etc.
The preparation method comprises the following steps: adding aldehyde, ortho-substituted phenyl nitroene, rhodium acetate,Molecular sieve and organic solvent, wherein the addition amount of the organic solvent is 25-30mL/mmol of ortho-substituted phenylnitroalkene; dissolving isatin diazo in an organic solvent to obtain a diazo solution, wherein the amount of the organic solvent for dissolving the isatin diazo is 25-30 mL/mmol; dropwise adding the diazo solution into a reaction bottle (0.7-1mL/h) by a peristaltic pump at room temperature, after the dropwise adding of the diazo solution is finished, adding 20% mol of DBU, reacting for 2h, performing rotary evaporation to remove the solvent to obtain a crude product, and performing column chromatography to obtain the 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound shown in the formula (I). Wherein, the isatin diazo is dripped for 1h, alkali is added for reaction for 2h, and the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound can be quickly constructed after the reaction time is totally 3 h. The invention adopts a one-pot method at room temperature, has short preparation route, namely, the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound is efficiently constructed with the yield of more than 50 percent.
The organic solvent in the invention is dichloromethane, trichloromethane and the like.
The invention provides a preparation and synthesis method of a 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound, which has the advantages of cheap and easily obtained raw materials, short preparation route, simple operation and no pollution. In order to achieve the purpose, the method of the invention is used for synthesizing the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound by using diazo compounds, aldehyde and nitroene under the catalysis of rhodium acetate and after adding alkali. The method comprises the steps of reacting isatin with aldehyde under the catalysis of Rh (II) to form carbonyl ylide, capturing the active intermediate through ortho-substituted phenylnitroene, performing cycloaddition to obtain a 3, 3-spiro (2-tetrahydrofuran) oxindole intermediate through [ 3+2 ], adding alkali, and further performing ring closure through Michael addition to construct the polycyclic compound shown in the formula (I) (the reaction process is shown in the formula (III)). The invention simultaneously constructs five chiral carbons and five rings including an oxindole ring and a tetrahydrofuran benzopyran ring in one step, and prepares and synthesizes the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound.
The organic solvent used in the invention and raw materials of salicylaldehyde, methyl propiolate and nitromethane for preparing ortho-substituted phenylnitroene (please refer to chem.Eur.J.2011,17, 6484-.
The raw materials of isatin diazo, aldehyde, ortho-substituted phenyl nitroene and organic solvent used in the invention are cheap and easily available, and the synthesis cost is low. The invention has simple synthetic route, and adopts a one-pot method to construct five target products with annular structures in one step. The method has the advantages of short preparation route, simple operation, mild reaction conditions, atom economy, high selectivity, high yield and the like, no environmental pollution and accordance with the requirements of green chemistry.
The invention also discloses a 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound which is synthesized by the preparation method and is shown in the formula (I). The invention synthesizes the 3, 3-spiro (2-tetrahydrofuran) oxindole derivative and the multi-component cyclic compound simply and quickly, belongs to intermediate fragments of natural products, is beneficial to further derivation, and finds that the compound has inhibitory activity on AURKA aurora kinase A (AURKA) through biological activity test, thereby destroying cell cycle, preventing cell proliferation and causing apoptosis of many types of tumor cells.
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 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 invention relates to a preparation method of a novel 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound, which comprises the following steps: firstly, weighing aldehyde, aryl nitroene and rhodium acetate according to the mol ratio of 1.5: 1.0: 0.02, adding aldehyde, ortho-substituted phenyl nitroene, rhodium acetate and organic solvent into a reaction bottle, and making water absorbentMolecular sieve 350-500mg/mmol of ortho-substituted phenylnitroalkene. Wherein the addition amount of the organic solvent is 5-10mL/mmol of ortho-substituted phenyl nitroene; next, isatin diazo was dissolved in an organic solvent in an amount of 1.5mmol/mmol of ortho-substituted phenylnitroalkene to obtain a diazo solution. Wherein the amount of the organic solvent for dissolving the diazonium is 2-5mL/mmol of isatin diazonium. Then at room temperature, dropwise adding a diazo solution into a reaction bottle through a peristaltic pump, after dropwise adding for 1 hour, adding DBU into the reaction system, wherein the addition amount is 0.2mmol/mmol of ortho-substituted phenylnitroene, and removing the solvent through rotary evaporation at 40-50 ℃ to obtain a crude product; and (3) carrying out column chromatography on the crude product by using a solution with the volume ratio of ethyl acetate to petroleum ether being 1: 50-1: 10 to obtain a pure product of the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound.
Example 1 preparation of compound 5a of the invention:
5-chlorophenyl nitroene 3a (0.20mmol), rhodium acetate (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol) were weighed,molecular sieves (70mg) they were placed in a small tube reactor and a redistilled 1.0mL of dichloromethane was added at room temperature. Dissolving N-methylindolydiazo 1a (0.30mmol) in 0.7mL of redistilled dichloromethane, injecting the solution into a reaction system through a peristaltic pump for 1 hour, adding DBU (0.04mmol) after the injection is finished, continuing to react for 2 hours, removing the solvent through rotary evaporation at 40 ℃, and separating by column chromatography (eluent: petroleum ether: ethyl acetate ═ 1: 50-1: 20) to obtain the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound 5 a. The yield is 80%, and the d.r. is 91: 9. See table 1.
Characterization of the product 3, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compound 5a of this example:
1H NMR(400MHz，CDCl3，25℃，TMS)：7.88(d，J＝7.3Hz，1H)，7.45(dd，J＝12.7，8.1Hz，3H)，7.32-7.15(m，3H)，7.05(dd，J＝8.7，2.0Hz，1H)，6.83(t，J＝7.9Hz，2H)，6.34(s，1H)，6.17(s，1H)，5.51(d，J＝6.5Hz，1H)，4.97(s，1H)，3.65(s，3H)，2.92(s，3H)，2.85-2.60(m，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝173.97，170.03，144.20，132.93，132.12，131.75，129.54，128.26，127.85，126.65，125.92，125.12，124.19，119.71，108.98，99.16，85.82，84.34，73.36，52.32，50.35，34.99，25.95.
examples 2 to 16 preparation of Compounds (5b to 5p)
Examples 2-16 are the same as example 1. The change of the substituents in the reaction, the compound numbers, the d.r. values, the yields, etc., are shown in Table 1.
TABLE 1
Characterization of the products, 3-spiro (2-tetrahydrofuran) oxoindole polycyclic compounds 5 b-5 p, is as follows:
5b：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝8.21(d，J＝8.2Hz，1H)，8.03(d，J＝7.5Hz，1H)，7.47(dd，J＝11.9，4.9Hz，1H)，7.42-7.33(m，1H)，7.24(d，J＝8.5Hz，1H)，7.18(s，1H)，7.12(dd，J＝8.7，2.4Hz，1H)，6.88(d，J＝8.7Hz，1H)，6.49(d，J＝2.2Hz，1H)，6.27(s，1H)，5.30(dd，J＝9.1，2.8Hz，1H)，4.89(s，1H)，3.58(s，3H)，2.77-2.41(m，2H)，2.12(s，3H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝175.39，169.56，169.49，150.04，140.25，132.27，132.05，131.94，130.05，128.62，127.89，126.71，126.09，126.06，125.21，124.49，122.18，120.45，117.14，99.15，86.29，85.55，72.23，52.31，51.58，34.29，29.70，25.69.
5c：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.93(d，J＝7.1Hz，1H)，7.53(t，J＝5.5Hz，1H)，7.44-7.19(m，4H)，7.15(dd，J＝8.7，2.5Hz，1H)，7.01(d，J＝6.6Hz，1H)，6.92(d，J＝8.7Hz，1H)，6.71(d，J＝7.8Hz，1H)，6.44(d，J＝2.2Hz，1H)，6.25(s，1H)，5.72(s，1H)，5.16(s，1H)，4.95(d，J＝15.8Hz，1H)，4.43(d，J＝15.9Hz，1H)，3.73(d，J＝2.9Hz，3H)，2.93(d，J＝4.8Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.05，170.24，151.56，143.68，134.65，133.17，132.16，131.78，129.57，129.08，128.43，128.02，127.74，126.88，126.37，126.22，125.06，124.26，124.24，119.85，110.31，99.20，85.73，84.15，73.91，52.38，50.31，43.99，35.31.
5d：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.72(dd，J＝7.3，2.3Hz，1H)，7.56(d，J＝8.4Hz，1H)，7.42-7.21(m，3H)，7.18(dd，J＝8.7，2.3Hz，1H)，7.06(ddd，J＝22.7，11.3，4.7Hz，2H)，6.95(d，J＝8.7Hz，1H)，6.64(dd，J＝8.6，4.0Hz，1H)，6.49(d，J＝1.9Hz，1H)，6.30(s，1H)，5.63(dd，J＝7.6，3.2Hz，1H)，5.09(s，1H)，4.92(d，J＝15.8Hz，1H)，4.41(d，J＝15.9Hz，1H)，3.73(d，J＝8.9Hz，3H)，2.87(d，J＝7.6Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝173.84，170.04，161.11，158.68，151.24，139.57，134.34，132.66，132.23，129.79，129.17，128.27，128.18，128.07，127.99，127.88，126.91，126.15，124.41，120.09，118.26，118.03，113.50，113.25，111.21，111.13，99.12，85.64，84.48，76.74，73.48，52.36，50.34，44.17，35.04，29.71.
5e：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.93(dd，J＝8.1，5.3Hz，1H)，7.55(d，J＝8.2Hz，2H)，7.39-7.22(m，6H)，7.18(dd，J＝8.7，1.9Hz，1H)，7.09-6.83(m，4H)，6.51(s，1H)，6.45(d，J＝8.5Hz，1H)，6.28(s，1H)，5.62(dd，J＝7.6，3.3Hz，1H)，5.10(s，1H)，4.92(d，J＝15.8Hz，1H)，4.40(d，J＝15.8Hz，1H)，3.72(s，3H)，2.87(d，J＝7.6Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.20，170.05，134.10，132.75，132.20，129.75， 129.22，128.26，128.21，127.98，126.90，126.76，126.06，124.36，120.07，110.67，110.44，99.36，99.16，99.09，85.29，84.24，73.51，52.34，50.14，44.16，35.06.
5f：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.90(d，J＝8.0Hz，1H)，7.55(d，J＝8.4Hz，1H)，7.37-7.24(m，3H)，7.18(dd，J＝8.7，2.3Hz，1H)，6.98(dd，J＝27.8，7.8Hz，2H)，6.71(d，J＝1.4Hz，1H)，6.52(d，J＝1.9Hz，1H)，6.29(s，1H)，5.60(dd，J＝7.8，3.0Hz，1H)，5.09(s，1H)，4.90(d，J＝15.8Hz，1H)，4.39(d，J＝15.9Hz，1H)，3.71(s，3H)，2.84(d，J＝8.2Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝173.94，170.01，151.14，144.89，137.63，134.10，132.64，132.21，129.82，129.24，128.28，128.24，127.98，126.87，126.32，126.08，124.85，124.39，124.20，121.20，120.14，110.87，99.20，85.25，84.38，73.39，52.36，50.10，44.11，34.99.
5g：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.71(s，1H)，7.55(d，J＝8.3Hz，1H)，7.39-7.13(m，4H)，7.01(d，J＝6.9Hz，1H)，6.92(d，J＝8.7Hz，1H)，6.60(d，J＝8.0Hz，1H)，6.45(d，J＝1.6Hz，1H)，6.24(s，1H)，5.72(t，J＝5.4Hz，1H)，5.15(s，1H)，4.93(d，J＝15.8Hz，1H)，4.42(d，J＝15.8Hz，1H)，3.74(s，3H)，2.95(d，J＝5.3Hz，1H)，2.45(s，3H)；13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.01，170.31，151.66，141.24，134.77，134.03，133.25，132.15，132.10，129.50，129.03，128.48，127.97，127.68，126.88，126.27，126.24，125.62，124.24，120.77，119.78，110.13，99.27，85.87，84.09，77.40，77.08，76.77，74.03，52.38，50.32，43.98，35.38，21.26.
5h：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝8.03-7.86(m，1H)，7.53-7.31(m，3H)，7.31-7.19(m，2H)，7.19-7.08(m，1H)，7.09-6.98(m，1H)，6.92(d，J＝8.7Hz，1H)，6.72(d，J＝7.7Hz，1H)，6.44(d，J＝1.9Hz，1H)，6.26(s，1H)，5.79(dd，J＝8.4，2.6Hz，1H)，5.21(s，1H)，4.96(d，J＝15.8Hz，1H)，4.46(d，J＝15.8Hz，1H)，3.75(s，3H)，2.99(dd，J＝9.4，5.5Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.18，170.45，151.79，143.68，134.70，134.17，131.68，130.02，129.45，129.05，128.93，127.88，127.70，126.88，126.56，126.23，125.03，124.20，119.75，110.25，99.19，85.68，84.84，74.18，52.35，50.39，43.96，35.41.
5i：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.75(d，J＝7.3Hz，1H)，7.48(d，J＝1.0Hz，1H)，7.35(t，J＝7.8Hz，1H)，7.30-7.18(m，5H)，7.13(dd，J＝8.7，2.2Hz，1H)，6.99(d，J＝6.4Hz，2H)，6.91(d，J＝8.7Hz，1H)，6.71(d，J＝7.8Hz，1H)，6.56(d，J＝3.2Hz，1H)，6.42(dd，J＝3.2，1.8Hz，1H)，6.35(d，J＝1.8Hz，1H)，6.05(t，J＝3.8Hz，2H)，5.17(s，1H)，5.01(d，J＝15.8Hz，1H)，4.45 (d，J＝15.8Hz，1H)，3.81(s，3H)，3.19(d，J＝17.0Hz，1H)，2.98(dd，J＝17.1，9.4Hz，1H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.06，170.63，152.19，147.66，144.07，143.57，134.60，131.71，129.28，129.03，127.70，127.52，126.80，126.61，126.20，124.83，124.25，119.35，119.07，111.14，110.96，110.20，95.77，85.60，74.28，52.38，50.17，44.04，35.67.
5j：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.89(d，J＝6.9Hz，1H)，7.50-6.84(m，8H)，6.71(d，J＝7.5Hz，1H)，6.44(d，J＝42.7Hz，1H)，5.83(s，1H)，5.20(s，1H)，4.98(d，J＝15.8Hz，1H)，4.44(d，J＝15.8Hz，1H)，3.76(s，3H)，3.11(s，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.04，170.57，152.03，143.66，136.18，134.64，131.78，129.44，129.06，129.00，127.84，127.72，127.30，127.21，127.17，126.91，126.87，126.31，126.18，125.04，124.29，119.68，110.27，98.39，85.52，81.19，74.35，52.38，50.41，43.99，35.55.
5k：
1H NMR(400MHz，CDC13，25℃，TMS)：＝7.79(d，J＝7.3Hz，1H)，7.57-7.21(m，11H)，7.13(dd，J＝8.6，1.8Hz，1H)，7.03(d，J＝7.0Hz，2H)，6.98-6.82(m，2H)，6.71(d，J＝7.8Hz，1H)，6.36(s，1H)，6.07(dd，J＝15.7，7.9Hz，1H)，5.73(dd，J＝21.7，8.2Hz，2H)，5.02(d，J＝15.0Hz，2H)，4.45(d，J＝15.8Hz，1H)，3.74(d，J＝18.6Hz，3H)，3.14(dd，J＝16.9，9.3Hz，1H)，2.97(d，J＝16.5Hz，1H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝175.18，171.69，153.25，144.76，139.12，136.42，135.81，132.79，130.43，130.18，130.08，129.84，128.85，128.82，128.35，127.98，127.47，127.20，126.04，125.30，121.98，120.74，111.35，98.97，86.93，84.41，75.40，53.46，51.99，45.11，36.48.
5l：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.95(d，J＝7.3Hz，1H)，7.63-7.50(m，2H)，7.38(d，J＝4.3Hz，2H)，7.34-7.19(m，6H)，7.16(d，J＝8.7Hz，1H)，7.02(d，J＝7.2Hz，2H)，6.93(d，J＝8.7Hz，1H)，6.73(d，J＝7.8Hz，1H)，6.44(s，1H)，6.25(s，1H)，5.73(t，J＝5.6Hz，1H)，5.16(s，1H)，4.95(d，J＝15.8Hz，1H)，4.45(d，J＝15.8Hz，1H)，3.75(s，3H)，2.94(d，J＝5.6Hz，2H).
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.00，170.20，151.50，143.67，136.35，134.63，133.12，131.78，130.39，129.85，129.56，129.06，128.02，127.72，126.87，126.30，126.19，125.57，125.13，124.25，122.99，119.84，110.28，99.17，85.75，83.88，73.86，52.36，50.30，43.98，35.31.
5m：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.93(d，J＝7.3Hz，1H)，7.49-7.33(m，3H)，7.33-7.18(m，5H)，7.14(dd，J＝8.7，2.3Hz，1H)，7.03(d，J＝7.1Hz，2H)，6.92(dd，J＝8.7，2.9Hz，3H)， 6.71(d，J＝7.8Hz，1H)，6.43(s，1H)，6.21(s，1H)，5.74(s，1H)，5.20(s，1H)，4.97(d，J＝15.8Hz，1H)，4.46(d，J＝15.8Hz，1H)，3.82(s，3H)，3.76(s，3H)，2.99(d，J＝7.6Hz，2H)；13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.19，170.51，160.82，143.67，134.70，131.62，129.39，129.04，128.20，127.83，127.68，126.86，126.64，126.21，125.99，124.98，124.16，119.71，114.33，110.21，99.01，85.44，84.72，74.24，55.29，52.33，50.35，43.94，35.43.
5n：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.76(d，J＝7.3Hz，1H)，7.51-6.98(m，14H)，6.98-6.75(m，3H)，6.63(d，J＝7.7Hz，1H)，6.27(d，J＝5.2Hz，2H)，5.98(d，J＝9.1Hz，1H)，5.10(s，1H)，4.93(d，J＝15.8Hz，1H)，4.37(d，J＝15.8Hz，1H)，3.70(s，3H)，3.09(d，J＝16.8Hz，1H)，2.80(dd，J＝16.9，9.5Hz，1H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.22，170.59，152.17，143.71，134.62，131.81，131.60，131.51，129.35，129.04，129.00，128.57，127.70，127.65，126.96，126.80，126.38，126.26，124.84，124.81，124.77，124.26，122.81，122.69，119.52，116.04，115.83，110.29，98.60，85.86，79.32，74.72，52.34，50.09，43.96，35.62，35.58，29.71.
5o：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.93(d，J＝7.0Hz，1H)，7.55(d，J＝8.5Hz，1H)，7.45-7.17(m，5H)，7.03(d，J＝7.0Hz，1H)，6.87(d，J＝8.7Hz，1H)，6.73(d，J＝7.8Hz，1H)，6.58(d，J＝1.8Hz，1H)，6.25(s，1H)，5.81-5.61(m，1H)，5.15(s，1H)，4.93(d，J＝15.8Hz，1H)，4.48(d，J＝15.9Hz，1H)，3.76(d，J＝10.2Hz，3H)，2.93(d，J＝5.3Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.08，170.21，143.67，134.62，133.14，132.46，132.15，131.75，129.16，129.12，128.40，127.71，126.87，126.36，125.03，124.23，120.21，115.34，110.28，99.12，85.76，84.17，52.35，50.26，44.01，35.30.
5p：
1H NMR(400MHz，CDCl3，25℃，TMS)：＝7.96(d，J＝7.3Hz，1H)，7.55(d，J＝8.2Hz，1H)，7.47-7.11(m，5H)，6.99(t，J＝7.2Hz，2H)，6.74(t，J＝6.6Hz，1H)，6.44(d，J＝7.7Hz，1H)，6.30(s，1H)，5.70(d，J＝8.0Hz，1H)，5.19(s，1H)，4.86(d，J＝15.7Hz，1H)，4.42(d，J＝15.7Hz，1H)，3.74(s，3H)，2.93(d，J＝9.0Hz，2H)；
13C NMR(400MHz，CDCl3，25℃，TMS)：＝174.18，170.40，143.71，134.89，133.34，132.09，131.42，129.37，128.69，128.41，127.70，127.41，126.94，126.53，125.16，124.13，124.01，123.11，118.45，109.94，99.70，85.88，84.25，73.58，52.28，50.61，43.83，35.36.
EXAMPLE 17 inhibition of Aurora kinase Activity by 3, 3-Spiro (2-tetrahydrofuran) oxindole polycyclic Compounds 5 a-5 p of the present invention
Aurora kinase is necessary for mitosis, AURKA plays an important role in mitotic spindle formation and centrosome maturation, AURKB is necessary for chromosome segregation and cytoplasm migration, studies show that inhibition of Aurora kinase activity destroys cell cycle, prevents cell proliferation, causes apoptosis of many types of tumor cells, and has no influence on non-dividing cells, and search for specific inhibitors of Aurora kinase provides a new approach for tumor therapy.
The experimental method comprises the following steps:
Protocol id：3
Protocol name：Aurora A activity assay，HTRF
the instrument comprises the following steps: envision (PerkinElmer, USA).
Materials: AURKA, aurora kinase A (AURKA), which is obtained by expression in an escherichia coli expression system in the laboratory. Detection kit, HTRF Kinase assay kit (Cisbio)
The process is as follows: the activity was measured using the HTRF kinase assay kit from Cisbio.
Sample treatment:
the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the detection activity.
Data processing and results description:
the activity of the sample is tested under a single concentration condition, e.g., 20. mu.g/ml, for primary screening. For samples that exhibit activity under certain conditions, e.g., an Inhibition% Inhibition of greater than 50, the activity dose dependence relationship, i.e., IC50/EC50 values, were tested by nonlinear fitting of sample activity to sample concentration, the software used for the calculation was Graphpad Prism4, the model used for the fitting was sigmoidal dose-response (variable slope), and for most inhibitor screening models, the bottom and top of the fitted curve were set at 0 and 100. In general, each sample was tested with multiple wells (n.gtoreq.2) and the results were expressed as Standard Deviation (SD) or Standard Error (SE). The results of activity under certain conditions are indicated by the activity column. The reported compounds were used as a reference for each test. The reference compound in this example is Staurosporine (Staurosporine), which is a carbazole alkaloid compound isolated from streptomyces, and has the following structure, and is a protein kinase c (pkc) inhibitor that can permeate cell membranes.
Reference compounds inhibit Aurora kinase activity, see table 2 below.
TABLE 2
The 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compounds 5 a-5 p of the present invention inhibit Aurora kinase activity, as shown in table 3 below.
TABLE 3
| ID | Sample numbering | Concentration of | Type (B) | Unit of | Results | Error of the measurement | Remarks for note |
| 1 | 5a | 0.1ug/mL | ％Inhibition | percent | 99.28 | 0.29 | |
| 2 | 5b | 0.1ug/mL | ％Inhibition | percent | 90.57 | 0.43 | |
| 3 | 5c | 0.1ug/mL | ％Inhibition | percent | 89.90 | 0.54 | |
| 4 | 5d | 0.1ug/mL | ％Inhibition | percent | 99.00 | 0.87 | |
| 5 | 5e | 0.1ug/mL | ％Inhibition | percent | 99.37 | 1.82 | |
| 6 | 5f | 0.1ug/mL | ％Inhibition | percent | 90.03 | 1.01 | |
| 7 | 5g | 0.1ug/mL | ％Inhibition | percent | 99.87 | 0.15 | |
| 8 | 5h | 0.1ug/mL | ％Inhibition | percent | 99.07 | 0.94 | |
| 9 | 5i | 0.1ug/mL | ％Inhibition | percent | 98.99 | 1.32 | |
| 10 | 5j | 0.1ug/mL | ％Inhibition | percent | 88.54 | 0.56 | |
| 11 | 5k | 0.1ug/mL | ％Inhibition | percent | 54.23 | 0.77 | |
| 12 | 5l | 0.1ug/mL | ％Inhibition | Percent | 79.83 | 0.45 | |
| 13 | 5m | 0.1ug/mL | ％Inhibition | percent | 98.53 | 0.63 | |
| 14 | 5n | 0.1ug/mL | ％Inhibition | percent | 43.19 | 0.32 | |
| 15 | 5o | 0.1ug/mL | ％Inhibition | percent | 99.74 | 1.86 | |
| 16 | 5p | 0.1ug/mL | ％Inhibition | percent | 100.76 | 1.94 |
The above experimental results show that: compared with a reference compound, the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compounds 5a to 5p all show good inhibition on Aurora kinase activity, wherein the compounds 5a, 5e, 5g, 5o and 5p show better performance and can be used as effective Aurora kinase inhibitors in the field of medicine.
Claims (7)
1. A preparation method of a 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound shown in a formula (I) is characterized in that isatin diazo, aldehyde and ortho-substituted phenyl nitroene are synthesized by a one-pot method through a reaction of adding organic base DBU after catalysis of rhodium acetate to obtain the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound;
the reaction formula of the preparation method is shown as the formula (II):
wherein,
R1is hydrogen, 5-methyl, 5-fluoro, 6-chloro;
R2is methyl, acetyl, benzyl;
R3is phenyl, m-bromophenyl, p-methoxyphenyl, o-fluorophenyl, styryl, 2-thienyl, 2-furyl;
R45-chloro, 5-bromo, hydrogen.
2. The process according to claim 1, wherein the molar ratio of isatin diazo, aldehyde, ortho-substituted phenylnitroene, rhodium acetate, base is 1.5: 1.5: 1.0: 0.02:0.2.
3. The process of claim 1, wherein the isatin diazonium is 5-methyl isatin diazonium, azomethine isatin diazonium, azoacetyl isatin diazonium or azobenzylisatin diazonium.
4. The method of claim 1, wherein the aldehyde is benzaldehyde, p-bromobenzaldehyde, m-bromobenzaldehyde, p-methoxybenzaldehyde, o-fluorobenzaldehyde, 2-furaldehyde, 2-thiophenecarboxaldehyde or cinnamaldehyde.
5. The method of claim 1, wherein the reacting step comprises: adding aldehyde, ortho-substituted phenyl nitroene, rhodium acetate,Molecular sieve and organic solvent, wherein the addition amount of the organic solvent is 5-10mL/mmol of ortho-substituted phenylnitroalkene; dissolving isatin diazoObtaining a diazo solution in an organic solvent, wherein the amount of the organic solvent for dissolving the isatin diazo is 2-4mL/mmol of the isatin diazo; dropwise adding the diazo solution into a reaction bottle (0.7-1mL/h) at room temperature by a peristaltic pump, adding 20% mol of DBU after the dropwise adding of the diazo solution is finished, reacting for 2h, and removing the solvent by rotary evaporation to obtain a crude product, and carrying out column chromatography to obtain the 3, 3-spiro (2-tetrahydrofuran) oxindole polycyclic compound shown in the formula (I).
6. The process according to claim 5, wherein the diazo solution of isatin diazo dissolved in organic solvent is added dropwise for 1 hour, and the organic base DBU is added and reacted for 2 hours.
7. The method of claim 5, wherein the organic solvent is dichloromethane or chloroform.
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