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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- CN103554120B CN103554120B CN201310484843.9A CN201310484843A CN103554120B CN 103554120 B CN103554120 B CN 103554120B CN 201310484843 A CN201310484843 A CN 201310484843A CN 103554120 B CN103554120 B CN 103554120B
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- 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
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 pharmaceutical synthesis technical field of chemistry, relate to a kind of preparation method of 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.
Background technology
The naked ring skeleton of Oxoindole, as a kind of important structures alone, is present in (Angew.Chem., Int.Ed.2007,46,8748-8758 in a lot of natural product and pharmaceutical activity intermediate; Tetrahedron Lett.2011,52,3945-3948).Wherein, the naked ring structure of Oxoindole and tetrahydrofuran (THF) is not only as the intermediate fragments of a lot of natural product, also there is good biological activity, such as following Ia-b is a kind of progesterone receptor inhibitor, and Ic is used for the treatment of hypertension, and IIa-b is used for the treatment of the (PCTInt.Appl.Patent2 such as skin pruritus and cancer, 000,066,167,2000; U.S.Patent4,226,860A, 1980; PCTInt.Appl.Patent2,006,110,917,2006).
Within 2004, Muthusamy teaches the multi-component reaction structure 3 of the diazoamines of first passage Rh catalysis, 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Org.Chem.2004,69,5631-5637), the Schreiber seminar silica reagent that also trial is induced with Lewis acid participates in, 3 are built by the method for isatin cyclisation, 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Am.Chem.Soc.2007,129,1020-1021).But on the defects such as substrate universality is low, severe reaction conditions that have method all to exist.Thus the synthetic method developing new Oxoindole and the naked ring structure of tetrahydrofuran (THF) has great importance.
Summary of the invention
The present invention overcomes the above-mentioned deficiency of prior art, proposes a kind of preparation method of 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound.The present invention forms Carbonyl ylide by isatin diazonium and aldehyde under the catalysis of rhodium acetate, 1 is occurred again with dipolarophile bodies such as ortho position substituted-phenyl nitro compds, 3-Dipolar Cycloaddition, form 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole scaffold intermediate 4, after adding alkali, ring is closed further by reversal of the Michael addition in molecule, and then build the polynuclear compound 5 (reaction mechanism is such as formula (III) Suo Shi) comprising 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole.The present invention is from the efficient rapid build of raw material one step simple and easy to get 3, the polynuclear compound of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole, biological activity test finds that this compounds has good inhibit activities, for oncotherapy provides novel method to aurora kinases A (AURKA).。
The present invention proposes a kind of such as formula 3 shown in (I), the preparation method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound, isatin diazonium, aldehyde, with phenyl nitro alkene in the catalysis of rhodium acetate and add alkali reaction synthesis 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound.
In formula (I), R
1for hydrogen, 5-methyl; 5-fluorine, 6-fluorine, 6-chlorine etc., R
2for methyl, ethanoyl, benzyl etc.; R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, 2-furyl etc.; R
4for 5-chlorine, 5-bromine, hydrogen etc.
The reaction formula of described preparation method is such as formula shown in (II):
In formula (II), R
1for hydrogen, 5-methyl; 5-fluorine, 6-fluorine, 6-chlorine etc., R
2for methyl, ethanoyl, benzyl etc.; R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, 2-furyl etc.; R
4for 5-chlorine, 5-bromine, hydrogen etc.
Wherein, the mol ratio of described isatin diazonium, aldehyde, nitro compds, rhodium acetate, alkali is 1.5: 1.5: 1.0: 0.02: 0.2.
Wherein, described isatin diazonium is 5-methylisatin diazonium, 5-fluoro indigo red diazonium, 6-fluoro indigo red diazonium, 6-chlorisatide diazonium, nitrogen methylisatin diazonium, nitrogen ethanoyl isatin diazonium, nitrogen benzyl isatin diazonium etc.
Wherein, described aldehyde is phenyl aldehyde, p-bromobenzaldehyde, 3-bromobenzaldehyde, aubepine, o fluorobenzaldehyde, 2 furan carboxyaldehyde, 2 thiophene carboxaldehyde, phenylacrolein etc.
Wherein, the R of described ortho position substituted-phenyl nitro compds (as shown in the formula 3 Suo Shi)
45-chlorine, 5-bromine, hydrogen etc.
Preparation method of the present invention comprises: add in reaction flask aldehyde, ortho position substituted-phenyl nitro compds, rhodium acetate,
molecular sieve, organic solvent, wherein, the add-on of organic solvent is 25-30mL/mmol ortho position substituted-phenyl nitro compds; Isatin diazonium being dissolved in organic solvent and obtaining diazo solution, wherein, is 25-30mL/mmol for dissolving the amount of the organic solvent of isatin diazonium; At room temperature by peristaltic pump, diazo solution is added drop-wise to (0.7-1mL/h) in reaction flask, after diazo solution dropwises, add 20%mol DBU, reaction 2h revolves to boil off to desolventize and obtains thick product, through column chromatography, obtain such as formula 3,3-spiral shells (2-tetrahydrofuran (THF)) the Oxoindole polynuclear compound shown in (I).Wherein, isatin diazonium drips 1h, adds alkali reaction 2h, and the reaction times amounts to 3h can rapid build 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.At ambient temperature, adopt one kettle way, syntheti c route is short, namely efficiently builds 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound with the productive rate being greater than 50% in the present invention.
Organic solvent described in the present invention is methylene dichloride, trichloromethane etc.
The invention provides that a kind of raw material is cheap and easy to get, syntheti c route is short, the preparation synthetic method of simple to operate, free of contamination 3,3-spiral shells (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound.In order to achieve the above object, the inventive method is with diazonium compound, and aldehyde and nitro compds synthesize 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound in rhodium acetate catalysis and after adding alkali.The present invention first forms Carbonyl ylide with aldehyde effect in diazonium by isatin under the catalysis of Rh (II), the phenyl nitro alkene replaced by ortho position again catches this active intermediate, 3 are obtained by [3+2] cycloaddition, 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole intermediate, closes ring further by Michael addition after adding alkali thus constructs the polynuclear compound (reaction mechanism is as Suo Shi above-mentioned formula (III)) such as formula (I).The present invention one step constructs five chiral carbon simultaneously, five rings, comprises the naked ring of Oxoindole, and tetrahydrofuran (THF) is pyranoid ring also, preparation synthesis 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound.
The raw material salicylic aldehyde of the organic solvent that the present invention is used and preparation ortho position substituted-phenyl nitro compds, Methyl propiolate and Nitromethane 99Min. (refer to Chem.Eur.J.2011,17,6484-6491), isatin diazonium Material synthesis refers to (Eur.J. Org.Chem.2012,12,2359-2366), methylene dichloride is before use through hydrolith processed, and other organic solvents process with making purifying during column chromatography all in advance or distilling before the reaction.
The present invention's raw materials used isatin diazonium, aldehyde, ortho position substituted-phenyl nitro compds and organic solvent are cheap and easy to get, synthesize with low cost.Synthetic route of the present invention is simple, adopts one kettle way one step to build the target product of five ring texturees.Syntheti c route of the present invention is short, simple to operate, and reaction conditions is gentle, has Atom economy, highly selective, high yield etc., non-environmental-pollution, meets the requirement of Green Chemistry.
The invention also discloses a kind of by preparation method of the present invention synthesis obtain such as formula 3,3-spiral shells (2-tetrahydrofuran (THF)) the Oxoindole polycyclic compound shown in (I).The present invention synthesizes 3 quickly and easily, 3-spiral shell (2-tetrahydrofuran (THF)) oxoindole derivative and polynary ring compound, belong to natural product intermediate fragments, be conducive to derivative further, biological activity test finds that this compounds has inhibit activities to AURKA aurora kinases A (AURKA), and then can the cell cycle be destroyed, stop cell proliferation, cause very eurypalynous apoptosis of tumor cells, this provides novel method for oncotherapy undoubtedly, has very important significance to new medicament screen and pharmaceutical technology simultaneously.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention new 3, the preparation method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound, its reaction scheme is specially: first take aldehyde in molar ratio: aromatic nitro alkene: rhodium acetate=1.5: 1.0: 0.02, by aldehyde, ortho position substituted-phenyl nitro compds, rhodium acetate and organic solvent add in reaction flask, water-retaining agent
molecular sieve 350-500mg/mmol ortho position substituted-phenyl nitro compds.Wherein, the add-on of organic solvent is 5-10mL/mmol ortho position substituted-phenyl nitro compds; Then, be dissolved in organic solvent by isatin diazonium, isatin diazonium add-on is 1.5mmol/mmol ortho position substituted-phenyl nitro compds, obtains diazo solution.Wherein, be 2-5mL/mmol isatin diazonium for dissolving the amount of the organic solvent of diazonium.Then at room temperature, be added drop-wise in reaction flask by peristaltic pump by diazo solution, within 1 hour, dropwise, in reaction system, add DBU, add-on is 0.2mmol/mmol ortho position substituted-phenyl nitro compds, and 40 DEG C-50 DEG C revolve to boil off and desolventize, and obtain thick product; Be ethyl acetate by thick product volume ratio: sherwood oil=1: 50 ~ 1: 10 solution carry out column chromatography, obtains 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound sterling.
Embodiment 1 prepares the compounds of this invention 5a:
Take 5-chloro-phenyl-nitro compds 3a (0.20mmol), rhodium acetate (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol),
they are put into small test tube reactor by molecular sieve (70mg), under room temperature condition, add the 1.0mL methylene dichloride heavily steamed.N-methyl-isatin diazonium 1a (0.30mmol) is dissolved in the methylene dichloride that 0.7mL heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, add DBU (0.04mmol), continue reaction 2h, reaction terminates, and 40 DEG C revolve to boil off and desolventize, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 50 ~ 1: 20) isolate and obtain 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound 5a.Yield 80%, d.r. is 91: 9.In table 1.
The sign of the present embodiment product 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a:
1H NMR(400MHz，CDCl
3，25℃，TMS)：δ7.88(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，CDCl
3，25℃，TMS)：δ＝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.
Embodiment 2-16 prepares compound (5b ~ 5p)
Embodiment 2-16 is with embodiment 1.Substituent change in reaction, compound number, d.r. value, productive rate etc., in table 1.
Table 1
The sign of product 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5b ~ 5p, see following:
5b：
1H NMR(400MHz，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDC1
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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，CDCl
3，25℃，TMS)：δ＝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.
Embodiment 17 the present invention 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a ~ 5p is to the suppression of Aurora A activity
Aurora A is that mitotic division process is required, AURKA is formed at mitotic spindle and plays important role in centrosome maturation process, it is necessary that AURKB moves for chromosome segregation and cytoplasm, research shows, suppress the activity of Aurora A to destroy the cell cycle, stop cell proliferation, cause very eurypalynous apoptosis of tumor cells, do not affect non-division cells, the specific inhibitor finding Aurora A is that oncotherapy provides novel method simultaneously.
Experimental technique:
Protocol id：3
Protocol name：Aurora A activity assay，HTRF
Instrument: Envision (PerkinElmer, USA).
Material: AURKA, aurora kinase A, aurora kinases A (AURKA), this laboratory utilizes escherichia expression system to express and obtains.Detection kit, HTRF Kinase AssayKit (Cisbio)
Process: the HTRF kinase assay test kit using Cisbio company, detection of active.
Sample preparation:
Sample DMSO dissolves, cryopreservation, and the concentration of DMSO in final system controls within the scope not affecting detection of active.
Data processing and result illustrate:
Under primary dcreening operation selects single concentration conditions, such as 20 μ g/ml, test the activity of sample.For showing active sample under certain condition, such as inhibiting rate %Inhibition is greater than 50, test agents amount dependence, i.e. IC50/EC50 value, by sample activity, sample concentration is carried out to Nonlinear Quasi and obtains, calculating software used is Graphpad Prism4, and the model that matching uses is sigmoidaldose-response (varible slope), for most of inhibitor screening model, bottom matched curve and top is set as 0 and 100.Generally, each sample all arranges multiple hole (n >=2) in testing, represents in the result with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE).We think that activated result all arranges in activity and are marked with * under certain condition.Each test all has the compound reported as reference.Reference compound in the present embodiment is staurosporine (Staurosporine), it is by the isolated carbazole alkaloid compounds of streptomycete, structure is as follows, be a kind of can protein kinase C (PKC) inhibitor of permeabilized cells film.
Reference compound, to the suppression of Aurora A activity, is shown in following table 2.
Table 2
The present invention 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a ~ 5p, to the suppression of Aurora A activity, is shown in following table 3.
Table 3
| ID | Sample number into spectrum | Concentration | Type | Unit | Result | Error | Remarks |
| 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 |
Above experimental result shows: contrast with reference compound, the present invention 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a ~ 5p all shows the good suppression to Aurora A activity, wherein compound 5a, 5e, 5g, 5o, 5p performance is better, can be used as effective Aurora A inhibitor and is applied to field of medicaments.
Claims (7)
1. one kind such as formula 3 shown in (I), the preparation method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound, it is characterized in that, isatin diazonium, aldehyde and ortho position substituted-phenyl nitro compds pass through one kettle way, after the catalysis of rhodium acetate, add organic bases DBU Reactive Synthesis obtain described 3,3-spiral shells (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound;
The reaction formula of described preparation method is such as formula shown in (II):
Wherein,
R
1for hydrogen, 5-methyl, 5-fluorine, 6-fluorine, 6-chlorine;
R
2for methyl, ethanoyl, benzyl;
R
3for phenyl, a bromophenyl, to bromophenyl, p-methoxyphenyl, adjacent fluorophenyl, styryl, 2-thienyl, 2-furyl;
R
4for 5-chlorine, 5-bromine, hydrogen.
2. preparation method as claimed in claim 1, it is characterized in that, the mol ratio of described isatin diazonium, aldehyde, ortho position substituted-phenyl nitro compds, rhodium acetate, alkali is 1.5:1.5:1.0:0.02:0.2.
3. preparation method as claimed in claim 1, it is characterized in that, described isatin diazonium is 5-methylisatin diazonium, nitrogen methylisatin diazonium, nitrogen ethanoyl isatin diazonium or nitrogen benzyl isatin diazonium.
4. preparation method as claimed in claim 1, it is characterized in that, described aldehyde is phenyl aldehyde, p-bromobenzaldehyde, 3-bromobenzaldehyde, aubepine, o fluorobenzaldehyde, 2 furan carboxyaldehyde, 2 thiophene carboxaldehyde or phenylacrolein.
5. preparation method as claimed in claim 1, it is characterized in that, reactions steps comprises: add in reaction flask aldehyde, ortho position substituted-phenyl nitro compds, rhodium acetate,
molecular sieve, organic solvent, wherein, the add-on of organic solvent is 5-10mL/mmol ortho position substituted-phenyl nitro compds; Isatin diazonium being dissolved in organic solvent and obtaining diazo solution, wherein, is 2-4mL/mmol isatin diazonium for dissolving the amount of the organic solvent of isatin diazonium; At room temperature by peristaltic pump, diazo solution is added drop-wise to (0.7-1mL/h) in reaction flask, after diazo solution dropwises, add 20%mol DBU, reaction 2h revolves to boil off to desolventize and obtains thick product, through column chromatography, obtain such as formula 3,3-spiral shells (2-tetrahydrofuran (THF)) the Oxoindole polycyclic compound shown in (I).
6. preparation method as claimed in claim 5, it is characterized in that, the time for adding that isatin diazonium is dissolved in the diazo solution in organic solvent is 1h, and organic bases DBU adds rear reaction 2h.
7. preparation method as claimed in claim 5, it is characterized in that, described organic solvent is methylene dichloride or trichloromethane.
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