CN103554120A - 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
- Publication number
- CN103554120A CN103554120A CN201310484843.9A CN201310484843A CN103554120A CN 103554120 A CN103554120 A CN 103554120A CN 201310484843 A CN201310484843 A CN 201310484843A CN 103554120 A CN103554120 A CN 103554120A
- Authority
- CN
- China
- Prior art keywords
- diazonium
- preparation
- isatin
- oxoindole
- thf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
Landscapes
- 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 medicine synthesising chemical technology field, relate to a kind of 3, the preparation method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.
Background technology
The naked ring skeleton of Oxoindole, as a kind of important structure monomer, is present in (Angew.Chem., Int.Ed.2007,46,8748-8758 in a lot of natural products and pharmaceutical activity intermediate; Tetrahedron Lett.2011,52,3945-3948).Wherein, the naked ring structure of Oxoindole and tetrahydrofuran (THF) is the intermediate fragments of a lot of natural products of conduct not only, also there is good biological activity, for example 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).
The multi-component reaction of the diazoamines of Muthusamy professor first passage Rh in 2004 catalysis builds 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Org.Chem.2004,69,5631-5637), Schreiber seminar also attempts that silica reagent with Lewis acid induction participates in, and the method by isatin cyclisation builds 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound (J.Am.Chem.Soc.2007,129,1020-1021).But on have method all to have the defects such as substrate universality is low, severe reaction conditions.Thereby the synthetic method that develops 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, proposed a kind of 3, the preparation method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole compound.The present invention forms carbonyl ylide by isatin diazonium and aldehyde under the catalysis of acetic acid rhodium, occur 1 with the dipolarophile body such as ortho position substituted-phenyl nitro alkene again, 3-Dipolar Cycloaddition, form 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole structure intermediate 4, adds after alkali, by reversal of the Michael addition in molecule, further closes ring, and then build the polynuclear compound 5 (reaction mechanism is suc as formula shown in (III)) comprise 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole.The present invention from the efficient rapid build of raw material simple and easy to get one step 3, the polynuclear compound of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole, it is active that biological activity test finds that this compounds has good inhibition to aurora kinases A (AURKA), for oncotherapy provides novel method.。
The present invention proposes a kind of suc 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 acetic acid rhodium and add synthetic 3,3-spiral shell (2-tetrahydrofuran (THF)) the Oxoindole compound of alkali reaction.
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.
Described preparation method's reaction formula is suc 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 alkene, acetic acid rhodium, 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 alkene (shown in 3)
45-chlorine, 5-bromine, hydrogen etc.
Preparation method of the present invention comprises: in reaction flask, add aldehyde, ortho position substituted-phenyl nitro alkene, acetic acid rhodium,
molecular sieve, organic solvent, wherein, the add-on of organic solvent is 25-30mL/mmol ortho position substituted-phenyl nitro alkene; Isatin diazonium is dissolved in organic solvent and obtains diazonium solution, wherein, is 25-30mL/mmol for dissolving the amount of the organic solvent of isatin diazonium; At room temperature by peristaltic pump, diazonium solution is added drop-wise to (0.7-1mL/h) in reaction flask, after diazonium solution dropwises, add 20%mol DBU, reaction 2h revolves to boil off to desolventize and obtains thick product, through column chromatography, obtain suc as formula 3 shown in (I) 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound.Wherein, isatin diazonium drips 1h, adds alkali reaction 2h, and the reaction times amounts to 3h and gets final product rapid build 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.The present invention at ambient temperature, adopts one kettle way, and syntheti c route is short, to be greater than 50% efficient 3,3-spiral shell (2-tetrahydrofuran (THF)) the Oxoindole polycyclic compound that builds of productive rate.
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, simple to operate, free of contamination 3, the preparation synthetic method of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound.In order to achieve the above object, the inventive method is with diazonium compound, and aldehyde and nitro alkene is synthetic 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polynuclear compound in the catalysis of acetic acid rhodium 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 replacing by ortho position again catches this active intermediate, by [3+2] cycloaddition, obtain 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole intermediate, further closes ring by Michael addition after alkali and constructs the polynuclear compound (reaction mechanism is as shown in above-mentioned formula (III)) suc as formula (I) thereby add.The present invention's one step has built five chiral carbon simultaneously, and five rings comprise the naked ring of Oxoindole, tetrahydrofuran (THF) also pyranoid ring, synthetic 3,3-spiral shell (2-tetrahydrofuran (THF)) the Oxoindole polynuclear compound of preparation.
The raw material salicylic aldehyde of the organic solvent that the present invention is used and preparation ortho position substituted-phenyl nitro alkene, Methyl propiolate and Nitromethane 99Min. (refer to Chem.Eur.J.2011,17,6484-6491), isatin diazonium raw material is synthetic to be referred to (Eur.J. Org.Chem.2012,12,2359-2366), methylene dichloride is before use through hydrolith processed, and other organic solvents all make in advance purifying before reaction and during column chromatography or distillation is processed.
The raw materials used isatin diazonium of the present invention, aldehyde, ortho position substituted-phenyl nitro alkene and organic solvent are cheap and easy to get, synthetic 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, and 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 synthetic obtain suc as formula 3 shown in (I), 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.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 further derivative, biological activity test finds that this compounds has and suppresses active AURKA aurora kinases A (AURKA), and then can destroy the cell cycle, stop cell proliferation, cause very eurypalynous apoptosis of tumor cells, this provides novel method for oncotherapy undoubtedly, new medicament screen and pharmaceutical technology is had very important significance 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.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, 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 in molar ratio aldehyde: aromatic nitro alkene: acetic acid rhodium=1.5: 1.0: 0.02, by aldehyde, ortho position substituted-phenyl nitro alkene, acetic acid rhodium and organic solvent add in reaction flask, water-retaining agent
molecular sieve 350-500mg/mmol ortho position substituted-phenyl nitro alkene.Wherein, the add-on of organic solvent is 5-10mL/mmol ortho position substituted-phenyl nitro alkene; Then, isatin diazonium is dissolved in organic solvent, isatin diazonium add-on is 1.5mmol/mmol ortho position substituted-phenyl nitro alkene, obtains diazonium solution.Wherein, for dissolving the amount of the organic solvent of diazonium, be 2-5mL/mmol isatin diazonium.Then at room temperature, by peristaltic pump, diazonium solution is added drop-wise in reaction flask, within 1 hour, dropwises, in reaction system, add DBU, add-on is 0.2mmol/mmol ortho position substituted-phenyl nitro alkene, and 40 ℃-50 ℃ revolve to boil off and desolventize, and obtain thick product; By thick product volume ratio, be ethyl acetate: 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 alkene 3a (0.20mmol), acetic acid rhodium (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol),
molecular sieve (70mg) is put into small test tube reactor by them, under room temperature condition, adds the 1.0mL methylene dichloride heavily steaming.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 finishes, and 40 ℃ 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 present embodiment product 3, the sign of 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 variation in reaction, compound number, d.r. value, productive rate etc., in Table 1.
Table 1
Product 3, the sign of 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, the inhibition of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a～5p to Aurora A activity
Aurora A is that mitotic division process is essential, AURKA has played the part of important role in mitotic spindle formation and centrosome maturation process, it is necessary that AURKB moves for chromosome segregation and cytoplasm, research shows, suppressing the activity of Aurora A can destroy the cell cycle, stops cell proliferation, causes very eurypalynous apoptosis of tumor cells, simultaneously on the not impact of non-division cells, the specific inhibitor of finding Aurora A provides novel method for oncotherapy.
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: use the HTRF kinase assay test kit of Cisbio company, detection of active.
Sample preparation:
Sample dissolves with DMSO, and cryopreservation, within the concentration of DMSO in final system is controlled at the scope that does not affect detection of active.
Data processing and presentation of results:
Primary dcreening operation is selected under single concentration conditions, and for example 20 μ g/ml, test the activity of sample.For showing active sample under certain condition, for example inhibiting rate %Inhibition is greater than 50, test agents amount dependence, it is IC50/EC50 value, by sample activity, sample concentration is carried out Nonlinear Quasi and obtained, calculating software used is Graphpad Prism4, and the model that matching is used is sigmoidaldose-response (varible slope), for most of inhibitor screening models, matched curve bottom and top are set as to 0 and 100.Generally, each sample all arranges multiple hole (n >=2) in test, in result, with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE), represents.We think that activated result is all listed as with * and is marked in activity under certain condition.Each test all has the compound of having reported as reference.Reference compound in the present embodiment is staurosporine (Staurosporine), and it is that structure is as follows by the isolated carbazole alkaloid compounds of streptomycete, is a kind of protein kinase C (PKC) inhibitor that can penetrating cytolemma.
The inhibition of reference compound to Aurora A activity, is shown in following table 2.
Table 2
The present invention 3, and the inhibition of 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound 5a～5p to 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 inhibition to Aurora A activity, compound 5a wherein, 5e, 5g, 5o, 5p performance is better, can be used as effective Aurora A inhibitor and is applied to field of medicaments.
Claims (8)
1. one kind suc 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 alkene pass through one kettle way, after the catalysis of acetic acid rhodium, add organic bases DBU reaction synthetic obtain described 3,3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound;
Described preparation method's reaction formula is suc 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, is characterized in that, the mol ratio of described isatin diazonium, aldehyde, ortho position substituted-phenyl nitro alkene, acetic acid rhodium, alkali is 1.5: 1.5: 1.0: 0.02: 0.2.
3. preparation method as claimed in claim 1, is characterized in that, 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 or nitrogen benzyl isatin diazonium.
4. preparation method as claimed in claim 1, 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, is characterized in that, reactions steps comprises: in reaction flask, add aldehyde, ortho position substituted-phenyl nitro alkene nitro alkene, acetic acid rhodium,
molecular sieve, organic solvent, wherein, the add-on of organic solvent is 5-10mL/mmol ortho position substituted-phenyl nitro alkene; Isatin diazonium is dissolved in organic solvent and obtains diazonium 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, diazonium solution is added drop-wise to (0.7-1mL/h) in reaction flask, after diazonium solution dropwises, add 20%mol DBU, reaction 2h revolves to boil off to desolventize and obtains thick product, through column chromatography, obtain suc as formula 3 shown in (I) 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.
6. preparation method as claimed in claim 5, is characterized in that, the time for adding that isatin diazonium is dissolved in the diazonium solution in organic solvent is 1h, and organic bases DBU adds rear reaction 2h.
7. preparation method as claimed in claim 5, is characterized in that, described organic solvent is methylene dichloride or trichloromethane.
8. by method described in claim 1, prepare suc as formula 3 shown in (I), 3-spiral shell (2-tetrahydrofuran (THF)) Oxoindole polycyclic compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310484843.9A CN103554120B (en) | 2013-10-16 | 2013-10-16 | Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310484843.9A CN103554120B (en) | 2013-10-16 | 2013-10-16 | Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103554120A true CN103554120A (en) | 2014-02-05 |
| CN103554120B CN103554120B (en) | 2015-06-24 |
Family
ID=50008517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310484843.9A Active CN103554120B (en) | 2013-10-16 | 2013-10-16 | Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103554120B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554121A (en) * | 2013-10-16 | 2014-02-05 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
| CN106565731A (en) * | 2016-11-01 | 2017-04-19 | 浙江师范大学 | Double-spiro isatin furan derivatives with antibacterial activity as well as synthesis method and application thereof |
| CN106883239A (en) * | 2017-02-22 | 2017-06-23 | 兰州大学 | Spiral shell indazole Oxoindole and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006110917A2 (en) * | 2005-04-11 | 2006-10-19 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their uses as therapeutic agents |
| WO2006125784A1 (en) * | 2005-05-24 | 2006-11-30 | Laboratoires Serono S.A. | Tricyclic spiro derivatives as crth2 modulators |
| WO2008060789A2 (en) * | 2006-10-12 | 2008-05-22 | Xenon Pharmaceuticals Inc. | Use of spiro-oxindole compounds as therapeutic agents |
| WO2010045251A2 (en) * | 2008-10-17 | 2010-04-22 | Xenon Pharmaceuticals, Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
| CN103554121A (en) * | 2013-10-16 | 2014-02-05 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
-
2013
- 2013-10-16 CN CN201310484843.9A patent/CN103554120B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006110917A2 (en) * | 2005-04-11 | 2006-10-19 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their uses as therapeutic agents |
| CN102153562A (en) * | 2005-04-11 | 2011-08-17 | 泽农医药公司 | Spiro-oxindole compounds and their uses as therapeutic agents |
| WO2006125784A1 (en) * | 2005-05-24 | 2006-11-30 | Laboratoires Serono S.A. | Tricyclic spiro derivatives as crth2 modulators |
| WO2008060789A2 (en) * | 2006-10-12 | 2008-05-22 | Xenon Pharmaceuticals Inc. | Use of spiro-oxindole compounds as therapeutic agents |
| WO2010045251A2 (en) * | 2008-10-17 | 2010-04-22 | Xenon Pharmaceuticals, Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
| CN103554121A (en) * | 2013-10-16 | 2014-02-05 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554121A (en) * | 2013-10-16 | 2014-02-05 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
| CN103554121B (en) * | 2013-10-16 | 2015-06-24 | 华东师范大学 | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof |
| CN106565731A (en) * | 2016-11-01 | 2017-04-19 | 浙江师范大学 | Double-spiro isatin furan derivatives with antibacterial activity as well as synthesis method and application thereof |
| CN106883239A (en) * | 2017-02-22 | 2017-06-23 | 兰州大学 | Spiral shell indazole Oxoindole and preparation method thereof |
| CN106883239B (en) * | 2017-02-22 | 2018-11-23 | 兰州大学 | Spiral shell indazole Oxoindole and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103554120B (en) | 2015-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yang et al. | Organocatalytic asymmetric synthesis of spiro-oxindole piperidine derivatives that reduce cancer cell proliferation by inhibiting MDM2–p53 interaction | |
| Liu et al. | Core scaffold-inspired stereoselective synthesis of spiropyrazolones via an organocatalytic Michael/cyclization sequence | |
| Derabli et al. | A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives | |
| Li et al. | Visible-light-mediated enantioselective photoreactions of 3-alkylquinolones with 4-O-tethered alkenes and allenes | |
| Tejedor et al. | General synthesis of substituted 1, 2-dihydropyridines | |
| Cao et al. | [4+ 2] Annulation of 3-nitroindoles with alkylidene malononitriles: Entry to substituted carbazol-4-amine derivatives | |
| Sravanthi et al. | Synthesis, docking, and evaluation of novel thiazoles for potent antidiabetic activity | |
| Zhang et al. | Access to 2′, 3′-dihydro-1′ H-spiro [indoline-3, 4′-pyridin]-2-ones via amino acid derived phosphine-catalyzed asymmetric [4+ 2] annulation with easily available oxindole-derived α, β-unsaturated imines | |
| Ghosh et al. | Enantioselective synthesis of spiro [cyclohexane-1, 3′-indolin]-2′-ones containing multiple stereocenters via organocatalytic Michael/aldol cascade reactions | |
| Yin et al. | Efficient synthesis of multicyclic spirooxindoles via a cascade Michael/Michael/oxa-Michael reaction of curcumins and isatylidene malononitriles | |
| CN103554120B (en) | Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound | |
| Yi et al. | An efficient one‐pot protocol for the synthesis of polysubstituted 4‐amino‐iminocoumarins and 4‐aminoquinolines by a copper‐catalyzed three‐component reaction | |
| Miura et al. | Stereoselective oxindole synthesis by palladium-catalyzed cyclization reaction of 2-(alkynyl) aryl isocyanates with amides | |
| Kumar et al. | Ionic liquid catalysed multicomponent synthesis, antifungal activity, docking studies and in silico ADMET properties of novel fused Chromeno-Pyrazolo-Phthalazine derivatives | |
| CN107235992B (en) | Indolone spiral shell thiophane class compound and its salt, preparation method and application | |
| Mahdavinia et al. | A rapid and simple diversity-oriented synthesis of novel 3-amino-2′-oxospiro [benzo [c] pyrano [3, 2-a] phenazine-1, 3′-indoline]-2-carbonitrile/carboxylate derivatives via a one-pot, four-component domino reaction | |
| Dai et al. | Cesium-Carbonate-Mediated Benzalation of Substituted 2-Aryl-3-nitro-2 H-chromenes with Substituted 4-Benzylidene-2-phenyloxazol-5 (4 H)-ones | |
| Eldebss et al. | Synthesis of some new pyrazolone‐based heterocycles containing sulphone moiety acting as α‐glucosidase and α‐amylase inhibitors | |
| CN102911105B (en) | 3-aroyl indole compound synthesis method | |
| Wang et al. | A Stereoselective Povarov Reaction Leading to exo‐Tetrahydroindolo [3, 2‐c] quinoline Derivatives Catalyzed by Iodine | |
| Chen et al. | Synthesis of Hydroxysuccinimide Substituted Indolin-3-ones via One-Pot Cascade Reaction of o-Alkynylnitrobenzenes with Maleimides under Au (III)–Cu (II) Relay/Synergetic Catalysis | |
| CN103554121B (en) | 3,3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound and application thereof | |
| Huguenot et al. | Metal-free 5-exo-dig cyclization of propargyl urea using TBAF | |
| Guo | Gold-catalyzed formation of C–O and C–C bonds: An efficient domino reaction synthesis of functionalized furans | |
| Ibrahim et al. | Sustainable synthetic approach for (pyrazol-4-ylidene) pyridines by metal catalyst-free aerobic C (sp2)–C (sp3) coupling reactions between 1-amino-2-imino-pyridines and 1-aryl-5-pyrazolones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190123 Address after: 528437 Zone C, 13th Floor, No. 1 Health Road, Torch Development Zone, Zhongshan City, Guangzhou City, Guangdong Province Patentee after: Guangdong and Bo Pharmaceutical Co., Ltd. Address before: 200062 Zhongshan North Road, Putuo District, Shanghai, No. 3663 Patentee before: East China Normal University |
|
| TR01 | Transfer of patent right |