CN102516151B - 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof - Google Patents
3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses 3-substituted-3-hydroxyindazolone derivatives, and a preparation method and application thereof. Isatin, amine and diazo compound are used as raw materials, rhodium acetate is used as a catalyst, and an organic solvent is used as a solvent, a one-step reaction is carried out to obtain the product 3-substituted-3-hydroxyindazolone derivatives. The preparation method disclosed by the invention has the advantages of high atom economical efficiency, high selectivity, high yield and the like, and is simple and safe to operate. The 3-substituted-3-hydroxyindazolone derivatives have bioactivity, and are applicable to preparing antineoplastic drugs.
Description
Technical field
The invention belongs to the synthetic chemical technology field of medicine, relate to 3-replacement-3-hydroxyindole ketone derivatives of a kind of biologically active and its preparation method and application particularly.
Background technology
The function of p53 can is combined and suppress to the albumen of oncogene MDM2 with cancer suppressor protein p53, promote the degraded of p53.The overexpression of MDM2 is one of important factor of tumour generation and development.Develop antitumor drug according to the MDM2-p53 composite structure and have good prospect.
Many pieces of bibliographical informations are arranged abroad some micromolecular MDM2-p53 inhibitor (J.Am.Chem.Soc.2008,130,12355-12369, Bioorg.Med.Chem.Lett.15,2005,1515-1520, J.Med.Chem.2006,49,3759-3762).3-replacement-3-hydroxyindole ketone derivatives is the skeleton structure of some natural radioactivity compounds, and it is similar that its structure and a class have active micromolecular MDM2-p53 inhibitor simultaneously, thereby be the compound of a class biologically active.
It is comparatively complicated that the present invention has overcome among the preparation method of prior art 3-replacement-3-hydroxyindole ketone derivatives existing operation, the defective that reactions steps is many, a kind of 3-replacement-3-hydroxyindole ketone derivatives and its preparation method and application has been proposed, preparation method of the present invention has efficient atom economy, highly selective, high yield, beneficial effects such as safety simple to operate.3-replacement-3-hydroxyindole the ketone derivatives of the present invention's preparation has the obvious suppression effect to the HCT116 cancer cells, and the p53 protein level is had certain rise effect, is applicable to the preparing anti-tumor medicine application.
Summary of the invention
The present invention proposes a kind of preparation method of 3-replacement-3-hydroxyindole ketone derivatives, be raw material with isatin, amine and diazonium compound, be catalyzer with the acetic acid rhodium, be solvent with the organic solvent, through single step reaction, obtain described 3-replacement-3-hydroxyindole ketone derivatives, shown in the following reaction formula (I):
Wherein,
R
1Comprise: 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine substituent or hydrogen;
Ar comprises: adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl, naphthyl;
R
2Comprise: anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl, morpholinyl.
R
3Comprise: hydrogen, methyl, ethyl, benzyl.
Wherein, the mol ratio of raw material and catalyzer is isatin in the described method: amine: diazonium compound: acetic acid rhodium=1: 1.0: 1.0: 0.01-1: 2.0: 2.0: 0.01.
Wherein, said method comprising the steps of: described isatin, amine, acetic acid rhodium are dissolved in the described organic solvent, under agitation, add the solution that described diazonium compound is dissolved in described organic solvent gained, obtain described 3-replacement-3-hydroxyindole ketone derivatives through reaction.
Wherein, the described 3-replacement-3-hydroxyindole ketone derivatives that reaction is obtained carries out separation and purification through column chromatography.
Wherein, described organic solvent comprises: tetrahydrofuran (THF), methylene dichloride, toluene, 1,2-ethylene dichloride, chloroform, ether.
The resulting 3-replacement-3-hydroxyindole of method produced according to the present invention ketone derivatives, following structural formula (1) expression:
Wherein,
R
1Comprise: 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine substituent or hydrogen;
Ar comprises: adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl, naphthyl;
R
2Comprise: anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl, morpholinyl.
R
3Comprise: hydrogen, methyl, ethyl, benzyl.
The feature of 3-replacement-3-hydroxyindole ketone derivatives of the present invention comprises that 3 of indolone is a quaternary carbon center, is connected with a hydroxyl, and 4,5,6,7 of indolone have different halogenic substituents, alkyl substituent is arranged on the nitrogen-atoms of indoles or do not have replacement.
The invention allows for described 3-replacement-3-hydroxyindole ketone derivatives and be applicable to the application for preparing in the antitumor drug.
The objective of the invention is to propose the preparation method of a kind of low cost, high yield, preparation 3-replacement-3-hydroxyindole ketone derivatives easy and simple to handle, and its biological activity is tested.
The general structure of 3-replacement-3-hydroxyindole ketone derivatives is as shown in the formula shown in (1):
Wherein:
R
1Be 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine or hydrogen.
Ar is adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl, naphthyl.
R
2Be anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl, morpholinyl.
R
3Comprise: hydrogen, methyl, ethyl, benzyl.
The feature of 3-replacement-3-hydroxyindole ketone derivatives of the present invention comprises that 3 of indolone is a quaternary carbon center, is connected with a hydroxyl, and 4,5,6,7 of indolone have different halogenic substituents, alkyl substituent is arranged on the nitrogen-atoms of indoles or do not have replacement.
Chemical reaction mechanism involved in the present invention is as follows: metal Louis acid catalysis diazonium compound is decomposed to form metal carbene, forms the ammonium ylide with the amine original position again, is caught by isatin then and forms a class 3-replacement-3-hydroxyindole ketone derivatives.
For realizing above-mentioned purpose of the present invention, the present invention adopts a step three component reaction to obtain product.Because multi-component reaction has high flexibility, highly selective, efficient Atom economy, the high characteristics such as energy and ease for operation of exploring, growing along with the Atom economy concept in recent years, multi-component reaction more and more becomes the focus of research.Multi-component reaction is applied to the synthetic field of medicine has very wide prospect.For this reason, the present invention designs a synthetic class 3-replacement-3-hydroxyindole ketone derivatives, is raw material with isatin, amine and diazonium compound, is catalyzer with the acetic acid rhodium, is solvent with the organic solvent, obtains product through single step reaction.
The reaction equation of the class 3-replacement-3-hydroxyindole ketone derivatives that the present invention proposes to synthesize is as shown in the formula shown in (I):
R wherein
1, R
2, the R in Ar group and the above-mentioned 3-replacement-3-hydroxyindole ketone derivatives general structure
1, R
2, the Ar group is identical, that is:
R
1Be 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine or hydrogen.
Ar is adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl, naphthyl.
R
2Be anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl, morpholinyl.
R
3Comprise: hydrogen, methyl, ethyl, benzyl.
The synthetic method of a class 3-replacement-3-hydroxyindole ketone derivatives of the present invention is as follows:
Being raw material with isatin, amine and diazonium compound, is catalyzer with the acetic acid rhodium, is solvent with the organic solvent, and through single step reaction, desolventizing gets crude product, gets product through column chromatographic isolation and purification.Concrete steps are: isatin and amine are dissolved in the organic solvent, stir down, in 1 hour, the drips of solution that diazonium compound is dissolved in the organic solvent composition is added in the reaction system, reacts after dropwising 1 hour again.Decompression is removed organic solvent and is got crude product after having reacted, and crude product gets product through column chromatography purification.Above-mentioned charging capacity mol ratio is isatin: amine: diazonium compound: acetic acid rhodium=1: 1.0: 1.0: 0.01-1: 2.0: 2.0: 0.01.
Above-mentioned isatin is 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromo-isatin, n-formyl sarcolysine base isatin, nitrogen ethyl isatin, nitrogen benzyl isatin or isatin.
Above-mentioned amine is adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl aniline or naphthyl.
Above-mentioned diazonium compound is diazonium Acetanilide, diazonium acetyl P-nethoxyaniline, diazonium acetyl cyclopropylamine, diazonium acetyl Tri N-Propyl Amine, diazonium acetyl piperidine, diazonium acetyl morphine.
Above-mentioned organic solvent is tetrahydrofuran (THF), methylene dichloride, toluene, 1,2-ethylene dichloride, chloroform, ether.
The effect that the present invention is useful is: can make up a class 3-replacement-3-hydroxyindole ketone derivatives by single step reaction, have atom economy, highly selective, advantages such as high yield, safety simple to operate.This compounds has certain biological activity.
Find that by biological activity test the influence to HCT116 cancer cells survival rate detects to The compounds of this invention 3-replacement-3-hydroxyindole ketone derivatives, has shown the obvious suppression cell growth effect.The highest toxic limit medium dose IC50 of The compounds of this invention is 27 μ M.In addition, The compounds of this invention exists certain rise effect to the p53 protein level.Therefore, The compounds of this invention can be used in preparation antitumor cell medicine.
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 that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and are protection domain with the appending claims.
Embodiment 1:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-1).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 84%, dr value: 32: 68.
1H-NMR(DMSO-d
6，400MHz)：δ10.47(s，1H)，9.65(s，1H)，6.62-7.69(m，14H)，5.73(d，1H)，4.37(s，1H).；
13C-NMR(DMSO-d
6，125MHz)：δ177.2，167.6，147.9，143.8，138.0，133.5，128.7，128.5，126.9，123.6，120.9，119.9，119.2，117.5，113.7，109.5，76.0，63.9.。
Embodiment 2:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium acetyl P-nethoxyaniline (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-2).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 85%, dr value: 30: 70.
1H-NMR(DMSO-d
6，400MHz)：δ10.49(s，1H)，10.15(s，1H)，6.47-7.55(m，12H)，6.47(s，1H)，4.70(d，1H)，4.34(d，1H)，3.71(s，3H).；
13C-NMR(DMSO-d
6，100MHz)：δ178.0，167.9，155.3，147.2，144.7，133.9，131.9，128.8，127.9，126.9，121.6，120.7，117.8，114.3，113.8，109.6，75.9，61.1，55.2。
Embodiment 3:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium acetyl Tri N-Propyl Amine (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-3).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 66%, dr value: 27: 73.
1H-NMR(DMSO-d
6，400MHz)：δ10.43(s，1H)，8.10(s，1H)，6.58-7.35(m，8H)，6.35(s，1H)，4.73(d，1H)，4.41(d，1H)，2.89-3.09(m，2H)，1.29(m，2H)，0.77(t，3H).；
13C-NMR(DMSO-d
6，100MHz)：178.0，167.0，147.3，144.5，133.8，128.7，127.6，127.2，120.9，117.6，114.1，109.5，75.4，60.9，40.5，22.1，11.3.。
Embodiment 4:
With 6-chlorisatide (0.28mmol); aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF); diazonium acetyl cyclopropylamine (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution; under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-4).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 51%, dr value: 37: 63.
1H-NMR(DMSO-d
6，400MHz)：δ8.50(s，1H)，6.59-7.27(m，10H)，5.23(s，1H)，4.38(s，1H)，4.12(m，2H)，2.52(m，1H)，0.64(m，2H).；
13C-NMR(DMSO-d
6，100MHz)：δ177.9，168.2，147.1，144.7，133.9，128.9，127.9，127.1，120.9，118.2，114.4，109.5，76.4，66.4，66.2，55.6，46.5，42.3.。
Embodiment 5:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium acetyl piperidine (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-5).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 65%, dr value: 40: 60.
1H-NMR(DMSO-d
6，400MHz)：δ10.45(s，1H)，6.63-7.33(m，8H)，6.38(s，1H)，4.96(d，1H)，4.52(d，1H)，3.43-3.66(m，4H)，1.40-1.58(m，6H).；
13C-NMR(DMSO-d
6，100MHz)：δ177.9，168.2，147.1，144.7，133.9，128.9，127.9，127.1，120.9，118.2，114.4，109.5，76.4，66.4，66.2，55.6，46.5，42.3.。
Embodiment 6:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium acetyl morphine (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-6).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 68%, dr value: 41: 59.
1H-NMR(DMSO-d
6，400MHz)：δ10.32(s，1H)，6.59-7.40(m，8H)，6.17(s，1H)，5.92(d，1H)，4.78(d，1H)，3.33-3.46(m，8H).；
13C-NMR(DMSO-d
6，100MHz)：δ178.1，167.8，147.2，144.7，133.8，128.9，127.9，127.4，120.9，118.1，114.4，109.5，76.4，55.7，46.9，42.7，26.1，25.5，23.9.。
Embodiment 7:
With 6-chlorisatide (0.28mmol), para-bromoaniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-7).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 85%, dr value: 41: 59.
1H-NMR(DMSO-d
6，400MHz)：δ10.55(s，1H)，10.37(s，1H)，6.64-7.99(m，14H)，4.94(d，1H).；
13C?NMR(DMSO-d
6，100MHz)：δ177.5，167.0，153.4，144.5，138.4，137.0，134.1，128.7，128.1，126.5，125.6，123.7，121.2，119.3，112.4，109.8，75.6，60.2.。
Embodiment 8:
With 6-chlorisatide (0.28mmol), P-nethoxyaniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-8).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 64%, dr value: 30: 70.
1H-NMR(DMSO-d
6，400MHz)：δ10.48(s，1H)，10.25(s，1H)，6.77-7.65(m，12H)，6.47(s，1H)，4.72(d，1H)，4.63(d，1H).；
13C-NMR(DMSO-d
6，100MHz)：δ177.9，168.4，144.7，143.8，138.6，133.9，128.6，127.9，126.7，123.4，121.0，119.2，115.5，115.2，114.9，109.6，75.9，61.9.。
Embodiment 9:
With 6-chlorisatide (0.28mmol), p-Chlorobenzoic acid amide (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-9).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 74%, dr value: 32: 68.
1H-NMR(DMSO-d
6，400MHz)：δ10.47(s，1H)，10.23(s，1H)，6.67-7.62(m，12H)，6.43(s，1H)，4.54(d，1H)，4.27(d，1H)，3.59(s，3H).；
13C-NMR(DMSO-d
6，100MHz)：δ177.2，167.8，152.0，144.8，143.8，141.9，138.0，133.5，，128.5，126.8，120.9，119.8，119.2，115.1，114.4，109.5，75.9，65.1，55.3.。
Embodiment 10:
With 6-chlorisatide (0.28mmol), m-bromoaniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-10).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 66%, dr value: 30: 70.
1H-NMR(DMSO-d
6，400MHz)：δ10.51(s，1H)，10.32(s，1H)，6.77-7.65(m，12H)，6.52(s，1H)，5.26(d，1H)，4.70(d，1H).；
13C-NMR(DMSO-d
6，100MHz)：177.3，167.1，149.9，143.9，138.2，133.5，130.5，128.6，128.4，127.0，123.7，122.1，121.0，119.9，119.3，115.9，112.5，109.5，76.6，63.2.。
Embodiment 11:
With 6-chloro-n-formyl sarcolysine base isatin (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-11).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 86%, dr value: 32: 68.
1H?NMR(CDCl
3，400MHz)：8.58(s，1H)，7.48(d，J＝7.8Hz，2H)，7.32-7.01(m，7H)，6.85(m，2H)，6.69(d，J＝7.3Hz，2H)，5.39(s，1H)，4.66(d，J＝9.5Hz，1H)，4.30(d，J＝9.5Hz，1H)，3.04(s，3H)；
13C?NMR(CDCl
3，125MHz)：175.6，169.1，146.6，146.0，136.8，136.5，129.5，129.1，126.1，125.8，125.1，123.4，120.8，120.6，115.4，109.5，76.5，64.9，26.5。
Embodiment 12:
With 5-bromoisatin (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-12).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 83%, dr value: 37: 63.
1H?NMR(DMSO-d
6，500MHz)：δ10.49(s，1H)，10.34(s，1H)，7.63(d，J＝10.0Hz，2H)，7.56(s，1H)，7.33(d，J＝5.0Hz，1H)，7.31(t，J＝10.0Hz，2H)，7.05-7.03(m，3H)，6.78-6.77(m，3H)，6.60(t，J＝10.0Hz，1H)，6.56(s，1H)，4.85(d，J＝15.0Hz，1H)，4.71(d，J＝10.0Hz，1H)；
13C?NMR(DMSO-d
6，125MHz)：177.6，168.8，147.2，142.5，138.7，132.3，129.4，128.8，128.7，128.5，123.5，119.3，117.8，114.2，113.1，111.6，76.3，61.2。
Embodiment 13:
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL methylene dichloride, diazonium Acetanilide (0.42mmol) is dissolved in the 2mL methylene dichloride forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in methylene dichloride with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-13).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 75%, dr value: 32: 68.
Embodiment 14
With 6-chlorisatide (0.28mmol), aniline (0.28mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.28mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under the normal temperature, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues at normal temperatures stirring reaction 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-14).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 62%, dr value: 30: 70.
Embodiment 15
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL tetrahydrofuran (THF), diazonium Acetanilide (0.42mmol) is dissolved in the 2mL tetrahydrofuran (THF) forms solution, under 40 ℃, the solution that the diazonium Acetanilide is dissolved in tetrahydrofuran (THF) with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues 40 ℃ of following stirring reactions 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-15).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 75%, dr value: 40: 60.
Embodiment 16
With 6-chlorisatide (0.28mmol), aniline (0.42mmol) and acetic acid rhodium (0.0028mmol) are dissolved in anabolic reaction system in the 4mL toluene, diazonium Acetanilide (0.42mmol) is dissolved in the 2mL toluene forms solution, under 70 ℃, the solution that the diazonium Acetanilide is dissolved in toluene with the automatic sampling pump was added drop-wise in the reaction system in 1 hour.Sample introduction finishes, and continues 70 ℃ of following stirring reactions 1 hour.The vacuum rotary steam desolventizing obtains crude product, and its structure is suc as formula shown in (1-16).Crude product is carried out column chromatography purification (sherwood oil: ethyl acetate=5: 1-2: 1) obtain pure products.Productive rate: 66%, dr value: 45: 55.
Embodiment 17
In the present embodiment The compounds of this invention biological activity is tested, The compounds of this invention is studied the restraining effect of tumour cell.In the present embodiment, what specifically use is HCT116 as cell.
Choose embodiment of the invention 1-embodiment 12 gained compounds HCT116 cancer cells survival rate is detected, detected result shows that The compounds of this invention has the effect of obvious suppression HCT116 cell growth, and IC50 (toxic limit medium dose) is 27 μ M.
Experimental result shows that 3-substituted indole ketone derivatives of the present invention is less to the influence of p53 protein level, and part 3-substituted indole of the present invention ketone derivatives has less rise effect.Simultaneously, 3-substituted indole ketone derivatives compound of the present invention is to the not obviously effect of p53 transcriptional activity.This shows that 3-substituted indole ketone derivatives of the present invention is applicable to the preparing anti-tumor medicine application.
Claims (8)
1. the preparation method of a 3-replacement-3-hydroxyindole ketone derivatives, it is characterized in that, described method is raw material with isatin, amine and diazonium compound, be catalyzer with the acetic acid rhodium, be solvent with the organic solvent, through single step reaction, obtain described 3-replacement-3-hydroxyindole ketone derivatives, shown in the following reaction formula (I):
Wherein,
R
1Be 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine substituent or hydrogen;
Ar is adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl or naphthyl;
R
2Be anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl or morpholinyl;
R
3Be hydrogen, methyl or ethyl.
2. the preparation method of 3-replacement-3-hydroxyindole ketone derivatives according to claim 1, it is characterized in that the mol ratio of raw material and catalyzer is isatin in the described method: amine: diazonium compound: acetic acid rhodium=1: 1.0: 1.0: 0.01-1: 2.0: 2.0: 0.01.
3. the preparation method of 3-replacement-3-hydroxyindole ketone derivatives according to claim 1, it is characterized in that, said method comprising the steps of: described isatin, amine, acetic acid rhodium are dissolved in the described organic solvent, under agitation, add described diazonium compound and be dissolved in the solution of described organic solvent gained, obtain described 3-replacement-3-hydroxyindole ketone derivatives through reaction.
4. the preparation method of 3-replacement-3-hydroxyindole ketone derivatives according to claim 1 is characterized in that, the described 3-replacement-3-hydroxyindole ketone derivatives that reaction is obtained carries out separation and purification through column chromatography.
5. the preparation method of 3-replacement-3-hydroxyindole ketone derivatives according to claim 1 is characterized in that, described organic solvent is tetrahydrofuran (THF), methylene dichloride, toluene, 1,2-ethylene dichloride, chloroform or ether.
6. the preparation method of 3-replacement-3-hydroxyindole ketone derivatives according to claim 1 is characterized in that, the temperature range of described reaction is 0 ℃-70 ℃.
7. one kind according to the resulting 3-replacement-3-hydroxyindole of claim 1 preparation method ketone derivatives, it is characterized in that the described following structural formula of 3-replacement-3-hydroxyindole ketone derivatives (1) expression:
Wherein,
R
1Be 4-fluorine, 4-chlorine, 4-bromine, 5-fluorine, 5-chlorine, 5-bromine, 6-fluorine, 6-chlorine, 6-bromine, 7-fluorine, 7-chlorine, 7-bromine substituent or hydrogen;
Ar is adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl, o-methoxyphenyl, a fluorophenyl, a chloro-phenyl-, a bromophenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, to ethoxyl phenenyl, p-methylphenyl, p-nitrophenyl or naphthyl;
R
2Be anilino, P-nethoxyaniline base, cyclopropyl amino, Tri N-Propyl Amine base, piperidyl or morpholinyl;
R
3Be hydrogen, methyl or ethyl.
8. the application of the described 3-replacement-3-hydroxyindole of claim 7 ketone derivatives in the preparation antitumor drug.
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