CN104031093B - A kind of ferrocene pyridine derivatives and its preparation method and application - Google Patents
A kind of ferrocene pyridine derivatives and its preparation method and application Download PDFInfo
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Abstract
The present invention discloses a kind of ferrocene pyridine derivatives and its preparation method and application, and the structural formula of described ferrocene pyridine derivatives is as follows：, wherein R is, or.Its preparation method prepares ferrocenecarboxylic acid first, then the ferrocenecarboxylic acid of gained is reacted under catalyst action in dichloromethane with 2 aminopyridines or 4 piconols, Jing washings, dichloromethane extraction, the distillation successively of the product of gained, with ethyl acetate as eluant column chromatography for separation, finally give ferrocene pyridine derivatives, the ferrocene pyridine derivatives have the effect for suppressing that breast carcinoma is the activity of 7 cell tumours of MCF, can be the lead compound application of 7 cell tumour medicines of MCF as screening anti-breast cancer.
Description
Technical field
The present invention relates to a kind of ferrocene pyridine derivatives and its preparation are suppressing breast carcinoma to be that MCF-7 cells swell with which
Application in tumor, which can be used as the lead compound application of screening anti-breast cancer medicines.
Background technology
Find for the first time this metallo-organic compound of ferrocene from nineteen fifty-one Pauson et al., people just always to it and
Its derivant is studied. ferrocene derivatives have it is good fat-soluble, easily by cell membrane, so as to various with intracellular
There is combination and acted in enzyme, DNA, RNA etc. and in 1980, Kopf-Maier etc. had found that ferrocene derivatives have for the first time
The effect of anti-malignant tumor cell propagation. it was developed so far from 1980, shows the metallo-organic compound of anti-tumor activity
Including the cisplatin of alkyls ferrocene, ferrocene alkyl azole, macromole ferrocene bioconjugates and ferrocene modification.
Pyridine compounds and their achieves breakthrough progress, pyridine in the pesticide synthesis such as insecticide, antibacterial, herbicide
Class compound also plays an important role in terms of pesticide bioactivity, the synthesis of pyridine compounds and their and bioactivity research,
One of study hotspot of region of chemistry and biosphere is become.Pyridine ring can significantly improve chemical combination microbic activity, significantly drop
The side effect such as hypotoxicity.The hydrophobicity of pyridine ring determines that noval chemical compound often has higher life by obtained from pyridine replaces
Selectivity of active, the lower toxicity of thing, higher absorbability and Geng Gao etc..
The content of the invention
An object of the present invention is to provide a kind of ferrocene pyridine derivatives, the ferrocene pyridine derivatives pair
Breast carcinoma is that MCF-7 cell tumours have certain inhibition, can be MCF-7 cell tumour medicines as screening anti-breast cancer
The lead compound application of thing.
The second object of the present invention is a kind of preparation method of the ferrocene pyridine derivatives for providing above-mentioned.
The third object of the present invention is that the above-mentioned ferrocene pyridine derivatives of research are swollen to breast carcinoma i.e. MCF-7 cells
The inhibitory action of tumor.
Technical scheme
A kind of ferrocene pyridine derivatives, its structural formula are as follows：
,
Wherein R is、Or。
A kind of above-mentioned ferrocene pyridine derivatives, Jing preliminary tests are MCF-7 cell tumours with breast carcinoma is suppressed
The effect of activity, can be the lead compound of MCF-7 cell tumour medicines as screening anti-breast cancer.
A kind of preparation method of above-mentioned ferrocene pyridine derivatives,
（One）, as R beWhen, specifically include step as follows：
（1）, under ice bath, ferrocene, succinic anhydride and dichloromethane are added in there-necked flask, by anhydrous three after stirring 1h
Aluminum chloride is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, Jing column chromatographies purification after concentration,
Ferrocenecarboxylic acid a is obtained, its structural formula is；
The amount of above-mentioned ferrocene used, succinic anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic acid
Acid anhydride：Dichloromethane：Aluminum trichloride (anhydrous) is 9.2g:11.0g:140ml:The ratio of 7.2g is calculated；
（2）, ferrocenecarboxylic acid a, catalyst 1 be dissolved in dichloromethane, after stirring 30min in ice-water bath, add 2- ammonia
Yl pyridines, continue stirring reaction 24h, washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography under room temperature
Separate, obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid a, catalyst 1, dichloromethane and PA used, by ferrocenecarboxylic acid a：
Catalyst 1：Dichloromethane：PA is 1mmol:2mmol::15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 1 is the mixture that EDCl, HOBt, DMAP, NMM, triethylamine or EDCl and HOBt are constituted；Wherein
The mixture of described EDCl and HOBt compositions, preferably for calculation in the molar ratio, EDCl：HOBt is 1：1；
Dichloromethane used by above-mentioned dissolving ferrocenecarboxylic acid a and catalyst 1 can use toluene, benzene, tetrahydrofuran, acetonitrile
Or DMF is substituted；
（Two）, as R beWhen, specifically include step as follows：
（1）, under ice bath, ferrocene, succinic anhydride and dichloromethane are added in there-necked flask, by anhydrous three after stirring 1h
Aluminum chloride is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, Jing column chromatographies purification after concentration,
Ferrocenecarboxylic acid a is obtained, its structural formula is；
The amount of above-mentioned ferrocene used, succinic anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic acid
Acid anhydride：Dichloromethane：Aluminum trichloride (anhydrous) is 9.2g:11.0g:140ml:The ratio of 7.2g is calculated；
（2）, ferrocenecarboxylic acid a, catalyst 2 be dissolved in dichloromethane, after stirring 30min in ice-water bath, add 4- pyrroles
Pyridine methanol, continues stirring reaction 24h, washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography under room temperature
Separate, obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid a, catalyst 2, dichloromethane and 4- piconols, by ferrocenecarboxylic acid a：Catalyst
2：Dichloromethane：4- piconols are 1mmol:1.1mmol:15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 2 is the mixture that EDCl, DMAP, HOBt, NMM, triethylamine or EDCl and DMAP are constituted；Wherein
The mixture of described EDCl and DMAP compositions, preferably for calculation in the molar ratio, EDCl：DMAP is 1：0.1；
Dichloromethane used by above-mentioned dissolving ferrocenecarboxylic acid a and catalyst 2 can use toluene, benzene, tetrahydrofuran, second
Nitrile or DMF are substituted；
（Three）, as R beWhen, specifically include step as follows：
（1）, under ice bath, ferrocene, glutaric anhydride and dichloromethane are added in there-necked flask, by anhydrous three after stirring 1h
Aluminum chloride is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, Jing column chromatographies purification after concentration,
Ferrocenecarboxylic acid b is obtained, its structural formula is；
The amount of above-mentioned ferrocene used, glutaric anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic acid
Acid anhydride：Dichloromethane：Aluminum trichloride (anhydrous) is 9.2g:12.2g:140ml:The ratio of 7.2g is calculated；
（2）, ferrocenecarboxylic acid b, catalyst 3 be dissolved in dichloromethane, after stirring 30min in ice-water bath, add 4- pyrroles
Pyridine methanol, continues stirring reaction 24h, washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography under room temperature
Separate, obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid b, catalyst 3, dichloromethane and 4- piconols used, by ferrocenecarboxylic acid a：
Catalyst 3：Dichloromethane：4- piconols are 1mmol:1.1mmol:15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 3 is the mixture that EDCl, DMAP, HOBt, NMM, triethylamine or EDCl and DMAP are constituted；Wherein
The mixture of described EDCl and DMAP compositions, preferably for calculation in the molar ratio, EDCl：DMAP is 1：0.1；
Dichloromethane used by above-mentioned dissolving ferrocenecarboxylic acid b and catalyst 3 can use toluene, benzene, tetrahydrofuran, acetonitrile
Or DMF is substituted.
Beneficial effects of the present invention
The present invention a kind of ferrocene pyridine derivatives, Jing preliminary tests, with suppress breast carcinoma be
The effect of MCF-7 cell tumours activity, which can suppress the breast carcinoma i.e. activity of MCF-7 cell tumours.Structural formula isFerrocene pyridine derivatives, its IC50It is worth for 44.2molL- 1；Structural formula isFerrocene pyridine derivatives, its IC50It is worth for 48.3 μm of olL- 1；Structural formula isFerrocene pyridine derivatives, its IC50It is worth for 24.2 μm of olL- 1.Therefore, the one of the present invention
Plant the lead compound application that ferrocene pyridine derivatives can be MCF-7 cell tumour medicines as screening anti-breast cancer.
Specific embodiment
The present invention is expanded on further below by specific embodiment, but is not intended to limit the present invention.
In various embodiments of the present invention, the model of instrument used and the information of manufacturer are as follows：
WPS-2A numeral melting point instruments, thermometer be not calibrated；
NMR (Nuclear Magnetic Resonance) spectrum:Switzerland's Bruker Avance III 500M type nuclear magnetic resonance analyser, TMS is internal standard；
Infrared spectrometer:Fourier transform infrared spectrometer 6700, Nicolet companies of the U.S., KBr tablettings；
Liquid chromatography mass combined instrument:LCMS-2020, Japanese Shimadzu Corporation；
High resolution mass spectrum:SolariX-70FT-MS Brooker,Switzerlands company;
It is pure that reagent used by various embodiments of the present invention is the pure and mild chemistry of commercially available analysis.
Embodiment 1
A kind of ferrocene pyridine derivatives, its structural formula are as follows：
, wherein R is。
A kind of preparation method of above-mentioned ferrocene pyridine derivatives, comprises the following steps that：
（1）, under ice bath, ferrocene 9.2g, succinic anhydride 11.0g and dichloromethane 140mL are added in there-necked flask,
Aluminum trichloride (anhydrous) 7.2g is added thereto after stirring 1h, at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction
Take, Jing column chromatographies purification after concentration obtains 11.4g ferrocenecarboxylic acid a, yield 81.0%；
（2）, weigh 2mmol ferrocenecarboxylic acid a, catalyst 1 i.e. EDCl412mg（2mmol）With HOBt270mg (2mmol）
The mixture of composition is dissolved in 30mL dichloromethane, and the PA of 2-4mmol, room after stirring 30min, are added in ice-water bath
Temperature is lower to continue stirring reaction 24h, and washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography for separation, are obtained
Orange/yellow solid 120mg, yield 30.1%.
The orange/yellow solid of above-mentioned gained is analyzed using WPS-2A numeral melting point instruments, the data of its fusing point are as follows
It is shown：
m.p.176-178.9℃.
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its H spectrum are as follows：
1H NMR (500 MHz, CDCl3): 8.71 (s,1H), 8.32 (d,J=3.5Hz,1H), 8.25 (d,J=
8.0Hz,1H), 7.72 (t,J=7.5Hz,1H), 7.05 (t,J=5.5Hz,1H), 5.32 (s,1H), 4.86 (s,
2H), 4.54 (s,2H), 4.26 (s,5H), 3.23 (t,J=6.0Hz,2H), 2.83 (t,J=6.0Hz,2H);
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its C spectrum are as follows：
13C NMR(CDCl3, 125 MHz)δ: 202.8, 171.2, 151.8, 147.7, 138.4, 119.6,
114.3, 78.4, 72.4, 70.0, 69.3, 34.5, 31.1;
The orange/yellow solid of above-mentioned gained is analyzed using Fourier transform infrared spectrometer 6700, its infrared number
According to as follows：
IR (KBr) ν: 3421, 3251, 2923, 1667, 1595, 1434, 1299, 786 cm-1;
Using LCMS-2020（Japanese Shimadzu Corporation）The orange/yellow solid of above-mentioned gained is analyzed, its mass spectrographic number
According to as follows：
ESI-MS m/z: 363[M+H]+;
Using SolariX-70FT-MS（Brooker,Switzerland company）The orange/yellow solid of above-mentioned gained is analyzed, its
The data of high resolution mass spectrum are as follows：
HRMS calcd for C19H18O2N2Fe 363.0796, found 363.0801.
Fusing point, nuclear magnetic resonance, NMR, infrared, mass spectrometric data as obtained by above-mentioned is analyzed, it can be deduced that, above-mentioned gained
Orange/yellow solid for structural formula isFerrocene pyridine derivatives.
Embodiment 2
A kind of ferrocene pyridine derivatives, its structural formula are as follows：
, wherein R is。
A kind of preparation method of above-mentioned ferrocene pyridine derivatives, comprises the following steps that：
（1）, under ice bath, 9.2g ferrocene, 11.0g succinic anhydrides and 140mL dichloromethane are added in there-necked flask, are stirred
7.2g aluminum trichloride (anhydrous)s are added thereto after mixing 1h, at 35 DEG C, are quenched with ice after continuing stirring 2h, dichloromethane extraction,
Jing column chromatographies purification after concentration, obtains 11.4g orange solids ferrocenecarboxylic acid a, yield 80.0%；
（2）, weigh 2mmol ferrocenecarboxylic acid a, catalyst 2 i.e. EDCl 412mg（2mmol）With DMAP 27mg
(0.2mmol）The mixture of composition is dissolved in 30mL dichloromethane, and the 4- pyrroles of 2-4mmol after stirring 30min, are added in ice-water bath
Pyridine methanol, continues stirring reaction 24h, washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography under room temperature
Separate, obtain yellow solid 125mg, yield 33%.
The orange/yellow solid of above-mentioned gained is analyzed using WPS-2A numeral melting point instruments, the data of its fusing point are as follows
It is shown：
m.p.79.5-81.0℃;
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its H spectrum are as follows：
1HNMR(CDCl3,500MHz):8.70(s,2H),7.33(s,2H),5.20(s,2H),4.83(s,2H),4.53
(s,2H),4.25(s,5H),3.13(t,J=6.3Hz,2H),2.82(t,J=6.3Hz,2H);
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its C spectrum are as follows：
13C NMR(CDCl3, 125 MHz) δ: 201.8, 172.7, 149.9, 145.2, 122.0, 78.3,
72.3, 70.2, 69.2, 64.5, 34.2, 27.9;
The orange/yellow solid of above-mentioned gained is analyzed using Fourier transform infrared spectrometer 6700, its infrared number
According to as follows：
IR(KBr)ν: 3434, 3093, 2929, 1736, 1667, 1455, 1278, 1157, 819 cm-1;
Using LCMS-2020（Japanese Shimadzu Corporation）The orange/yellow solid of above-mentioned gained is analyzed, its mass spectrographic number
According to as follows：
ESI-MS m/z: 378[M+H]+;
Using SolariX-70FT-MS（Brooker,Switzerland company）The orange/yellow solid of above-mentioned gained is analyzed, its
The data of high resolution mass spectrum are as follows：
HRMS calcd for C20H19O3N1Fe 378.0793,found 378.0810.
Fusing point, nuclear magnetic resonance, NMR, infrared, mass spectrometric data as obtained by above-mentioned is analyzed, it can be deduced that, above-mentioned gained
Orange/yellow solid for structural formula isFerrocene pyridine derivatives.
Embodiment 3
A kind of ferrocene pyridine derivatives, its structural formula are as follows：
, wherein R is。
A kind of preparation method of above-mentioned ferrocene pyridine derivatives, step are as follows：
（1）, under ice bath, 9.2g ferrocene, 12.2g glutaric anhydrides and 140mL dichloromethane are added in there-necked flask, are stirred
7.2g aluminum trichloride (anhydrous)s are added thereto after mixing 1h, at 35 DEG C, are quenched with ice after continuing stirring 2h, dichloromethane extraction,
Jing column chromatographies purification after concentration, obtains Orange red solid ferrocenecarboxylic acid b11.2g, yield 75.3%；
（2）, weigh 2mmol ferrocenecarboxylic acid b, catalyst 3 i.e. EDCl 412mg（2mmol）With DMAP 27mg
(0.2mmol）The mixture of composition is dissolved in 30mL dichloromethane, and the 4- pyrroles of 2-4mmol after stirring 30min, are added in ice-water bath
Pyridine methanol, continues stirring reaction 24h, washing, dichloromethane extraction, distillation, with ethyl acetate as eluant column chromatography under room temperature
Separate, obtain yellow solid 195mg, yield 50%.
The orange/yellow solid of above-mentioned gained is analyzed using WPS-2A numeral melting point instruments, the data of its fusing point are as follows
It is shown：
m.p.82.8-83.1℃;
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its H spectrum are as follows：
1H NMR(CDCl3, 500 MHz)δ: 8.64(s,2H), 7.28(s,2H), 5.18(s,2H), 4.79(s,
2H), 4.52(s,2H), 4.20(s,5H), 2.83(s,2H), 2.58(s,2H), 2.10(s,2H);
The orange/yellow solid of above-mentioned gained is carried out using Switzerland's Bruker Avance III 500M types nuclear magnetic resonance analyser
Analysis, the data of its C spectrum are as follows：
13C NMR(CDCl3, 125 MHz) δ: 203.4, 172.8, 149.8, 144.8, 122.7, 78.9,
72.3, 69.8, 69.3, 64.3, 38.2, 33.3, 19.5;
The orange/yellow solid of above-mentioned gained is analyzed using Fourier transform infrared spectrometer 6700, its infrared number
According to as follows：
IR (KBr) ν: 3427, 3098, 2922, 1743, 1671, 1456, 1281, 1172, 796 cm-1;
Using LCMS-2020（Japanese Shimadzu Corporation）The orange/yellow solid of above-mentioned gained is analyzed, its mass spectrographic number
According to as follows：
ESI-MS m/z: 392[M+H]+;
Using SolariX-70FT-MS（Brooker,Switzerland company）The orange/yellow solid of above-mentioned gained is analyzed, its
High-resolution data are as follows：
HRMS calcd for C21H21O3N1Fe 392.0949, found 392.0981.
Fusing point, nuclear magnetic resonance, NMR, infrared, mass spectrometric data as obtained by above-mentioned is analyzed, it can be deduced that, above-mentioned gained
Orange/yellow solid for structural formula isFerrocene pyridine derivatives.
Application Example
Use mtt assay（List of references：Xu YC, Xu GL, Liu L, Xu DS, Liu JW. Anti-invasion
effect of rosmarinic acid via the extracellular signal-regulated kinase and
oxidation–reduction pathway in Ls174-T cells. J Cell Biochem 2010;111:370–9）
The target compound determined obtained by embodiment 1, embodiment 2 and the embodiment 3 of synthesis is that MCF-7 cell tumours are external to breast carcinoma
Anti-tumor activity；
Breast cancer cell line MCF-7 is purchased from Shanghai Chinese Academy of Sciences cell bank.MCF-7 cells remain multiple mammary gland for having broken up
The characteristic of epithelium, including：Estradiol can be processed by cytoplasmic oestrogen-receptor and circular complex can be formed（domes）.Tissue
Originate as adenocarcinoma, mammary gland, hydrothorax, form are epithelial cell.Its culture medium and additive are as follows：MEM culture medium (GIBCO, article No.
41500034, add NaHCO31.5g/L, glucose 2.5g/L, Sodium Pyruvate 0.11g/L, 90%；High-quality hyclone,
10%;
Its cultural method is：After receiving cell, whole cell growth status are observed under inverted microscope：If cell is not
Covering with, being put in super bacterium platform after whole bottle sterilization being sprayed with 75% ethanol, strict aseptic technique is opened Tissue Culture Flask, stays 10ml
Culture fluid continues culture.If cell is covered with（Up to 80-90%）.Can be passed on, be comprised the following steps that：
1, culture fluid is discarded, is washed 1-2 time with PBS；
2,1.0-2.0ml trypsin solutions are added into bottle, the observation of cell digestion situation under inverted microscope, if cell
Major part is rounded, and brings back rapidly operating board, draws trypsin, plus containing culture fluid of the 6ml containing 10% serum, gently blows and beats thin
Born of the same parents；
3, the culture fluid of equivalent is added, gently piping and druming suctions out half after mixing, and assigns to new culture；
4, pass on ratio：1:2-1:3.
Collect the MCF-7 cells adjustment MCF-7 concentration of cell suspension of above-mentioned logarithmic (log) phase（Solvent be RPMI-1640 culture medium+
10% hyclone+1% is dual anti-）, in 96 hole flat undersides add 100 μ L, bed board to make every hole MCF-7 cell densities to be measured be per hole
1000～10000, the aseptic PBS of edge hole（Phosphate buffer）, then in 37 DEG C of volume fractions be 5% CO2In incubator
Culture 24h to MCF-7 cell monolayers are paved with bottom hole；
Then by embodiment 1, the ferrocene pyridine derivatives obtained by embodiment 2 and embodiment 3, setting 7 is terraced respectively
Degree concentration is added sequentially in 96 above-mentioned orifice plates, and its Concentraton gradient is respectively 0 μm of ol/L, 12.5 μm of ol/L, 25 μm of ol/L, 50
μm ol/L, 100 μm of ol/L, 150 μm of ol/L, 200 μm of ol/L, are 100 μ L per hole addition, each Concentraton gradient set 3 it is parallel
Hole；
After having added the ferrocene pyridine derivatives obtained by embodiment 1, embodiment 2 and embodiment 3, in 37 DEG C of volume integrals
Number is 5%CO2Cultivate in incubator and observed under 24h, inverted microscope,（Find under microscope that drug level is bigger, in hole
Number of viable cells it is fewer, in 200 μm of ol/L, there's almost no living cells.Thus illustrate that this medicine can suppress swollen
The propagation of oncocyte, has anti-tumor activity.Then the supernatant in 96 orifice plates is discarded, 20 μ L MTT solution (5mg/ is added per hole
ML, i.e. 0.5%MTT), continue culture 4h；
Then the supernatant in 96 orifice plates is discarded, 150 μ L dimethyl sulfoxide is added per hole, low-speed oscillation on shaking table is put
10min, makes crystal fully dissolve；
Then 96 orifice plate of monoblock is put in full-automatic multi-functional microplate reader（Microplate reader manufacturer：Perkinelmer）, instrument
Device goes out the light absorption value of the MTT- formazans for detecting each hole DMSO dissolvings in OD570 and 630nm, is then calculated according to light absorption value,
Embodiment 1, the ferrocene pyrrole obtained by embodiment 2 or embodiment 3 are added in finally giving breast carcinoma cell strain (MCF-7 cell strains)
IC after pyridine analog derivative50Value, such as following table：
IC in upper table50Value, has further demonstrated that the ferrocene pyridines obtained by embodiment 1, embodiment 2 and embodiment 3 are spread out
Biology plays the role of to suppress breast carcinoma i.e. MCF-7 cell tumours activity.
Summary is described, a kind of ferrocene pyridine derivatives Jing preliminary tests of the present invention, with breast carcinoma is suppressed is
The effect of MCF-7 cell tumours activity, therefore, a kind of ferrocene pyridine derivatives of the present invention can be used as screening anti-breast cancer
That is the lead compound application of MCF-7 cell tumours medicine.
Above said content is only the basic explanation under present inventive concept, and according to appointing that technical scheme is made
What equivalent transformation, all should belong to protection scope of the present invention.
Claims (3)
1. a kind of preparation method of ferrocene pyridine derivatives, the following institute of structural formula of described ferrocene pyridine derivatives
Show：
Wherein R isIt is characterized in that its preparation process is concrete
Comprise the steps：
(1), when R isWhen, specifically include step as follows：
(1), under ice bath, ferrocene, succinic anhydride and dichloromethane are added in there-necked flask, by anhydrous tri-chlorination after stirring 1h
Aluminum is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, and after concentration, Jing column chromatographies purification, obtains
Ferrocenecarboxylic acid a, its structural formula is
The amount of above-mentioned ferrocene used, succinic anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic anhydride：Two
Chloromethanes：Aluminum trichloride (anhydrous) is 9.2g:11.0g:140ml:The ratio of 7.2g is calculated；
(2), ferrocenecarboxylic acid a, catalyst 1 are dissolved in dichloromethane, after 30min being stirred in ice-water bath, add 2- amino pyrroles
Pyridine, continues stirring reaction 24h under room temperature, washing, dichloromethane extraction are distilled, with ethyl acetate as eluant column chromatography for separation,
Obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid a, catalyst 1, dichloromethane and PA used, by ferrocenecarboxylic acid a：Catalysis
Agent 1：Dichloromethane：PA is 1mmol:2mmol:15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 1 is the mixture that EDCl and HOBt is constituted, or is EDCl, HOBt, DMAP, NMM or triethylamine；
(2), when R isWhen, specifically include step as follows：
(1), under ice bath, ferrocene, succinic anhydride and dichloromethane are added in there-necked flask, by anhydrous tri-chlorination after stirring 1h
Aluminum is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, and after concentration, Jing column chromatographies purification, obtains
Ferrocenecarboxylic acid a, its structural formula is
The amount of above-mentioned ferrocene used, succinic anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic anhydride：Two
Chloromethanes：Aluminum trichloride (anhydrous) is 9.2g:11.0g:140ml:The ratio of 7.2g is calculated；
(2), ferrocenecarboxylic acid a, catalyst 2 are dissolved in dichloromethane, after 30min being stirred in ice-water bath, add 4- pyridine first
Alcohol, continues stirring reaction 24h under room temperature, washing, dichloromethane extraction are distilled, with ethyl acetate as eluant column chromatography for separation,
Obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid a, catalyst 2, dichloromethane and 4- piconols used, by ferrocenecarboxylic acid a：Catalysis
Agent 2：Dichloromethane：4- piconols are 1mmol:1.1mmol:15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 2 is the mixture that EDCl and DMAP is constituted, or is EDCl, HOBt, DMAP, NMM or triethylamine；
(3), when R isWhen, specifically include step as follows：
(1), under ice bath, ferrocene, glutaric anhydride and dichloromethane are added in there-necked flask, by anhydrous tri-chlorination after stirring 1h
Aluminum is added thereto, and at 35 DEG C, is quenched with ice after continuing stirring 2h, dichloromethane extraction, and after concentration, Jing column chromatographies purification, obtains
Ferrocenecarboxylic acid b, its structural formula is
The amount of above-mentioned ferrocene used, glutaric anhydride, dichloromethane and aluminum trichloride (anhydrous), by ferrocene：Succinic anhydride：Two
Chloromethanes：Aluminum trichloride (anhydrous) is 9.2g:12.2g:140ml:The ratio of 7.2g is calculated；
(2), by ferrocenecarboxylic acid b, catalyst 3 is dissolved in dichloromethane, after stirring 30min, adds 4- pyridine first in ice-water bath
Alcohol, continues stirring reaction 24h under room temperature, washing, dichloromethane extraction are distilled, with ethyl acetate as eluant column chromatography for separation,
Obtaining structural formula isFerrocene pyridine derivatives；
The amount of above-mentioned ferrocenecarboxylic acid b, catalyst 3, dichloromethane and 4- piconols used, by ferrocenecarboxylic acid b：Catalysis
Agent 3：Dichloromethane：4- piconols are 1mmol:1.1mmol:15ml:The ratio of 1-2mmol is calculated；
Above-mentioned catalyst 3 is the mixture that EDCl and DMAP is constituted, or is EDCl, HOBt, DMAP, NMM or triethylamine.
2. the preparation method of ferrocene pyridine derivatives as claimed in claim 1, it is characterised in that
(1), when R isWhen, used by the described dissolving ferrocenecarboxylic acid a and catalyst 1 in step (2)
Dichloromethane toluene, benzene, tetrahydrofuran, acetonitrile or DMF are substituted；
(2), when R isWhen, used by the above-mentioned dissolving ferrocenecarboxylic acid a and catalyst 2 described in step (2)
Dichloromethane toluene, benzene, tetrahydrofuran, acetonitrile or DMF substitute；
(3), when R isWhen, the dichloro used by dissolving ferrocenecarboxylic acid b and catalyst 3 described in step (2)
Methane toluene, benzene, tetrahydrofuran, acetonitrile or DMF are substituted.
3. the preparation method of ferrocene pyridine derivatives as claimed in claim 1, it is characterised in that
(1), when R isWhen, the mixture of the described EDCl and HOBt composition in step (2), in molar ratio
Calculate, EDCl：HOBt is 1：1；
(2), when R isWhen, the mixture of the EDCl and DMAP composition described in step (2), in molar ratio
Calculate, EDCl：DMAP is 1：0.1；
(3), when R isWhen, the mixture of the EDCl and DMAP composition described in step (2), according to the molar ratio
Calculate, EDCl：DMAP is 1：0.1.
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