CN106905380A - A kind of Aminylferrocene analog derivative containing pyrimidine ring and its production and use - Google Patents
A kind of Aminylferrocene analog derivative containing pyrimidine ring and its production and use Download PDFInfo
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Abstract
The invention discloses a kind of Aminylferrocene analog derivative containing pyrimidine ring and its production and use, wherein the structure of the Aminylferrocene analog derivative containing pyrimidine ring is represented by below general formula (1) or formula (2)：Wherein R is selected from 4 chlorine, 4 methoxyl groups, 4 methyl, 3 chlorine, 3,5 dimethoxys, 3,5 dichloros, 4 ethyls, 4 fluorine, 4 bromines, 3 bromines, 3 methyl, 4 trifluoromethoxies or hydrogen.Aminylferrocene analog derivative containing pyrimidine ring of the invention has obvious Developing restraint to act on to mouse skin MC (B16 F10) and human lung carcinoma cell line (A549), therefore can be used for preparing anti-tumor drug.
Description
First, technical field
The present invention relates to a kind of ferrocene analog derivative, specifically a kind of Aminylferrocene class containing pyrimidine ring is spread out
Biology and its production and use.
2nd, background technology
Ferrocene (Ferrocene) is orange-yellow prism-shaped or powdered crystalline solid, chemical entitled cyclopentadienyl group iron,
It is made up of two cyclopentadiene and a ferrous ion.One iron atom of folder in the middle of two luxuriant rings, is one typical
Two type complexs of interlayer structure, with armaticity, structure is very stable, and less than 470 DEG C will not decompose.Its chemical property with
Aromatic compound is similar to, and is susceptible to reduction reaction, and electrophilic substitution reaction easily occurs.Structures shape property, ferrocene knot
The particularity of structure determines that Ferrocene and its derivative has a multiple biological activities, including antitumor, anti-anemia action, anti-malarial, kills
Bacterium, plant growth regulating etc..
Cancer is one of important diseases that current serious threaten human health, and its treatment and prevention causes attention extensively.Mesh
Preceding treatment method has surgery excision, radiotherapy, chemotherapy etc., but still main based on chemotherapy.When
Before be clinically used for treating cancer chemicals species it is more, such as platinum class, nitrogen mustards, triazole type, but most drug due to
Toxicity is big, adverse reaction is more, bioavilability is low and make its application be restricted.Therefore high-efficiency low-toxicity, anticancer spectrum are found wide
Cancer therapy drug be always the research of many Pharmaceutical Chemists focus.With going deep into for studying Ferrocene and its derivative, people
Find that some ferrocene derivatives have active anticancer, such as the ferrocene congener of TAM.Long-term use breast cancer is controlled
Treating medicine TAM can increase the danger of pulmonary blood grumeleuse, and produce drug resistance.Knots of the Jaouen et al. in TAM
Ferrocenyl is introduced in structure, a series of derivative of ferrocenyl TAMs is prepared for, the activity of its anti-breast cancer is preferable, and
And reduce cytotoxicity.
3rd, the content of the invention
The present invention is intended to provide a kind of Aminylferrocene analog derivative containing pyrimidine ring and its production and use, institute
The technical problem to be solved is that drug effect functional group is introduced in the structure of ferrocene by MOLECULE DESIGN is antitumor so as to strengthen its
Activity.
The present invention selects amides compound and is introduced into the structure of ferrocene.
Aminylferrocene analog derivative containing pyrimidine ring of the invention, its structure is by below general formula (1) or formula (2) table
Show：
Wherein R be selected from 4- chlorine, 4- methoxyl groups, 4- methyl, 3- chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine,
4- bromines, 3- bromines, 3- methyl, 4- trifluoromethoxies or hydrogen.
Two R bases in Aminylferrocene analog derivative structural formula containing pyrimidine ring are identical.
With reference to effect, preferred group is R=4- ethyls.
One of preparation method of Aminylferrocene analog derivative containing pyrimidine ring of the invention, comprises the following steps：
A, weigh formylferrocene (1) and be dissolved in acetone, sodium hydroxide solution is then added dropwise, at room temperature stirring reaction,
TLC is detected, is stopped reacting after formylferrocene (1) runs out of；To added water in reaction solution Precipitation completely, suction filtration,
Dry, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2, v/v) obtains intermediate (2) methyl vinylferrocene base
Ketone；The mol ratio of formylferrocene and NaOH is 5:1；The consumption of acetone is every mM of ferrocenyl methyl ketone 5mL third
Ketone.
B, intermediate (2) is dissolved in dimethylformamide, DMF dimethylacetal is added, at 125 DEG C
Back flow reaction 2.5h, TLC detection, reaction terminates rear cooling reaction system, adds dichloromethane, washing, the anhydrous sulphur of organic phase
Sour sodium is dried, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2, v/v), obtains intermediate (3) (1E, 4E) -1-
(dimethylamino) -5- vinylferrocene base -1,4- diene -3- ketone；Intermediate (2) and N,N-dimethylformamide dimethylacetal
Mol ratio is 1:5；The consumption of dimethylformamide is every mM of intermediate (2) 3mL dimethylformamides.
C, intermediate (3), guanidine hydrochloride and potassium carbonate are dissolved in 2-methyl cellosolve, back flow reaction 24h, TLC at 125 DEG C
Detection, reaction terminates rear cooling reaction system, is poured into water, ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, column chromatography
(eluent is ethyl acetate/petroleum ether=1/2, v/v) is separated, intermediate (4) (E) -4- vinylferrocene yl pyrimidines -2- is obtained
Amine；The mol ratio of intermediate (3), guanidine hydrochloride and potassium carbonate is 1:1.5:2；The consumption of 2-methyl cellosolve is every mM of centre
Body (3) 10mL 2-methyl cellosolves.
D, weigh intermediate (4,0.5mmol) and substituted benzoyl chloride (1.5mmol) is dissolved in 10mL dichloromethane, add
Three drop triethylamines, room temperature reaction, TLC detections, question response adds water, ethyl acetate to be extracted after stopping, and organic phase is being passed through
Washing, sample is mixed after saturated common salt washing carries out column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/3, v/v), finally
Obtain target product 4a-m.
The structural formula of the substituted benzoyl chloride is：Wherein R is selected from hydrogen, 4- chlorine, 4- methoxyl groups, 4- first
Base, 3- chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine, 4- bromines, 3- bromines, 3- methyl or 4- trifluoromethoxies.
The two of the preparation method of the Aminylferrocene analog derivative containing pyrimidine ring of the invention, comprise the following steps：
A, ferrocenyl methyl ketone (5) is dissolved in dimethylformamide, adds DMF dimethylacetal,
Back flow reaction 2.5h at 125 DEG C, TLC detect that reaction terminates rear cooling reaction system, add dichloromethane, and washing, organic phase is used
Anhydrous sodium sulfate drying, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2, v/v), obtains intermediate (6) (E) -3-
(dimethylamino) -1- ferrocenyl -2- alkene -1- ketone；Ferrocenyl methyl ketone (5) and N,N-dimethylformamide dimethylacetal rub
You are than being 1:5；The consumption of dimethylformamide is every mM of ferrocenyl methyl ketone (5) 3mL dimethylformamides.
B, intermediate (6), guanidine hydrochloride and potassium carbonate are dissolved in 2-methyl cellosolve, back flow reaction 24h, TLC at 125 DEG C
Detection, reaction terminates rear cooling reaction system, is poured into water, ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, column chromatography
(eluent is ethyl acetate/petroleum ether=1/2, v/v) is separated, intermediate (7) 4- ferrocene pyrimidine -2- amine is obtained；Intermediate
(6), the mol ratio of guanidine hydrochloride and potassium carbonate is 1:1.5:2；The consumption of 2-methyl cellosolve is every mM of intermediate (6) 10mL
2-methyl cellosolve.
C, weigh intermediate (7,0.5mmol) and substituted benzoyl chloride (1.5mmo) is dissolved in 10mL dichloromethane, add
Three drop triethylamines, room temperature reaction, TLC detections, question response adds water, ethyl acetate to be extracted after stopping, and organic phase is being passed through
Washing, sample is mixed after saturated common salt washing carries out column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/3, v/v), finally
Obtain target product 7a-m.
The structural formula of the substituted benzoyl chloride is：Wherein R is selected from hydrogen, 4- chlorine, 4- methoxyl groups, 4- first
Base, 3- chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine, 4- bromines, 3- bromines, 3- methyl or 4- trifluoromethoxies.
The purposes of the Aminylferrocene analog derivative containing pyrimidine ring of the invention, is to prepare treatment cutaneous melanoma medicine
Application in thing or anti-lung-cancer medicament.
The Aminylferrocene analog derivative containing pyrimidine ring of the invention to mouse skin MC (B16-F10) and
Human lung carcinoma cell line (A549) has obvious Developing restraint to act on, therefore can be used for preparing anti-tumor drug.
4th, illustrate
Fig. 1 is syntheti c route schematic diagram of the present invention.
5th, specific embodiment
The present invention is further described by following examples, but should be noted that the scope of the present invention is not implemented by these
Any limitation of example.
Embodiment 1：(E) the chloro- N- of -4- (4- chlorophenylmethyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzoyl
The preparation of amine (4a)
A, formylferrocene (1) (4.8g, 20mmol) is weighed in 250mL single-necked flasks, add acetone (100mL),
Then sodium hydroxide solution (2mL, 2mol/L) is added dropwise, stirs at room temperature, TLC detections stop after formylferrocene runs out of
Only react, add water to Precipitation completely, suction filtration is dried, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2,
V/v), intermediate (2) methyl vinylferrocene base ketone 4.22g is obtained.Dark red solid, yield 83.7%, fusing point：125-127℃.
1H NMR(CDCl3):δ 7.42 (d, J=16.0Hz, 1H), 6.34 (d, J=16.0Hz, 1H), 4.50 (s, 2H),
4.44(s,2H),4.15(s,5H),2.29(s,3H).MS(ESI):255.1(C14H14FeO,[M+H]+)。
B, weigh intermediate (2) (254mg, 1mmol) and be dissolved in 3mL dimethylformamides, add N, N- dimethyl formyls
Amine dimethylacetal 595mg, 125 DEG C of oil bath 2.5h, 30mL dichloromethane, washing, the anhydrous sulphur of organic phase are added after being cooled to room temperature
Sour sodium is dried, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2, v/v), obtains intermediate (3)
(1E, 4E) -1- (dimethylamino) -5- vinylferrocene base -1,4- diene -3- ketone 266mg.Yield 86%, it is dark red
Color solid, fusing point：201-202℃.
1H NMR(CDCl3):δ 7.71 (d, J=12.4Hz, 1H), 7.43 (d, J=15.6Hz, 1H), 6.40 (d, J=
15.5Hz, 1H), 5.18 (d, J=12.5Hz, 1H), 4.48 (d, J=1.1Hz, 2H), 4.35 (d, J=1.2Hz, 2H), 4.13
(d, J=0.6Hz, 5H), 3.10 (s, 3H), 2.87 (s, 3H) .MS (ESI):309.2(C17H19FeNO,[M+H]+)。
C, weigh intermediate (3) (309mg, 1mmol), guanidine hydrochloride (144mg, 1.5mmol) and potassium carbonate (276mg,
2mmol) it is dissolved in 10mL 2-methyl cellosolves, 125 DEG C of backflow 24h, TLC detections, reaction terminates rear cooling reaction system,
Enter in 50mL water, ethyl acetate is extracted, organic phase anhydrous sodium sulfate drying, (eluent is ethyl acetate/oil to column chromatography for separation
Ether=1/2, v/v), obtain intermediate (4) (E) -4- vinylferrocene yl pyrimidines -2- amine 241mg.Yield 79%, peony precipitation,
197-199 DEG C of fusing point.
1H NMR(CDCl3):δ 8.21 (d, J=4.6Hz, 1H), 7.55 (d, J=15.8Hz, 1H), 6.61 (d, J=
4.8Hz, 1H), 6.51 (d, J=15.9Hz, 1H), 4.97 (s, 2H), 4.53 (s, 2H), 4.38 (s, 2H), 4.16 (s, 5H) .MS
(ESI):306.1(C16H15FeN3,[M+H]+)。
D, intermediate (4) 0.5mmol and 4- chlorobenzoyl chloride 1.5mmol are weighed, be dissolved in 10mL dichloromethane, add three
Drop triethylamine, room temperature reaction, TLC point plates, question response adds 10mL water after stopping, 20mL ethyl acetate, extraction, organic phase is being passed through
Washing is crossed, sample column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/3, v/v) is mixed after saturated common salt washing, obtain target
Product (4a) (E) -4- chloro- N- (4- chlorophenylmethyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzamide.Yield
75%, dark red solid, fusing point：157-159℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.1Hz, 1H), 7.78 (d, J=7.4Hz, 4H), 7.43 (d, J=
15.6Hz, 1H), 7.38 (t, J=8.7Hz, 4H), 6.92 (d, J=5.1Hz, 1H), 6.45 (d, J=15.6Hz, 1H), 4.47
(s,2H),4.41(s,2H),4.11(s,5H).13C NMR(151MHz,CDCl3):δ174.25,167.09,162.69,
161.34,142.58,141.77,135.54,133.18,131.67,123.78,117.86,82.55,73.50,72.24,
70.96,32.36.MS(ESI):583.2(C30H21Cl2FeN3O2,[M+H]+)。
Embodiment 2：(E) -4- methoxyl groups-N- (4- methoxybenzoyls base)-N- (4- ferrocenyls vinyl) pyrimidine -2-
Base) benzamide (4b) preparation
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorine with 4- methoxy benzoyl chlorides in step c
Chlorobenzoyl chloride, obtains target product (4b) (E) -4- methoxyl groups-N- (4- methoxybenzoyls base)-N- (4- ferrocenyl ethene
Base) pyrimidine -2-base) benzamide.Yield 77%, dark red solid, fusing point：91-93℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.1Hz, 1H), 7.78 (d, J=7.4Hz, 4H), 7.43 (d, J=
15.6Hz, 1H), 7.38 (t, J=8.7Hz, 4H), 6.92 (d, J=5.1Hz, 1H), 6.45 (d, J=15.6Hz, 1H), 4.47
(s,2H),4.41(s,2H),4.11(s,5H).13C NMR(151MHz,CDCl3):δ174.88,166.85,165.72,
163.49,161.24,141.93,134.27,129.65,124.16,117.36,116.53,82.79,73.29,72.18,
70.87,58.07,32.29.MS(ESI):574.4(C32H27FeN3O4,[M+H]+)。
Embodiment 3：(E) -4- methyl-N- (4- methyl benzoyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
The preparation of benzamide (4c)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzenes with 4- methyl benzoyl chlorides in step c
Formyl chloride, obtains target product (4c) (E) -4- methyl-N- (4- methyl benzoyls)-N- (4- ferrocenyls vinyl) phonetic
Pyridine -2- bases) benzamide.Yield 77%, dark red solid, fusing point：35-37℃.
1H NMR(CDCl3):δ 8.50 (d, J=5.2Hz, 1H), 7.77 (d, J=8.0Hz, 4H), 7.44 (d, J=
15.6Hz, 1H), 7.18 (d, J=8.0Hz, 4H), 6.88 (d, J=5.2Hz, 1H), 6.44 (d, J=15.6Hz, 1H), 4.46
(s,2H),4.38(s,2H),4.08(s,5H),2.34(s,6H).13C NMR(151MHz,CDCl3):δ175.38,166.78,
163.28,161.26,145.96,141.94,134.62,132.07,131.92,124.03,117.50,82.78,73.29,
72.17,70.87,32.34,24.30.MS(ESI):542.4(C32H27FeN3O2,[M+H]+)。
Embodiment 4：(E) the chloro- N- of -3- (3- chlorobenzene formacyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzene first
The preparation of acid amides (4d)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzene first with 3- chlorobenzoyl chlorides in step c
Acyl chlorides, obtains target product (4d) (E) -3- chloro- N- (3- chlorobenzene formacyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
Benzamide.Yield 83%, dark red solid, fusing point：137-139℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.2Hz, 1H), 7.86 (s, 2H), 7.68 (d, J=7.7Hz, 2H), 7.47
(d, J=8.0Hz, 2H), 7.39 (d, J=15.4Hz, 1H), 7.32 (t, J=7.9Hz, 2H), 6.90 (d, J=5.2Hz, 1H),
(s, the 5H) of 6.45 (d, J=15.5Hz, 1H), 4.48 (s, 2H), 4.41 (s, 2H), 4.1113C NMR(151MHz,CDCl3):δ
173.92,166.98,161.40,142.68,138.88,137.54,135.36,132.53,131.93,129.63,123.64,
118.04,82.23,73.51,72.26,70.98.MS(ESI):583.2(C30H21Cl2FeN3O2,[M+H]+)。
Embodiment 5：(E) -3,5- dimethoxys-N- (3,5- methoxybenzoyls base)-N- (4- ferrocenyls vinyl)
Pyrimidine -2-base) benzamide (4e) preparation
The preparation method of the present embodiment is with embodiment 1, the difference is that being replaced with 3,5- dimethoxy-benzoyl chlorides in step c
4- chlorobenzoyl chlorides, obtain target product (4e) (E) -3,5- methoxyl groups-N- (3,5- Dimethoxybenzoyl)-N- (4- bis-
Luxuriant ironbased ethylene base) pyrimidine -2-base) benzamide.Yield 79%, dark red solid, fusing point：39-40℃.
1H NMR(CDCl3):δ 8.49 (d, J=5.1Hz, 1H), 7.46 (s, 4H), 7.42 (d, J=15.6Hz, 1H),
7.09 (s, 2H), 6.88 (d, J=5.2Hz, 1H), 6.47 (d, J=15.6Hz, 1H), 4.46 (s, 2H), 4.39 (s, 2H),
4.09(s,5H),2.28(s,13H).13C NMR(151MHz,CDCl3):δ175.80,166.87,163.20,161.19,
141.96,140.78,137.40,136.92,129.63,124.14,117.58,82.76,73.31,72.20,70.87,
23.85.MS(ESI):570.5(C34H31FeN3O2,[M+H]+)。
Embodiment 6：(E) the chloro- N- of -3,5- (3,5- dichloro-benzoyls base)-N- (4- ferrocenyls vinyl) pyrimidine -2-
Base) benzamide (4f) preparation
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorine with 3,5- dichlorobenzoyl chlorides in step c
Chlorobenzoyl chloride, obtains target product (4f) (the E)-chloro- N- of 3,5- (3,5- chlorobenzene formacyl)-N- (4- ferrocenyls vinyl) phonetic
Pyridine -2- bases) benzamide.Yield 85%, dark red solid, fusing point：146-148℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.1Hz, 1H), 7.67 (s, 4H), 7.50 (s, 2H), 7.40 (d, J=
15.5Hz, 1H), 6.95 (d, J=5.2Hz, 1H), 6.47 (d, J=15.5Hz, 1H), 4.50 (s, 2H), 4.44 (s, 2H),
4.13(s,5H).13C NMR(151MHz,CDCl3):δ172.51,167.17,161.88,161.48,143.12,139.74,
138.21,135.22,129.91,123.45,118.40,82.31,73.65,72.30,71.05.MS(ESI):652.2
(C30H19Cl4FeN3O2,[M+H]+)。
Embodiment 7：(E) -4- ethyls-N- (4- ethylbenzyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzene
The preparation of formamide (4g)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzenes with 4- ethylbenzoyls chloro in step c
Formyl chloride, obtains target product (4g) (E) -4- ethyls-N- (4- ethylamino benzonitriles acyl group)-N- (4- ferrocenyls vinyl) phonetic
Pyridine -2- bases) benzamide.Yield 89%, dark red solid, fusing point：42-45℃.
1H NMR(CDCl3):δ 8.50 (d, J=5.1Hz, 1H), 7.80 (d, J=7.5Hz, 4H), 7.46 (d, J=
15.5Hz, 1H), 7.20 (d, J=7.7Hz, 4H), 6.89 (d, J=5.1Hz, 1H), 6.45 (d, J=15.6Hz, 1H), 4.46
(s, 2H), 4.38 (s, 2H), 4.08 (s, 5H), 2.64 (q, J=7.6Hz, 4H), 1.20 (t, J=7.5Hz, 6H)13C NMR
(151MHz,CDCl3):δ175.45,166.81,163.28,161.28,152.09,141.94,134.74,132.17,
130.75,124.03,117.55,82.77,73.30,72.18,70.87,31.54,17.66.MS(ESI):570.5
(C34H31FeN3O2,[M+H]+)。
Embodiment 8：(E) the fluoro- N- of -4- (4- fluoro benzoyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzene first
The preparation of acid amides (4h)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzene first with 4- fluorobenzoyl chlorides in step c
Acyl chlorides, obtains target product (4h) (E) -4- fluoro- N- (4- fluoro benzoyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
Benzamide.Yield 87%, dark red solid, fusing point：143-145℃.
1H NMR(CDCl3):δ 8.49 (d, J=5.0Hz, 1H), 7.90-7.83 (m, 4H), 7.43 (d, J=15.6Hz,
1H), 7.08 (t, J=8.1Hz, 4H), 6.93 (d, J=5.1Hz, 1H), 6.46 (d, J=15.6Hz, 1H), 4.47 (s, 2H),
4.41(s,2H),4.11(s,5H).13C NMR(151MHz,CDCl3):δ174.17,168.78,167.08,161.33,
142.46,134.42,133.40,123.85,118.63,118.48,117.75,82.56,73.46,72.23,70.93.MS
(ESI):550.4(C30H21F2FeN3O2,[M+H]+)。
Embodiment 9：(E) the bromo- N- of -4- (4- benzoyl bromides)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzene first
The preparation of acid amides (4i)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzene first with 4- bromo-benzoyl chlorides in step c
Acyl chlorides, obtains target product (4i) (E) -4- bromo- N- (4- benzoyl bromides)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
Benzamide.Yield 94%, dark red solid, fusing point：127-129℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.1Hz, 1H), 7.70 (d, J=7.7Hz, 4H), 7.54 (d, J=
7.9Hz, 4H), 7.43 (d, J=15.6Hz, 1H), 6.93 (d, J=5.1Hz, 1H), 6.45 (d, J=15.5Hz, 1H), 4.47
(s,2H),4.42(s,2H),4.11(s,5H).13C NMR(151MHz,CDCl3):δ174.38,167.10,162.64,
161.34,142.60,135.98,134.65,133.27,130.41,127.30,123.80,117.90,73.58,72.34,
71.03.MS(ESI):672.2(C30H21Br2FeN3O2,[M+H]+)。
Embodiment 10：(E) the bromo- N- of -3- (3- benzoyl bromides)-N- (4- ferrocenyls vinyl) pyrimidine -2-base) benzene first
The preparation of acid amides (4j)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzene first with 3- bromo-benzoyl chlorides in step c
Acyl chlorides, obtains target product (4j) (E) -3- bromo- N- (3- benzoyl bromides)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
Benzamide.Yield 85%, dark red solid, 121-122 DEG C of fusing point.
1H NMR(CDCl3):δ 8.48 (d, J=5.2Hz, 1H), 8.02 (s, 2H), 7.72 (d, J=7.7Hz, 2H), 7.63
(d, J=8.0Hz, 2H), 7.39 (d, J=15.6Hz, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 6.91 (d, J=5.2Hz,
1H), (s, the 5H) of 6.45 (d, J=15.6Hz, 1H), 4.49 (s, 2H), 4.42 (s, 2H), 4.1213C NMR(151MHz,
CDCl3):δ173.77,166.99,162.42,161.39,142.69,139.04,138.25,134.85,132.74,
130.06,125.46,123.65,118.04,82.48,73.51,72.28,71.01.MS(ESI):672.2
(C30H21Br2FeN3O2,[M+H]+)。
Embodiment 11：(E) -3- methyl-N- (3- methyl benzoyls)-N- (4- ferrocenyls vinyl) pyrimidine -2-base)
The preparation of benzamide (4k)
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzenes with 3- methyl benzoyl chlorides in step c
Formyl chloride, obtains target product (4k) (E) -3- methyl-N- (3- methyl benzoyls)-N- (4- ferrocenyls vinyl) phonetic
Pyridine -2- bases) benzamide.Yield 79%, dark red solid, fusing point：36-37℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.0Hz, 1H), 7.71 (s, 2H), 7.63 (d, J=7.0Hz, 2H), 7.41
(d, J=15.5Hz, 1H), 7.28 (d, J=7.0Hz, 2H), 7.27-7.21 (m, 2H), 6.87 (d, J=5.0Hz, 1H), 6.45
(d, J=15.6Hz, 1H), 4.45 (s, 2H), 4.38 (s, 2H), 4.09 (s, 5H), 2.34 (s, 6H)13C NMR(151MHz,
CDCl3):δ175.63,166.84,163.12,161.26,142.04,141.10,137.35,136.04,132.54,
131.01,128.95,124.04,117.63,82.74,73.33,72.21,70.88,23.99.MS(ESI):542.4
(C32H27FeN3O2,[M+H]+)。
Embodiment 12：(E) -4- trifluoromethoxies-N- (4- trifluoromethoxies benzoyl)-N- (4- ferrocenyl ethene
Base) pyrimidine -2-base) benzamide (4l) preparation
The preparation method of the present embodiment is with embodiment 1, the difference is that being replaced with 4- trifluoromethoxies chlorobenzoyl chloride in step c
4- chlorobenzoyl chlorides, obtain target product (4l) (E) -4- trifluoromethoxies-N- (4- trifluoromethoxy benzaldehydes formoxyl)-N- (4- bis-
Luxuriant ironbased ethylene base) pyrimidine -2-base) benzamide.Yield 89%, dark red solid, fusing point：137-139℃.
1H NMR(CDCl3):δ 8.47 (d, J=5.0Hz, 1H), 7.89 (d, J=8.0Hz, 4H), 7.45 (d, J=
15.6Hz, 1H), 7.22 (d, J=8.3Hz, 4H), 6.94 (d, J=5.1Hz, 1H), 6.47 (d, J=15.6Hz, 1H), 4.47
(s,2H),4.41(s,2H),4.11(s,5H).13C NMR(151MHz,CDCl3):δ173.92,167.26,162.66,
161.34,154.86,142.64,135.35,133.77,123.77,123.11,122.00,117.93,82.52,73.51,
72.23,70.95.MS(ESI):682.4(C32H21F6FeN3O4,[M+H]+)。
Embodiment 13：(E)-N- benzoyl-Ns-(4- ferrocenyls vinyl) pyrimidine -2-base) benzamide (4m)
Prepare
The preparation method of the present embodiment is with embodiment 1, the difference is that replacing 4- chlorobenzoyls with chlorobenzoyl chloride in step c
Chlorine, obtains target product (4m) (E)-N- benzoyl-Ns-(4- ferrocenyls vinyl) pyrimidine -2-base) benzamide.Yield
88%, dark red solid, fusing point：136-137℃.
1H NMR(CDCl3):δ 8.48 (d, J=5.1Hz, 1H), 7.87 (d, J=7.8Hz, 4H), 7.48 (t, J=
7.2Hz, 2H), 7.41 (d, J=5.4Hz, 2H), 7.39 (t, J=7.5Hz, 5H), 6.87 (d, J=5.2Hz, 1H), 6.43 (d,
J=15.5Hz, 1H), 4.45 (s, 2H), 4.38 (s, 2H), 4.09 (s, 5H)13C NMR(151MHz,CDCl3):δ175.44,
166.83,163.03,161.32,142.17,137.36,135.25,131.88,131.23,123.89,117.68,82.69,
73.34,72.21,70.89.MS(ESI):514.4(C30H23FeN3O2,[M+H]+)。
Embodiment 14：The preparation of the chloro- N- of 4- (4- chlorobenzene formacyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide
(7a)
A, ferrocenyl methyl ketone (5) (228mg, 1mmol) is weighed, be dissolved in 3mL dimethylformamides, add N, N- diformazans
Base formamide dimethylacetal 595mg, 125 DEG C of oil bath 2.5h, after being cooled to room temperature, add 30mL dichloromethane, washing, organic phase
Anhydrous sodium sulfate drying, column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/2, v/v), obtains intermediate (6) (E) -3-
(dimethylamino) -1- ferrocenyl -2- alkene -1- ketone 235mg, yield 83%, peony precipitation, fusing point：221-222℃.
1H NMR(CDCl3):δ 7.71 (d, J=12.4Hz, 1H), 5.36 (d, J=12.4Hz, 1H), 4.78 (s, 2H),
4.38(s,2H),4.16(s,5H),3.00(s,6H).MS(ESI):284.1(C15H17FeNO,[M+H]+)。
B, weigh intermediate (6) (283mg, 1mmol), guanidine hydrochloride (144mg, 1.5mmol) and potassium carbonate (276mg,
2mmol), it is dissolved in 10mL 2-methyl cellosolves, 125 DEG C of backflow 24h, TLC detections, reaction terminates rear cooling reaction system,
Enter in 50mL water, ethyl acetate is extracted, organic phase anhydrous sodium sulfate drying, (eluent is ethyl acetate/oil to column chromatography for separation
Ether=1/2, v/v), obtain intermediate (7) 4- ferrocene pyrimidine -2- amine 223mg.Yield 80%, peony precipitation, fusing point：195-
196℃。
1H NMR(CDCl3):δ 8.14 (d, J=5.2Hz, 1H), 6.71 (d, J=5.2Hz, 1H), 5.01 (s, 2H), 4.90
(s,2H),4.45(s,2H),4.08(s,5H).MS(ESI):280.1(C14H13FeNO,[M+H]+)。
C, intermediate (7) 0.5mmol and 4- chlorobenzoyl chloride 1.5mmol are weighed, be dissolved in 10mL dichloromethane, add three
Drop triethylamine, room temperature reaction, TLC point plates, question response adds 10mL water after stopping, 20mL ethyl acetate, extraction, organic phase is being passed through
Washing is crossed, sample column chromatography for separation (eluent is ethyl acetate/petroleum ether=1/3, v/v) is mixed after saturated common salt washing, obtain target
Product 7a.Yield 78%, dark red solid, fusing point：162-164℃.
1H NMR(CDCl3):δ 8.44 (d, J=5.2Hz, 1H), 7.80 (d, J=7.9Hz, 4H), 7.39 (d, J=
8.0Hz, 4H), 7.06 (d, J=5.2Hz, 1H), 4.76 (s, 2H), 4.48 (s, 2H), 3.87 (s, 5H)13C NMR(151MHz,
CDCl3):δ174.05,173.36,160.27,141.81,135.64,133.21,131.72,116.56,81.01,74.48,
72.71,70.80,32.35.MS(ESI):557.2(C28H29Cl2FeN3O2,[M+H]+)。
Embodiment 15：4- methoxyl groups-N- (4- methoxybenzoyls base)-N- (4- ferrocenyls pyrimidine -2-base) benzoyl
The preparation of amine (7b)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- with 4- methoxy benzoyl chlorides in step c
Chlorobenzoyl chloride, obtains target product (7b) 4- methoxyl groups-N- (4- methoxybenzoyls base)-N- (4- ferrocenyl pyrimidines -2-
Base) benzamide.Yield 86%, dark red solid, fusing point：118-120℃.
1H NMR(CDCl3):δ 8.46 (d, J=5.0Hz, 1H), 7.87 (d, J=7.9Hz, 4H), 7.03 (d, J=
5.1Hz, 1H), 6.89 (d, J=7.9Hz, 4H), 4.78 (s, 2H), 4.44 (s, 2H), 3.82 (s, 3H), 3.80 (s, 5H)13C
NMR(151MHz,CDCl3):δ174.68,172.81,165.76,163.53,160.25,134.27,129.78,116.60,
116.01,81.40,74.21,72.62,70.76,58.11.MS(ESI):548.4(C30H25FeN3O4,[M+H]+)。
Embodiment 16：4- methyl-N- (4- methyl benzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide
The preparation of (7c)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorine with 4- methyl benzoyl chlorides in step c
Chlorobenzoyl chloride, obtains target product (7c) 4- methyl-N- (4- methyl benzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzene
Formamide.Yield 73%, dark red solid, fusing point：78-80℃.
1H NMR(CDCl3):δ 8.45 (d, J=5.2Hz, 1H), 7.79 (d, J=7.8Hz, 4H), 7.19 (d, J=
7.8Hz, 4H), 7.01 (d, J=5.3Hz, 1H), 4.77 (s, 2H), 4.43 (s, 2H), 3.80 (s, 5H), 2.34 (s, 6H)13C
NMR(151MHz,CDCl3):δ175.17,172.82,163.31,160.24,146.01,134.74,132.04,116.12,
81.36,74.20,72.59,70.74,32.34,24.30.MS(ESI):516.4(C30H25FeN3O2,[M+H]+)。
Embodiment 17：The chloro- N- of 3- (3- chlorobenzene formacyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide (7d)
Prepare
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorobenzenes with 3- chlorobenzoyl chlorides in step c
Formyl chloride, obtains target product (7d) 3- chloro- N- (3- chlorobenzene formacyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide.
Yield 86%, dark red solid, fusing point：144-146℃.
1H NMR(CDCl3):δ 8.44 (d, J=5.3Hz, 1H), 7.86 (s, 2H), 7.72 (d, J=7.7Hz, 2H), 7.48
(d, J=8.0Hz, 2H), 7.34 (t, J=7.9Hz, 2H), 7.06 (d, J=5.3Hz, 1H), 4.78 (s, 2H), 4.48 (s,
2H),3.85(s,5H).13C NMR(151MHz,CDCl3):δ173.45,173.39,162.97,160.30,139.56,
138.54,133.19,132.91,131.01,125.71,116.66,80.96,74.51,72.72,70.79,32.34.MS
(ESI):557.2(C28H19Cl2FeN3O2,[M+H]+)。
Embodiment 18：3,5- dimethyl-N -s (3,5- dimethylbenzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzene
The preparation of formamide (7e)
The preparation method of the present embodiment is with embodiment 14, the difference is that being replaced with 3,5- dimethyl benzoyl chlorides in step c
4- chlorobenzoyl chlorides, obtain target product (7e) 3,5- dimethyl-N-(3,5- dimethylbenzoyl)-N- (4- ferrocenyls
Pyrimidine -2-base) benzamide.Yield 77%, dark red solid, fusing point：68-69℃.
1H NMR(CDCl3):δ 8.49 (d, J=4.8Hz, 1H), 7.72 (s, 1H), 7.50 (s, 4H), 7.22 (s, 1H),
7.11 (s, 2H), 7.03 (d, J=4.8Hz, 1H), 4.79 (s, 2H), 4.44 (s, 2H), 3.77 (s, 5H), 2.30 (s, 12H)
.13C NMR(151MHz,CDCl3):δ175.61,172.79,163.25,160.22,140.87,137.55,136.99,
129.66,116.13,82.2,74.23,72.60,70.76,23.86.MS(ESI):544.4(C32H29FeN3O2,[M+H]+)。
Embodiment 19：The chloro- N- of 3,5- bis- (3,5- dichloro-benzoyls base)-N- (4- ferrocenyls pyrimidine -2-base) benzoyl
The preparation of amine (7f)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorine with 3,5- chlorobenzoyl chlorides in step c
Chlorobenzoyl chloride, obtains chloro- N- (3,5- dichloro-benzoyl base)-N- (the 4- ferrocenyl pyrimidines -2- of target product (7f) 3,5- bis-
Base) benzamide.Yield 75%, dark red solid, fusing point：178-180℃.
1H NMR(CDCl3):δ 8.44 (d, J=5.3Hz, 1H), 7.69 (s, 4H), 7.51 (s, 2H), 7.10 (d, J=
5.3Hz,1H),4.80(s,2H),4.52(s,2H),3.90(s,5H).13C NMR(151MHz,CDCl3)δ173.83,
172.32,162.00,160.34,139.82,138.31,135.29,129.95,117.03,82.96,74.70,72.77,
70.85.MS(ESI):626.1(C28H17Cl4FeN3O2,[M+H]+)。
Embodiment 20：4- ethyls-N- (4- ethylamino benzonitriles acyl group)-N- (4- ferrocenyls pyrimidine -2-base) benzamide
The preparation of (7g)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorine with 4- ethylbenzoyls chloro in step c
Chlorobenzoyl chloride, obtains target product (7g) 4- ethyls-N- (4- ethylamino benzonitriles acyl group)-N- (4- ferrocenyls pyrimidine -2-base) benzene
Formamide.Yield 84%, dark red solid, fusing point：72-75℃.
1H NMR(CDCl3):δ 8.47 (d, J=5.2Hz, 1H), 7.84 (s, 2H), 7.82 (s, 2H), 7.24 (s, 2H),
7.22 (s, 2H), 7.02 (d, J=5.3Hz, 1H), 4.77 (s, 2H), 4.43 (s, 2H), 3.76 (s, 5H), 2.65 (q, J=
7.6Hz, 4H), 1.19 (t, J=7.6Hz, 6H)13C NMR(151MHz,CDCl3):δ175.19,172.87,163.32,
160.28,152.12,134.90,132.21,130.81,116.13,81.34,74.21,72.60,70.74,31.53,
17.63.MS(ESI):544.4(C32H29FeN3O2,[M+H]+)。
Embodiment 21：The system of the fluoro- N- of 4- (4- benzyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide (7h)
It is standby
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorobenzenes with 4- fluorobenzoyl chlorides in step c
Formyl chloride, obtains target product (7h) 4- fluoro- N- (4- fluoro benzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide.
Yield 92%, dark red solid, fusing point：153-155℃.
1H NMR(CDCl3):δ 8.45 (d, J=5.2Hz, 1H), 7.92-7.86 (m, 4H), 7.10 (t, J=8.4Hz,
4H), (s, the 5H) of 7.06 (d, J=5.5Hz, 1H), 4.78 (s, 2H), 4.47 (s, 2H), 3.8613C NMR(151MHz,D2O):δ
171.38,170.73,164.55,157.71,131.85,116.09,115.94,113.87,71.86,70.12,68.23.MS
(ESI):524.3(C28H19F2FeN3O2,[M+H]+)。
Embodiment 22：The system of the bromo- N- of 4- (4- Brombenzyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide (7i)
It is standby
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorobenzenes with 4- bromo-benzoyl chlorides in step c
Formyl chloride, obtains target product (7i) 4- bromo- N- (4- benzoyl bromides)-N- (4- ferrocenyls pyrimidine -2-base) benzamide.
Yield 90%, dark red solid, fusing point：136-139℃.
1H NMR(CDCl3):δ 8.43 (d, J=5.1Hz, 1H), 7.72 (d, J=7.5Hz, 4H), 7.56 (d, J=
7.6Hz, 4H), 7.06 (d, J=5.2Hz, 1H), 4.76 (s, 2H), 4.47 (s, 2H), 3.87 (s, 5H)13C NMR(151MHz,
CDCl3):δ174.16,173.36,162.76,160.25,136.12,134.68,133.30,130.42,116.55,81.03,
74.46,72.71,70.80.MS(ESI):646.1(C28H19Br2FeN3O2,[M+H]+)。
Embodiment 23：The bromo- N- of 3- (3- benzoyl bromides)-N- (4- ferrocenyls pyrimidine -2-base) benzamide (7j)
Prepare
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorobenzenes with 3- bromo-benzoyl chlorides in step c
Formyl chloride, obtains target product (7j) 3- bromo- N- (3- benzoyl bromides)-N- (4- ferrocenyls pyrimidine -2-base) benzamide.
Yield 87%, dark red solid, fusing point：131-132℃.
1H NMR(CDCl3):δ 8.43 (d, J=5.2Hz, 1H), 8.01 (s, 2H), 7.76 (d, J=7.7Hz, 2H), 7.63
(d, J=8.0Hz, 2H), 7.29 (d, J=7.9Hz, 2H), 7.06 (d, J=5.3Hz, 1H), 4.78 (s, 2H), 4.48 (s,
2H),3.85(s,5H).13C NMR(151MHz,CDCl3):δ173.53,173.41,160.31,139.14,138.30,
134.86,132.81,130.11,125.54,116.65,80.94,74.50,72.72,70.79,32.34.MS(ESI):
646.1(C28H19Br2FeN3O2,[M+H]+)。
Embodiment 24：3- methyl-N- (3- methyl benzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzamide
The preparation of (7k)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing 4- chlorine with 3- methyl benzoyl chlorides in step c
Chlorobenzoyl chloride, obtains target product (7k) 3- methyl-N- (3- methyl benzoyls)-N- (4- ferrocenyls pyrimidine -2-base) benzene
Formamide.Yield 77%, dark red solid, fusing point：58-61℃.
1H NMR(CDCl3):δ 8.45 (d, J=5.3Hz, 1H), 7.73 (s, 2H), 7.66 (d, J=7.1Hz, 2H), 7.30
(d, J=7.3Hz, 2H), 7.28 (s, 2H), 7.02 (d, J=5.3Hz, 1H), 4.78 (s, 2H), 4.44 (s, 2H), 3.79 (s,
5H).13C NMR(151MHz,CDCl3):δ175.36,172.95,163.13,160.25,141.18,137.48,136.07,
132.58,131.07,128.97,116.19,81.38,74.24,72.62,70.75,23.97.MS(ESI):516.4
(C30H25FeN3O2,[M+H]+)。
Embodiment 25：4- trifluoromethoxies-N- (4- trifluoromethoxies benzoyl)-N- (4- ferrocenyl pyrimidines -2-
Base) benzamide (7l) preparation
The preparation method of the present embodiment with embodiment 14, unlike in step c with 4- trifluoromethoxy chlorobenzoyl chloride generations
For 4- chlorobenzoyl chlorides, target product (7l) 4- trifluoromethoxies-N- (4- trifluoromethoxies benzoyl)-N- (4- bis- are obtained
Luxuriant iron-based pyrimidine -2-base) benzamide.Yield 85%, dark red solid, fusing point：142-145℃.
1H NMR(CDCl3):δ 8.43 (d, J=5.0Hz, 1H), 7.92 (d, J=8.0Hz, 4H), 7.24 (d, J=
8.9Hz, 4H), 7.06 (d, J=5.0Hz, 1H), 4.78 (s, 2H), 4.48 (s, 2H), 3.86 (s, 5H)13C NMR(151MHz,
CDCl3):δ173.69,162.60,160.31,154.78,135.46,133.79,126.80,123.14,116.62,80.97,
74.50,72.68,70.80,32.37.MS(ESI):656.3(C30H19F6FeN3O4,[M+H]+)。
Embodiment 26：The preparation of N- benzoyl-Ns-(4- ferrocenyls pyrimidine -2-base) benzamide (7m)
The preparation method of the present embodiment is with embodiment 14, the difference is that replacing benzene with 3,5- dimethoxyanilines in step c
Amine, obtains target product (7m) N- benzoyl-Ns-(4- ferrocenyls pyrimidine -2-base) benzamide.Yield 83%, peony
Solid, fusing point：156-157℃.
1H NMR(CDCl3):δ 8.44 (d, J=5.2Hz, 1H), 7.89 (d, J=7.8Hz, 4H), 7.50 (t, J=
7.3Hz, 2H), 7.40 (t, J=7.5Hz, 4H), 7.02 (d, J=5.2Hz, 1H), 4.76 (s, 2H), 4.44 (s, 2H), 3.80
(s,5H).13C NMR(151MHz,CDCl3):δ175.18,172.99,160.27,137.46,135.27,131.93,
131.29,116.28,81.22,74.28,72.65,70.75,32.34.MS(ESI):488.3(C28H21FeN3O2,[M+H]+)。
Embodiment 27：The anti tumor activity in vitro research of the Aminylferrocene analog derivative containing pyrimidine ring of the invention
Pyrimidine is contained to determine using MTT [3- (4,5)-bis- methyl -2- thiazoles-(2,5)-phenyl bromination tetrazole is blue] method
The Aminylferrocene analog derivative of ring is to mouse skin melanoma cell strain (B16-F10) and human lung carcinoma cell line (A549)
Antiproliferative activity.
(1) preparation of RPMI-1640 nutrient solutions：Chinese holly hyclone is taken to be inactivated in 56 DEG C of thermostat water bath
30min.Then take 50mL inactivation hyclone by aperture for 0.22 μm of filtering with microporous membrane is added to 450mL RPMI-
In 1640 culture mediums, 4 DEG C of Refrigerator stores.In addition, taking nutrient solution that 50mL prepares in small size sterile culture flask, bottle is screwed
Lid, in 37 DEG C, cultivates observation 2 days in 5% CO2gas incubator, abnormal conditions do not occur, can be used for cell culture.
(2) preparation of MTT solution：0.5g MTT solids are weighed, is dissolved in 100mL PBS solutions, then it is micro- with 0.22 μm
Hole membrane filtration, packing, -20 DEG C of Refrigerator stores of MTT solution not used in a short time.
(3) preparation of liquid is tested：Test sample is first dissolved the storing solution for being made into 1mg/mL with DMSO, storing solution is preserved
It is standby in -20 DEG C of refrigerators.Then the nutrient solution for taking storing solution plus serum-free is diluted to 10 μ g/mL as sample primary dcreening operation concentration.
In addition, the nutrient solution for taking storing solution plus serum-free is diluted to 3 concentration gradients as sample secondary screening.Wherein DMSO is in nutrient solution
Concentration it is unsuitable excessive, the final concentration of DMSO is usually no more than 0.05%-0.1% in the every hole cell suspension after dosing.
(4) culture of mouse skin melanoma cell strain (B16-F10)：Be adherent growth cell, cellar culture in
(contain 10% calf serum) in RPMI-1640 nutrient solutions, put 37 DEG C, 5%CO2Cultivated in incubator, one was passed on every 3-4 days
It is secondary.Original fluid is first discarded during passage, then is washed with PBS；Then with 0.5% Trypsin Induced 1min or so, plus
Enter a small amount of fresh medium and terminate digestion；Piping and druming, makes attached cell be split away off from culture bottle wall；Pipette appropriate to fresh training
Support in bottle, be supplemented with fresh medium to original volume (nutrient solution volume is about the 1/10 of blake bottle capacity).
(5) culture of human lung carcinoma cell line (A549)：It is adherent growth cell, cellar culture is in RPMI-1640 nutrient solutions
Interior (containing 10% calf serum), put 37 DEG C, 5%CO2Cultivated in incubator, every passage in 3-4 days once.Original is first discarded during passage
Nutrient solution, then washed with PBS；Then with 0.5% Trypsin Induced 1min or so, a small amount of fresh medium end is added
Only digest；Piping and druming, makes attached cell be split away off from culture bottle wall；Pipette in the appropriate bottle to fresh cultured, be supplemented with fresh
Nutrient solution is to original volume (nutrient solution volume is about the 1/10 of blake bottle capacity).
(6) cell incubation：Take the logarithm two kinds of tumour cells in growth period, it is 1 × 10 to adjust concentration of cell suspension4Individual ml-1.
Add the μ l of cell suspension 100 per hole in 96 well culture plates, put 37 DEG C, 5%CO224h is cultivated in incubator.After culture 24h, press respectively
Design adds liquid.
(7) sample primary dcreening operation：The sample of primary dcreening operation concentration will be made into first to be added separately in each hole, each concentration sets 3
Parallel hole.Experiment be divided into drug test group (being separately added into the test medicine of various concentrations), control group (only plus nutrient solution and cell,
It is not added with testing medicine) and blank group (only adding nutrient solution, be not added with cell and test medicine).96 orifice plates after by dosing are placed in 37 DEG C, 5%
CO248h is cultivated in incubator.
(8) sample secondary screening：According to primary dcreening operation result, activity preferably sample is therefrom selected to be used for secondary screening.Concentration ladder will be prepared
The sample of degree is added separately in each hole, and each concentration sets 3 parallel holes.Experiment is divided into drug test group and (is separately added into not
With the test medicine of concentration), control group (only plus nutrient solution and cell, be not added with testing medicine) and blank group (only add nutrient solution, not refinement
Born of the same parents and test medicine), using 5 FU 5 fluorouracil (5-Fu) as positive control.96 orifice plates after by dosing are placed in 37 DEG C, 5%CO2Training
48h is cultivated in foster case.
(9) measure of survivaling cell：In 96 orifice plates after having cultivated 48h, the μ l of MTT solution 40 are added per hole.Put at 37 DEG C
After putting 4h, supernatant is removed.Add 150 μ l DMSO per hole, vibrate 10min, formazan is crystallized dissolving.Finally, using automatic
ELIASA detects the optical density (OD values) in each hole at 578nm wavelength.
(10) IC of tumour cell50The calculating of value：
Improvement Kou Shifa：lgIC50=Xm-I (P- (3-Pm-Pn)/4).
Wherein Xm：Lg maximum doses, I：Lg (maximum dose/adjacent dosage), P：Positive reaction rate sum, Pm：Maximum sun
Property reactivity, Pn：Minimum positive reaction rate.
(11) Structure-activity Relationship analysis and discussion
By mtt assay, we determine 28 Aminylferrocene analog derivatives containing pyrimidine ring to mouse skin black
Plain tumor cell strain (B16-F10) and the antiproliferative activity of human lung carcinoma cell line (A549), Activity Results are shown in Table 1.
The listed Aminylferrocene analog derivative antitumor activity (IC containing pyrimidine ring of the present invention of table 150,μM)
a Antitumor activity was measured by the MTT method.Values are the
average of three independent experiments run in triplicate.Variation was
Generally 5-10%.
As can be seen from Table 1, in addition to 4b, 4d, 7c, 7d, other compounds are to mouse skin for the compound selected by secondary screening
The proliferation inhibition activity of melanoma cell strain (B16-F10) is all better than positive control 5-Fu.Wherein, compound 7g is to mouse skin
The proliferation inhibition activity of skin melanoma cell strain (B16-F10) is 23.3 times of 5-Fu, shows that it may be in treatment melanin
Knurl aspect has potential application value.
Meanwhile, compound 4,4b, 4c, 4e, 4f, 4g, 4h, 4j, 4l, 7,7b, 7c, 7e, 7f, 7g, 7h, 7j, 7k, 7l, 7m
Antiproliferative activity to human lung carcinoma cell line (A549) is better than positive control 5-Fu.Wherein ICs of the compound 4g to A54950Value
It it is 1.2 μM, active highest is 27.2 times of positive control 5-Fu；Next to that compound 7e, its IC50It is 2.8 μM to be worth, and activity is
11.6 times of positive control 5-Fu.
Claims (10)
1. a kind of Aminylferrocene analog derivative containing pyrimidine ring, it is characterised in that its structure is by below general formula (1) or formula
(2) represent：
Wherein R is selected from 4- chlorine, 4- methoxyl groups, 4- methyl, 3- chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine, 4-
Bromine, 3- bromines, 3- methyl, 4- trifluoromethoxies or hydrogen.
2. the Aminylferrocene analog derivative containing pyrimidine ring according to claim 1, it is characterised in that：
R is 4- ethyls.
3. the preparation method of the Aminylferrocene analog derivative containing pyrimidine ring described in a kind of claim 1, it is characterised in that
Comprise the following steps：
A, weigh formylferrocene 1 and be dissolved in acetone, sodium hydroxide solution is then added dropwise, at room temperature stirring reaction, TLC inspections
Survey, reaction is stopped after formylferrocene 1 runs out of；To Precipitation is added water in reaction solution completely, suction filtration is dried, post
Chromatography, obtains intermediate 2-methyl vinylferrocene base ketone；
B, intermediate 2 is dissolved in dimethylformamide, adds DMF dimethylacetal, flowed back at 125 DEG C anti-
2.5h is answered, TLC detections, reaction terminates rear cooling reaction system, adds dichloromethane, and washing, organic phase is dry with anhydrous sodium sulfate
Dry, column chromatography for separation obtains intermediate 3-(1E, 4E)-1- (dimethylamino)-5- vinylferrocene base-Isosorbide-5-Nitrae-diene-3- ketone；
C, intermediate 3, guanidine hydrochloride and potassium carbonate are dissolved in 2-methyl cellosolve, back flow reaction 24h at 125 DEG C, TLC detections,
Reaction terminates rear cooling reaction system, is poured into water, ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, column chromatography for separation,
Obtain intermediate 4-(E)-4- vinylferrocene yl pyrimidines-2- amine；
D, weigh 0.5mmol intermediates 4 and 1.5mmol substituted benzoyl chlorides are dissolved in 10mL dichloromethane, add three to drip three second
Amine, room temperature reaction, TLC detections, question response adds water, ethyl acetate to be extracted after stopping, and organic phase is by washing, saturation
Sample is mixed after salt washing carries out column chromatography for separation, final to obtain target product 4a-m；
The structural formula of the substituted benzoyl chloride is：Wherein R is selected from hydrogen, 4- chlorine, 4- methoxyl groups, 4- methyl, 3-
Chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine, 4- bromines, 3- bromines, 3- methyl or 4- trifluoromethoxies.
4. preparation method according to claim 3, it is characterised in that：
In step a, the mol ratio of formylferrocene 1 and NaOH is 5:1；The consumption of acetone is 5mL acetone/mmol acetyl
Base ferrocene.
5. preparation method according to claim 3, it is characterised in that：
In step b, the mol ratio of intermediate 2 and DMF dimethylacetal is 1:5；The consumption of dimethylformamide
It is 3mL dimethylformamides/mmol intermediates 2.
6. preparation method according to claim 3, it is characterised in that：
In step c, the mol ratio of intermediate 3, guanidine hydrochloride and potassium carbonate is 1:1.5:2；The consumption of 2-methyl cellosolve is
10mL2- methyl cellosolves/mmol intermediates 3.
7. the preparation method of the Aminylferrocene analog derivative containing pyrimidine ring described in a kind of claim 1, it is characterised in that
Comprise the following steps：
A, ferrocenyl methyl ketone 5 is dissolved in dimethylformamide, DMF dimethylacetal is added, at 125 DEG C
Back flow reaction 2.5h, TLC detection, reaction terminates rear cooling reaction system, adds dichloromethane, washing, the anhydrous sulphur of organic phase
Sour sodium is dried, and column chromatography for separation obtains intermediate 6-(E)-3- (dimethylamino)-1- ferrocenyl-2- alkene-1- ketone；
B, intermediate 6, guanidine hydrochloride and potassium carbonate are dissolved in 2-methyl cellosolve, back flow reaction 24h at 125 DEG C, TLC detections,
Reaction terminates rear cooling reaction system, is poured into water, ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, column chromatography for separation,
Obtain intermediate 7-4- ferrocene pyrimidine-2- amine；
C, weigh 0.5mmol intermediates 7 and 1.5mmo substituted benzoyl chlorides are dissolved in 10mL dichloromethane, add three to drip three second
Amine, room temperature reaction, TLC detections, question response adds water, ethyl acetate to be extracted after stopping, and organic phase is by washing, saturation
Sample is mixed after salt washing carries out column chromatography for separation, final to obtain target product 7a-m；
The structural formula of the substituted benzoyl chloride is：Wherein R is selected from hydrogen, 4- chlorine, 4- methoxyl groups, 4- methyl, 3-
Chlorine, 3,5- dimethoxys, 3,5- dichloros, 4- ethyls, 4- fluorine, 4- bromines, 3- bromines, 3- methyl or 4- trifluoromethoxies.
8. preparation method according to claim 7, it is characterised in that：
In step a, the mol ratio of ferrocenyl methyl ketone 5 and DMF dimethylacetal is 1:5；Dimethylformamide
Consumption be 3mL dimethylformamides/mmol ferrocenyl methyl ketones 5.
9. preparation method according to claim 7, it is characterised in that：
In step b, the mol ratio of intermediate 6, guanidine hydrochloride and potassium carbonate is 1:1.5:2；The consumption of 2-methyl cellosolve is
10mL2- methyl cellosolves/mmol intermediates 6.
10. the purposes of the Aminylferrocene analog derivative containing pyrimidine ring described in a kind of claim 1, it is characterised in that：It is
Application in treatment dermal melanin tumor medicine or anti-lung-cancer medicament is prepared.
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