CN107056713A - 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivatives and its preparation method and application - Google Patents
4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivatives and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivatives and its preparation method and application, are related to tumour medicine.Preparation method：Prepare intermediate p -guanidinobenzoic acid ethyl ester nitrate；Prepare the ketone of intermediate 1 (substituted aryl) 3 (dimethylamino) 2 propylene 1；Prepare intermediate 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) ethyl benzoate；Prepare intermediate 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine；Prepare 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivatives.One class 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivative is used to prepare the purposes in the medicine for treating or preventing tumor-related illness.With the significant effect for suppressing growth of tumour cell and inducing apoptosis of tumour cell, available for the medicine for preparing treatment or prevention tumor-related illness.
Description
Technical field
The present invention relates to tumour medicine, spread out more particularly, to 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine
Biology and its preparation method and application.
Background technology
Tumor pharmacother starts from the 1940s, developing by 70 years, and whole world clinical practice is antitumor at present
About 100 kinds of medicine.Into 21 century, with the development of modern medicine, the deep of tumor cells Mechanism Study, modern biotechnology medicine
The maturation of technology, global antineoplastic research and development achieve great success.According to incompletely statistics, the current whole world is in clinical investigation phase
Antitumor new drug candidates have kind more than 450,2850 remainder clinical researches are related to altogether, wherein III phase clinical research totally 223, is related to
New drug more than 80 is planted.Antineoplastic species are various, but preferably tumour medicine is less, and existing cancer therapy drug is more or less all
Have the shortcomings that bioavilability is low, toxic side effect is big.Therefore design synthesis have that bioavilability is high, active anticancer substantially and
The antineoplastic of low toxin remains the focus studied at present.
The content of the invention
The first object of the present invention is to provide 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative.
The second object of the present invention is to provide 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative
Preparation method.
The third object of the present invention is that providing a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derives
Thing is used to prepare the medicine for treating or preventing tumor-related illness.
The structural formula of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) the benzoyl hydrazine derivative is：
Wherein, R1Represent C1~C4Straight chained alkyl, C5Or C6Cycloalkyl, unsubstituted aromatic alkyl, substituted-phenyl；R2
Represent Cl or H；X represents O or S；Y represents N or C.
The preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) the benzoyl hydrazine derivative includes following step
Suddenly：
1) intermediate p -guanidinobenzoic acid ethyl ester nitrate is prepared；
2) intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone is prepared；
3) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate is prepared；
4) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine is prepared；
5) 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative is prepared.
In step 1) in, it is described prepare intermediate p -guanidinobenzoic acid ethyl ester nitrate specific method can be：In drying
Reaction bulb in sequentially add ethylaminobenzoate, cyanamide and absolute ethyl alcohol；Added under stirring after hydrochloric acid, heating
To flowing back, 22~24h is reacted；After thin-layer chromatography (TLC) detection reaction, stop reaction；Reaction solution be concentrated under reduced pressure except after solvent plus
Enter water, in 0 DEG C plus the aqueous solution of ammonium nitrate, insulation reaction after addition, filtering collects filter cake, dries to obtain white solid product pair
Guanidinobenzoic acid ethyl ester nitrate, yield 75%~80%；The ethylaminobenzoate, cyanamide, hydrochloric acid, ammonium nitrate rub
Your ratio can be 1 ︰ (2.5~3) ︰ (1.2~1.5) ︰ (2~2.5).
In step 2) in, it is described to prepare the specific of intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone
Method can be：2- acetylpyridines (or 3- acetylpyridines, 4- acetylpyridines, 4- chlorobenzene second are sequentially added in dry reaction bulb
Ketone), DMF dimethylacetal is heated to 110 DEG C, after back flow reaction 18~20h, TLC detection reaction, stopped
Reaction, reaction solution adds ethyl acetate after being concentrated under reduced pressure, stirring, suction filtration collects filter cake, dries to obtain solid product 1- (substitution virtues
Base) -3- (dimethylamino) -2- propylene -1- ketone, yield 56%~60%；The 2- acetylpyridines (or 3- acetylpyridines, 4- second
Acyl pyridine, 4- chloro-acetophenones), the mol ratio of DMF dimethylacetal can be 1 ︰ (1.1~1.2).
In step 3) in, the tool for preparing intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate
Body method can be：P -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3- (two are sequentially added in dry reaction bulb
Methylamino) -2- propylene -1- ketone, sodium hydrate solid, absolute ethyl alcohol, be heated to backflow, react 18~22h, TLC detection reaction
Afterwards, stop reaction, be cooled to suction filtration after room temperature, collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals)
Amino) ethyl benzoate, yield 84%~90%；It is described to state p -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3-
(dimethylamino) -2- propylene -1- ketone, the mol ratio of sodium hydroxide can be 1 ︰ (1~1.1) ︰ (1.2~1.5).
In step 4) in, it is described to prepare the specific of intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine
Method can be：4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate, hydration are sequentially added in dry reaction bulb
Hydrazine, absolute ethyl alcohol, are heated to backflow, react 18~20h, after TLC detection reactions, stop reaction, be cooled to suction filtration after room temperature, receive
Collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine, yield 66%~70%；Institute
The mol ratio for stating 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoates and hydrazine hydrate can be 1 ︰ (18~20).
In step 5) in, it is described to prepare the specific of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative
Method can be：4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine solid, N are sequentially added in dry reaction bulb,
Dinethylformamide, is heated to 100 DEG C, treats that solid dissolving completely, is cooled to 70 DEG C, and adding isocyanates (can be different for fat
Cyanate, substituted or unsubstituted phenyl isocyanate, substituted or unsubstituted phenyl isocyanates, unsubstituted fragrance
Alkyl isocyanate, unsubstituted aromatic alkyl isothiocyanic acid ester), 3~4h of insulation reaction；After TLC detection reactions, stop anti-
Should, it is cooled to after room temperature and adds water, suction filtration collects filter cake, and drying, obtained crude product separates that (eluant, eluent is by body through silica gel column chromatography
Product is than for the ︰ 1 of Er Lv Jia Wan ︰ methanol=50) obtain solid product 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine and spread out
Biology, yield 56%~60%；4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine, mole of isocyanates
Than that can be 1 ︰ (1~1.1).
One class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) the benzoyl hydrazine derivative, which is used to prepare, to be treated or prevented
Purposes in the medicine of tumor-related illness.
One class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) the benzoyl hydrazine derivative has significant suppression tumour
The effect of cell growth and inducing apoptosis of tumour cell, available for the medicine for preparing treatment or prevention tumor-related illness.
The present invention a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative, its synthetic reaction into
This is low, and course of reaction is simple and easy to control, it is adaptable to industrialized production, and there is the analog derivative the significant tumour cell that suppresses to give birth to
The effect of long and inducing apoptosis of tumour cell, can the extensive use on antineoplastic is prepared.
Brief description of the drawings
Fig. 1 is N- cyclohexyl-2- (4-((4- (4- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
To tumour cell HepG2 growth inhibitory effect figure.In Fig. 1, abscissa is the compound effects time (h), and ordinate is made a living
Long inhibiting rate (%), set concentration gradient be：Curve a is 5 μM/L, and b is 10 μM/L, and c is 20 μM/L, action time point difference
For 24h, 48h, 72h and 96h.
Fig. 2 is N- cyclohexyl-2- (4-((4- (4- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
The WB detection figures for causing HepG2 cells PARP to cut.In fig. 2, the concentration gradient of compound is 5 μM/L, 10 μM/L and 20 μM
/ L, control group adds corresponding DMSO and compareed, and GAPDH is internal reference.
Embodiment
For the ease of understanding the present invention, in conjunction with embodiment, the invention will be further described, further to annotate
The present invention is released, but does not constitute the limitation of any mode to the present invention.
Embodiment 1：The synthesis of p -guanidinobenzoic acid ethyl ester nitrate
In single neck bottle that 200mL is dried, ethylaminobenzoate (5.0g, 0.030mol), cyanogen are sequentially added first
Amine (50%w/w, 7.6g, 0.091mol), absolute ethyl alcohol (20mL)；Again under stirring be added dropwise concentrated hydrochloric acid (3.8mL,
0.045mol), it is warming up to after completion of dropwise addition after backflow, reaction 24h, TLC detection reactions are complete, stop reaction.Reaction solution subtracts
Pressure concentration remove solvent after add 50mL water, then at 0 DEG C be added dropwise ammonium nitrate (4.8g, 0.061mol) the aqueous solution, completion of dropwise addition
Insulation reaction 1h, filtering, collect filter cake, dry to obtain the g of white solid product p -guanidinobenzoic acid ethyl ester nitrate 6.3, yield afterwards
78%.
Embodiment 2：The synthesis of 1- (2- pyridine radicals) -3- (dimethylamino) -2- propylene -1- ketone
2- acetylpyridines (5.0g, 0.041mol), N, N- dimethyl formyls are sequentially added in single neck bottle that 100mL is dried
Amine dimethylacetal (5.4g, 0.045mol), is heated to after 110 DEG C, back flow reaction 18h, and TLC detection reactions are complete, stop
Reaction.Reaction solution adds 5mL ethyl acetate after being concentrated under reduced pressure, and 1h is stirred at room temperature, and suction filtration collects filter cake, dries to obtain greenish yellow solid
4.2g, yield 58%.Spectral data：1H NMR(600MHz,DMSO-d6)：8.55~8.69 (m, 1H), 7.98 (d, J=
7.7Hz, 1H), 7.91 (dt, J=1.7,7.66Hz, 1H), 7.80 (d, J=12.6Hz, 1H), 7.50 (ddd, J=1.2,
4.77,7.52Hz, 1H), 6.38 (d, J=10.6Hz, 1H), 3.18 (s, 3H), 2.92 (s, 3H)
Embodiment 3：The synthesis of 4- ((4- (2- pyridine radicals) -2- pyrimidine radicals) amino) ethyl benzoate
1- (2- pyridine radicals) -3- (dimethylamino) -2- propylene -1- ketone is sequentially added in single neck bottle that 50mL is dried
(1.00g, 0.0056 mol), p -guanidinobenzoic acid ethyl ester nitrate (1.53g, 0.0056mol), sodium hydrate solid
(0.273g, 0.0068mol), absolute ethyl alcohol (10mL) is heated to after backflow, reaction 18h, TLC detection reactions are complete, stop
Reaction.Suction filtration after room temperature is cooled to, filter cake is collected, drying obtains pale solid 1.52g, yield 84%.Spectral data：1H
NMR(600MHz, CDCl3)：8.73 (d, J=4.4Hz, 1H), 8.62 (d, J=4.9Hz, 1H), 8.42 (d, J=7.7Hz,
1H), 8.07 (d, J=8.2 Hz, 2H), 7.89-7.91 (m, 1H), 7.87 (d, J=5.6Hz, 1H), 7.81 (d, J=8.0Hz,
2H), (t, J=6.9Hz, the 3H) of 7.56 (br.s., 1H), 7.40~7.45 (m, 1H), 4.38 (q, J=7.0Hz, 2H), 1.41
Embodiment 4：The synthesis of 4- ((4- (2- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine
4- ((4- (2- pyridine radicals) -2- pyrimidine radicals) amino) ethyl benzoate is sequentially added in single neck bottle that 50mL is dried
(1.52g, 0.0047mol), hydrazine hydrate (5.00mL), absolute ethyl alcohol (5mL) is heated to after backflow, reaction 20h, TLC detections
Reaction is complete, stops reaction.Suction filtration after room temperature is cooled to, filter cake is collected, drying obtains pink solid product 1.7g.Yield
70%.Spectral data：1H NMR(600MHz,DMSO-d6)：10.06(br.s.,1H),9.62(br.s.,1H),8.77(d,J
=2.9Hz, 1H), 8.70 (d, J=4.7Hz, 1H), 8.43 (d, J=7.5Hz, 1H), 8.07 (t, J=7.4Hz, 1H), 7.93
(d, J=8.4Hz, 2H), 7.84 (d, J=8.2Hz, 2H), 7.79 (d, J=4.7Hz, 1H), 7.54~7.64 (m, 1H),
4.50(br.s., 2H).
Embodiment 5：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative：The N- tert-butyl groups -2-
(4-((4- (2- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
4- ((4- (2- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.100g, 0.00032mol), DMF (5mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add t-butylisocyanate (0.032g, 0.00035mol), insulation reaction 3h.TLC detection reactions are complete, stop anti-
Should.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, drying, obtained crude product separates (eluant, eluent through silica gel column chromatography
For dichloromethane:The ︰ 1, v/v of methanol=50) obtain yellow solid product 0.090g, yield 68%.Spectral data：1H NMR(600
MHz,DMSO-d6):10.10 (s, 1H), 9.95 (d, J=2.0Hz, 1H), 8.76 (d, J=4.0Hz, 1H), 8.71 (d, J=
4.9 Hz, 1H), 8.43 (d, J=7.8Hz, 1H), 8.07 (dt, J=1.6,7.70Hz, 1H), 7.93~7.96 (m, 2H),
7.87-7.90 (m, 2H), 7.80 (d, J=4.9Hz, 1H), 7.58~7.61 (m, 2H), 6.08 (br.s., 1H), 1.27 (s,
9H).13C NMR (151MHz,DMSO-d6):166.3,163.4,160.2,160.1,157.8,153.9,150.2,144.1,
138.1,128.7,126.3, 125.6,121.6,118.2,109.2,49.9,29.6.HRMS(+):calcd for
C21H24N7O2 +[M+H]+406.1986,found 406.1982；calcd for C21H23N7O2Na+[M+Na]+428.1805,
found 428.1802.
Embodiment 6：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative：N- phenyl -2-
(4-((4- (2- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- thioformamides
4- ((4- (2- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.100g, 0.00032mol), DMF (5mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add isothiocyanic acid phenyl ester (0.044g, 0.00035mol), insulation reaction 3h.TLC detection reactions are complete, stop
Reaction.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, drying, obtained crude product separates (elution through silica gel column chromatography
Agent is dichloromethane:The ︰ 1, v/v of methanol=50) obtain white solid product 0.070g, yield 50%.Spectral data：1H NMR
(600MHz,DMSO-d6):10.39 (s, 1H), 10.13 (s, 1H), 9.80 (br.s., 1H), 9.68 (s, 1H), 8.76~8.78
(m, 1H), 8.72 (d, J=4.9Hz, 1H), 8.43 (d, J=7.8Hz, 1H), 8.07 (dt, J=1.7,7.7Hz, 1H), 7.98
(s, 4H), 7.81 (d, J=5.1Hz, 1H), 7.59 (ddd, J=1.1,4.7,7.5Hz, 1H), 7.46 (d, J=1.8Hz,
2H), 7.34 (t, J=7.7Hz, 2H), 7.13~7.19 (m, 1H)13C NMR(151MHz,DMSO-d6):166.1,163.4,
160.2,160.1, 153.9,150.2,144.3,139.8,138.1,129.3,128.4,126.5,126.3,125.5,
125.4,121.6,118.0,109.3. HRMS(+):calcd for C23H20N7OS+[M+H]+442.1445,found
442.1444,calcd for C23H19N7OSNa+ [M+Na]+464.1264,found 464.1265.
Embodiment 7：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative:N- (the chloro- 4- of 3-
Methylbenzene
Base)-2- (4-((4- (4- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
4- ((4- (4- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.150g, 0.00048mol), DMF (7mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add the chloro- 4- methylphenyl isocyanates (0.090g, 0.00054mol) of 3-, insulation reaction 3h.TLC detections have been reacted
Entirely, reaction is stopped.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, drying, obtained crude product divides through silica gel column chromatography
From (eluant, eluent is dichloromethane:The ︰ 1, v/v of methanol=50) obtain yellow solid product 0.120g, yield 51%.Spectral data：1H NMR(600MHz,DMSO-d6)：10.18(s,1H),10.15(s,1H),8.97(br.s.,1H),8.81(br.s.,2H),
8.73 (d, J=5.1Hz, 1H), 8.23 (br.s., 1H), 8.12 (d, J=5.8Hz, 2H), 7.95~7.98 (m, 2H), 7.91
~7.94 (m, 2H), 7.68 (d, J=1.6Hz, 1H), 7.62 (d, J=4.9Hz, 1H), 7.29 (br.s., 1H), 7.22 (d, J
=8.2Hz, 1H), 2.25 (s, 3H)13C NMR(151MHz,DMSO-d6)：166.7,162.0,160.5,160.4,151.0,
144.3, 144.1,139.4,133.4,131.5,128.9,128.7,125.6,121.5,118.3,109.8,19.2.HRMS
(+):calcd for C24H21ClN7O2 +[M+H]+474.1440,found 474.1440；calcd for C24H20ClN7O2Na+
[M+Na]+496.1259, found 496.1259.
Embodiment 8：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative:N- cyclohexyl -2-
(4-((4- (4- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
4- ((4- (4- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.100g, 0.00033mol), DMF (5mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add the chloro- 4- methylphenyl isocyanates (0.045g, 0.00036mol) of 3-, insulation reaction 3h.TLC detections reaction is
Completely, reaction is stopped.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, dries, obtained crude product is through silica gel column chromatography
(eluant, eluent is dichloromethane for separation:The ︰ 1, v/v of methanol=50) obtain white solid product 0.070g, yield 50%.Wave spectrum number
According to：10.18 (s, 1H), 10.15 (s, 1H), 8.97 (br.s., 1H), 8.81 (br.s., 2H), 8.73 (d, J=5.1Hz, 1H),
8.23 (br. s., 1H), 8.12 (d, J=5.8Hz, 2H), 7.95~7.98 (m, 2H), 7.91~7.94 (m, 2H), 7.68 (d,
J=1.6Hz, 1H), 7.62 (d, J=4.9Hz, 1H), 7.29 (br.s., 1H), 7.22 (d, J=8.2Hz, 1H), 2.25 (s,
3H).13C NMR(151 MHz,DMSO-d6):166.4,162.0,160.4,158.2,151.1,144.2,143.9,128.8,
125.7,121.4,118.3,109.8, 48.6,33.5,25.7,25.1.HRMS(+):calcd for C23H26N7O2 +[M+H]+
432.2142,found 432.2141；calcd for C23H25N7O2Na+[M+Na]+454.1962,found 454.1960.
Embodiment 9：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative:N- butyl -2-
(4-((4- (4- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
4- ((4- (4- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.100g, 0.00033mol), DMF (5mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add butyl isocyanate (0.035g, 0.00036mol), insulation reaction 3h.TLC detection reactions are complete, stop anti-
Should.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, drying, obtained crude product separates (eluant, eluent through silica gel column chromatography
For dichloromethane:The ︰ 1, v/v of methanol=50) obtain faint yellow solid product 0.080g, yield 60%.Spectral data：1H NMR
(600MHz,DMSO-d6):10.16 (s, 1H), 9.96 (s, 1H), 8.80~8.83 (m, 2H), 8.73 (d, J=5.1Hz, 1H),
8.12~8.14 (m, 2H), 7.93~7.95 (m, 2H), 7.89~7.92 (m, 2H), 7.74 (s, 1H), 7.62 (d, J=
5.1Hz, 1H), 6.45 (br.s., 1H), 3.03 (q, J=6.7Hz, 2H), 1.38 (quin, J=7.2Hz, 2H), 1.28
(sxt, J=7.3Hz, 2H), 0.87 (t, J=7.3Hz, 3H)13C NMR(151MHz,DMSO-d6):166.5,161.9,
160.5,159.0,150.9,144.4, 143.9,128.9,125.8,121.5,118.3,109.8,39.3,32.5,19.9,
14.2.HRMS(+):calcd for C21H24N7O2 + [M+H]+406.1986,found 406.1985；calcd for
C21H23N7O2Na+[M+Na]+428.1805,found 428.1806.
Embodiment 10：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative:N- phenethyls-
2- (4-((4- (3- pyridine radicals)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- formamides
4- ((4- (3- pyridine radicals) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.150g, 0.00049mol), DMF (7mL), is heated to 100 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add phenethyl isocyanates (0.079g, 0.00054mol), insulation reaction 3h.TLC detection reactions are complete, stop
Reaction.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, drying, obtained crude product separates (elution through silica gel column chromatography
Agent is dichloromethane:The ︰ 1, v/v of methanol=50) obtain yellow solid product 0.126g, yield 57%.Spectral data:1H NMR
(600MHz,DMSO-d6):10.09 (s, 1H), 9.99 (br.s., 1H), 9.35 (d, J=2.0Hz, 1H), 8.74 (dd, J=
1.4,4.7Hz, 1H), 8.66 (d, J=5.1Hz, 1H), 8.52 (td, J=1.9,7.9Hz, 1H), 7.92~7.95 (m, 2H),
7.88~7.90 (m, 2H), 7.86 (s, 1H), 7.61 (dd, J=4.8,7.9Hz, 1H), 7.58 (d, J=5.1Hz, 1H),
7.26~7.30 (m, 2H), 7.20~7.23 (m, 2H), 7.17~7.19 (m, 1H), 6.53 (br.s., 1H), 3.22~3.29
(m, 2H), 2.71 (t, J=7.3 Hz, 2H)13C NMR(151MHz,DMSO-d6):166.6,162.2,160.3,160.0,
159.0,152.1,148.6,144.1, 140.0,135.0,132.5,129.1,128.9,128.8,126.5,125.6,
124.5,118.2,109.5,41.4,36.4.HRMS(+): calcd for C25H24N7O2 +[M+H]+454.1986,found
454.1981；calcd for C25H23N7O2Na+[M+Na]+ 476.1805,found 476.1801.
Embodiment 11：The preparation of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative:N- benzyls -2-
(4-((4- (4- chlorphenyls)-2- pyrimidine radicals) amino) benzoyl) hydrazine-1- thioformamides
4- ((4- (4- chlorphenyls) -2- pyrimidine radicals) amino) benzoyl hydrazine is sequentially added in the two-neck bottle that 50mL is dried
(0.100g, 0.00029mol), DMF (7mL), is heated to 120 DEG C, treats that solid dissolving completely, is cooled to
70 DEG C, add benzyl isothiocyanic acid ester (0.048g, 0.00032mol), insulation reaction 3.5h.TLC detection reactions are complete, stop
Only react.It is cooled to after room temperature plus 10mL water, suction filtration, collects filter cake, dries, obtained crude product is separated through silica gel column chromatography (to be washed
De- agent is dichloromethane:The ︰ 1, v/v of methanol=50) obtain white solid product 0.110g, yield 76%.Spectral data：1H NMR
(600MHz,DMSO-d6):10.26 (s, 1H), 10.08 (s, 1H), 9.42 (s, 1H), 8.64 (d, J=5.3Hz, 2H), 8.20-
8.23 (m, 2H), 7.90~7.96 (m, 4H), 7.63~7.67 (m, 2H), 7.52 (d, J=5.1Hz, 1H), 7.28~7.34
(m, 4H), 7.19~7.24 (m, 1H), 4.75 (d, J=6.0Hz, 2H)13C NMR(151MHz,DMSO-d6):166.2,
163.0, 160.3,159.9,144.3,140.0,136.3,135.8,129.5,129.2,128.5,127.5,127.0,
125.3,118.0,109.2, 47.2.HRMS(+):calcd for C25H22ClN6OS+[M+H]+489.1259,found
489.1259；calcd for C25H21ClN6OSNa+[M+Na]+511.1078,found 511.1075。
Claims (10)
1.4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative, it is characterised in that its structural formula is：
Wherein, R1Represent C1~C4Straight chained alkyl, C5Or C6Cycloalkyl, unsubstituted aromatic alkyl, substituted-phenyl；R2Represent
Cl or H；X represents O or S；Y represents N or C.
2. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 1, its
It is characterised by comprising the following steps：
1) intermediate p -guanidinobenzoic acid ethyl ester nitrate is prepared；
2) intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone is prepared；
3) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate is prepared；
4) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine is prepared；
5) 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative is prepared.
3. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
Be characterised by step 1) in, it is described prepare intermediate p -guanidinobenzoic acid ethyl ester nitrate specific method be：Dry
Ethylaminobenzoate, cyanamide and absolute ethyl alcohol are sequentially added in reaction bulb；Add after hydrochloric acid, be warming up under stirring
Backflow, reacts 22~24h；After thin-layer chromatography detection reaction, stop reaction；Reaction solution is concentrated under reduced pressure except water is added after solvent, 0
DEG C plus ammonium nitrate the aqueous solution, insulation reaction after addition, filtering, collect filter cake, dry white solid product to guanidine radicals benzene first
Acetoacetic ester nitrate；The ethylaminobenzoate, cyanamide, hydrochloric acid, ammonium nitrate mol ratio for 1 ︰ (2.5~3) ︰ (1.2~
1.5) ︰ (2~2.5).
4. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
It is characterised by step 2) in, it is described to prepare the specific of intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone
Method is：2- acetylpyridines and DMF dimethylacetal, or 3- second are sequentially added in dry reaction bulb
Acyl pyridine and DMF dimethylacetal, or 4- acetylpyridines and DMF dimethylacetal,
Or 4- chloro-acetophenones and DMF dimethylacetal, it is heated to 110 DEG C, back flow reaction 18~20h, TLC detection
After reaction, stop reaction, reaction solution adds ethyl acetate after being concentrated under reduced pressure, stirring, suction filtration collects filter cake, dries to obtain solid product
1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone；The 2- acetylpyridines and N,N-dimethylformamide dimethyl
Acetal, or 3- acetylpyridines and DMF dimethylacetal, or 4- acetylpyridines and DMF
Dimethylacetal, or the mol ratio of 4- chloro-acetophenones and DMF dimethylacetal is 1 ︰ (1.1~1.2).
5. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
It is characterised by step 3) in, the tool for preparing intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate
Body method is：P -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3- (diformazans are sequentially added in dry reaction bulb
Amino) -2- propylene -1- ketone, sodium hydrate solid, absolute ethyl alcohol, be heated to backflow, react 18~22h, TLC detection reaction after,
Stop reaction, be cooled to suction filtration after room temperature, collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals) ammonia
Base) ethyl benzoate；It is described state p -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3- (dimethylamino) -2- propylene -
1- ketone, the mol ratio of sodium hydroxide are 1 ︰ (1~1.1) ︰ (1.2~1.5).
6. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
It is characterised by step 4) in, it is described to prepare the specific of intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine
Method is：4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate, hydration are sequentially added in dry reaction bulb
Hydrazine, absolute ethyl alcohol, are heated to backflow, react 18~20h, after TLC detection reactions, stop reaction, be cooled to suction filtration after room temperature, receive
Collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine；4- ((the 4- substitution virtues
Base -2- pyrimidine radicals) amino) mol ratio of ethyl benzoate and hydrazine hydrate is 1 ︰ (18~20).
7. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
It is characterised by step 5) in, it is described to prepare the specific of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative
Method is：4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine solid, N, N- are sequentially added in dry reaction bulb
Dimethylformamide, is heated to 100 DEG C, treats that solid dissolving completely, is cooled to 70 DEG C, and it (can be fatty isocyanide to add isocyanates
Acid esters, substituted or unsubstituted phenyl isocyanate, substituted or unsubstituted phenyl isocyanates, unsubstituted fragrant alkane
Based isocyanate, unsubstituted aromatic alkyl isothiocyanic acid ester), 3~4h of insulation reaction；After TLC detection reactions, stop anti-
Should, it is cooled to after room temperature and adds water, suction filtration collects filter cake, dries, obtained crude product is through the isolated solid product of silica gel column chromatography
4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative；The 4- ((4- substituted aryl -2- pyrimidine radicals) amino)
Benzoyl hydrazine, the mol ratio of isocyanates are 1 ︰ (1~1.1).
8. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its
It is characterised by step 5) in, the eluant, eluent is by volume the ︰ 1 of Er Lv Jia Wan ︰ methanol=50.
9. a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative, which is used to prepare, treats or prevents tumour phase
Purposes in the medicine of related disorders.
10. a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative has significant suppression tumour cell
Growth and the effect of inducing apoptosis of tumour cell, the medicine of tumor-related illness is treated or prevented for preparing.
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| CN110156672A (en) * | 2019-05-22 | 2019-08-23 | 浙江师范大学 | A kind of application of semicarbazide compound preparation method and obtained compound |
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| CN107602536A (en) * | 2017-10-13 | 2018-01-19 | 厦门大学 | ((base of (substituted-phenyl) pyrimidine 2) amino) the benzoyl hydrazine derivative of N` substituent methyls subunit 4 and preparation |
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| CN111196783A (en) * | 2020-01-19 | 2020-05-26 | 郑州大学 | 2,4, 6-substituted pyrimidine derivatives containing acyl urea structure, and preparation method and application thereof |
| CN111196783B (en) * | 2020-01-19 | 2022-09-27 | 郑州大学 | 2,4, 6-substituted pyrimidine derivatives containing acyl urea structure, and preparation method and application thereof |
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