CN105949139B - A kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application - Google Patents
A kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application, there is provided a kind of tetrazine compound that is new, having preferable anticancer (especially human leukemia or human cervical carcinoma) activity；The preparation method of the tetrazine compound is provided, the preparation method is simple, easily operated, and raw material is easy to get and production cost is relatively low, suitable for practicality, is expected to be applied to prepare in the medicine for preventing or treating tumor disease.
Description
(1) technical field
The present invention relates to N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides and its preparation
Method, and application of the compound in prevention or tumor is prepared.
(2) background technology
Tetrazine kind compound have it is many preferably physical property, spectral quality and higher reactivities, especially one
The tetrazine derivatives of a little special constructions have obvious antiviral activity, antitumor activity, and can be used as agricultural chemicals and desinsection
Agent.Such as agricultural chemicals has two kind (clofentezine and flufenzine) listings at present, (antineoplastic is not for for the existing kind of medicine
Azoles amine) listing.
1978, document report 3,6- hexichol alkynyl-hexahydro -1,2, there is 4,5- tetrazines antitumor activity (to refer to
Eremeev,A.V.；Tikhomirova,D.A.；Tyusheva,V.A.；Liepins,
F.Khim.Geterotsikl.Soedin, 1978,753), this is that 1,2,4,5- tetrazine kind compounds are reported may have first
Potential antitumor activity.Afterwards, reporting some 1,2,4,5- tetrazine kind compounds successively has antitumor activity, such as has
Double (2'- hydroxyl -5'- the chlorphenyls) -1,2,4,5- tetrazines of 3,6- for having antitumor activity (refer to Rao, G.-W.；Hu,W.-
X.Bioorg.Med.Chem.Lett.2006,16(14),3702)、N1,N4- two (aminomethyl phenyl) -3,6- dimethyl -1,2,
4,5- tetrazine -1,4- diformamides (refer to Rao, G.-W.；Guo,Y.-M.；Hu,W.-X.ChemMedChem,2012,7(6),
973) etc..Certain most of 1,2,4,5- tetrazine kind compounds simultaneously do not have antitumor activity.
(3) content of the invention
First purpose of the present invention is to provide a kind of new with anti-human promyelocytic leukemia and human cervical carcinoma's activity
Type tetrazine compound --- N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides.
Second object of the present invention is to provide the N- sec-butyls -3,6- diphenyl -1,4- dihydros -1,2,4,5- four
The preparation method of piperazine -1- formamides, the preparation method is easy, and easily operated, raw material is easy to get, and production cost is relatively low, suitable for work
Industry application.
Third object of the present invention is to provide the N- sec-butyls -3,6- diphenyl -1,4- dihydros -1,2,4,5- four
Application of the piperazine -1- formamides in prevention or treatment human promyelocytic leukemia or human cervical carcinoma's medicine is prepared.
The technical solution adopted in the present invention is illustrated below.
The invention provides a kind of new tetrazine compound, i.e. N- sec-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,
5- tetrazine -1- formamides, it has following structural (I)：
Present invention also offers described N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formyls
The preparation method of amine (I), the preparation method include：Triphosgene is added in organic solvent A, under -10~12 DEG C of stirring conditions,
It is added dropwise molten containing the 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines shown in formula (II) and the organic solvent A of base catalyst
Liquid, drip off rear reaction solution and be warmed to room temperature, back flow reaction removes organic solvent under reduced pressure, add organic solvent after 0.5~20 hour
B, under -10~12 DEG C of stirring conditions, the organic solvent B solution containing sec-butylamine is added dropwise, drips off rear reaction solution and is warmed to room temperature, backflow is anti-
After answering 1~50 hour, reaction solution through isolating and purifying to obtain N- sec-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1 shown in formula (I),
2,4,5- tetrazine -1- formamides, the base catalyst are one of following：Triethylamine, DMAP (DMAP), pyridine
Or sodium hydroxide；
N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- the formamides (I) of the present invention of preparing
Reaction is as shown in following reaction equation (a), and reaction equation (a) is there is not yet document report：
Further, 3 described, 6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines (II) and base catalyst, triphosgene,
The ratio between amount for the material that feeds intake of sec-butylamine is the ﹕ 1~8 of 1 ﹕, 0.1~3 ﹕ 0.1~3.
Further, the organic solvent A or organic solvent B are selected from one of following：Dichloromethane, chloroform or toluene.Institute
State organic solvent A or organic solvent B dosage with can dissolve triphosgene, 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines,
Base catalyst, reaction intermediate, sec-butylamine, preferable organic solvent A cumulative volumes dosage is with compound thing shown in formula (II)
The amount of matter is calculated as 6-18mL/mmol, wherein organic solvent A volumetric usage is with compound thing shown in formula (II) used in dissolving triphosgene
The amount of matter is calculated as 1-10mL/mmol, and organic solvent B cumulative volume dosage is calculated as 6- with the amount of combinations of materials shown in formula (II)
18mL/mmol, wherein organic solvent B volumetric usage used in dissolving sec-butylamine is calculated as 1- with the amount of combinations of materials shown in formula (II)
8mL/mmol。
Further, with TLC tracing detections, (solvent is volume ratio 0.5~20 to course of reaction：1 petroleum ether and acetic acid second
Ester mixed solution), to determine reaction end, the General reactions time was at 0.5~50 hour.
Further, it is described to isolate and purify using following steps：After reaction terminates, reaction solution washing, organic phase is separated, is evaporated off
After solvent, residue column chromatography obtains N- sec-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2 shown in formula (I), and 4,5- tetrazines -
1- formamides.
Further, the operating procedure of the column chromatography is specific as follows：The residue after solvent is evaporated off is taken in single port bottle,
Add organic solvent C to be dissolved, obtain lysate, the column chromatography of 1~2 times of amount of residue quality is then added into lysate
Silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels), after mixing, is evaporated off solvent, obtain dry residue with
The mixture of silica gel, mixture is filled into post loading, then using volume ratio as 0.5~20：1 petroleum ether and ethyl acetate mixing is molten
Liquid is eluant, eluent, is eluted, and (solvent is volume ratio 0.5~20 to TLC tracing detections：1 petroleum ether and ethyl acetate mixing
Solution), the eluent containing compound shown in formula (I) is collected according to TLC detections, eluent is concentrated and dried, obtained shown in formula (I)
Compound；The organic solvent C is one of following：Petroleum ether, dichloromethane, chloroform or ethyl acetate；The organic solvent C is used
Amount is with being capable of dissolution residual substance.
Organic solvent A of the present invention, organic solvent B, organic solvent C, it is represented all referring to for reacting or post
The organic solvent of chromatography, letter here do not have the implication for refering in particular to certain some organic solvent, and letter is only to facilitate table is answered
It is clear, appear in organic solvent in different steps for distinguishing these.Above-mentioned organic solvent A is same organic solvent, is had
Solvent A, B or C can be same solvent, or not homogeneous solvent.
The present invention also provides a kind of N- sec-butyls -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formyls
Amine (I) is suppression people in loop strain HL-60 preparing the application in treating leukemia medicament, preferably described medicine
The medicine of activity.
The present invention also provides a kind of N- sec-butyls -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formyls
Amine (I) is preparing the application in treating human cervical carcinoma's medicine, and preferably described medicine is active to suppress human cervical carcinoma cell lines Siha
Medicine.
N- sec-butyls -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (I) of the present invention are to people
Promyelocytic leukemia cell line HL-60 has significant inhibiting rate, also there is certain inhibiting rate to human cervical carcinoma cell lines Siha,
It can be applied to prepare prevention or treatment human leukemia or the medicine of human cervical carcinoma.
The beneficial effects are mainly as follows：(1) provide it is a kind of it is new, have preferable anticancer (especially
Human leukemia or human cervical carcinoma) activity tetrazine compound；(2) preparation method of the tetrazine compound, the preparation side are provided
Method is simple, easily operated, and raw material is easy to get and production cost is relatively low, suitable for practicality, is expected to be applied to prepare prevention or treatment tumour
In the medicine of disease.
(4) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment is to illustrate the present invention, rather than
It limit the invention in any way.
3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines (II) prepare reference literature (Rao, G.-W.；Hu,W.-
X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702) method is prepared.
Embodiment 1：The preparation of N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (I)
10mL chloroform is dissolved into 0.297g (1.0mmol) triphosgene, under the conditions of -10 DEG C of magnetic agitations, dropwise addition contains
2.363g (10.0mmol) 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines (II) and 0.122g (1.0mmol) DMAP's
50mL chloroformic solutions, drip off rear reaction solution and be warmed to room temperature, (course of reaction uses TLC tracing detections to back flow reaction, expansion within 20 hours
Agent is volume ratio 1：2 petroleum ether and ethyl acetate mixture), remove organic solvent under reduced pressure, add 50mL chloroforms, -10
Under the conditions of DEG C magnetic agitation, the 10mL chloroformic solutions containing 0.731g (10.0mmol) sec-butylamine are added dropwise, drips off rear reaction solution and rises to
Room temperature, (course of reaction uses TLC tracing detections to back flow reaction, and solvent is volume ratio 1 after 50 hours：2 petroleum ether and acetic acid
Ethyl ester mixed solution), reaction solution is washed with (50mL × 3), is separated organic phase, after solvent is evaporated off, residue column chromatography, that is, is taken steaming
Dissolved except the residue after solvent adds 10 milliliters of petroleum ether solvents, obtain lysate, 1.0 are then added into lysate
Gram silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel), after mixing, is evaporated off solvent, obtains dry residue and silicon
The mixture of glue, mixture is filled into post, then with volume ratio 1：2 petroleum ether and ethyl acetate mixture is eluant, eluent, is washed
De-, (solvent is volume ratio 1 to TLC tracing detections：2 petroleum ether and ethyl acetate mixture), collection is detected according to TLC and contained
Solvent is evaporated off in the eluent of compound shown in formula (I), the eluent of collection, is dried to obtain faint yellow solid product, i.e. N- is secondary
Butyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazine -1- formamides (I), yield 25.2% (with 3,6- diphenyl -1,
4- dihydros -1,2, the gauge of 4,5- tetrazine materials, similarly hereinafter), 214~217 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:7.982
(s, 1H), 7.683-7.700 (m, 2H), 7.491-7.553 (m, 3H), 7.366-7.436 (m, 5H), 6.240 (d, J=
8.5Hz, 1H), 3.825-3.869 (m, 1H), 1.537-1.599 (m, 2H), 1.228 (d, J=6.7Hz, 3H), 0.973 (t, J
=7.4Hz, 3H) .IR (KBr, cm-1)ν:3391,3269,2965,2922,1675,1522,1500,1461,1343,1174,
1086,1029,1007,931,899,780,765,693.
Embodiment 2：The preparation of N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (I)
100mL dichloromethane is dissolved into 8.903g (30.0mmol) triphosgene, under the conditions of 12 DEG C of magnetic agitations, dropwise addition contains
There are 2.363g (10.0mmol) 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines (II) and 2.373g (30.0mmol) pyridine
80mL dichloromethane solutions, drip off rear reaction solution and be warmed to room temperature, (course of reaction is using TLC tracking inspections for back flow reaction 0.5 hour
Survey, solvent is volume ratio 20：1 petroleum ether and ethyl acetate mixture), remove organic solvent under reduced pressure, add 100mL
Dichloromethane, under the conditions of 12 DEG C of magnetic agitations, the 80mL dichloromethane solutions containing 5.851g (80.0mmol) sec-butylamine, drop is added dropwise
Reaction solution is warmed to room temperature after complete, and (course of reaction uses TLC tracing detections to back flow reaction, and solvent is volume ratio 20 after 1 hour：1
Petroleum ether and ethyl acetate mixture), reaction solution with (50mL × 3) wash, separate organic phase, after solvent is evaporated off, residual
Thing column chromatography, that is, take the residue after solvent is evaporated off to add 10 milliliters of dichloromethane solvents and dissolved, obtain lysate, then
1.0 grams of silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel) are added into lysate, after mixing, solvent is evaporated off,
The residue and the mixture of silica gel that must be dried, mixture is filled into post, then with volume ratio 20：1 petroleum ether and ethyl acetate
Mixed solution is eluant, eluent, and elution, (solvent is volume ratio 20 to TLC tracing detections：1 petroleum ether and ethyl acetate mixing is molten
Liquid), the eluent containing the compound shown in formula (I) is collected according to TLC detections, the eluent of collection is evaporated off solvent, is dried to obtain
Faint yellow solid product, i.e. N- sec-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazine -1- formamides (I), yield
36.5%, 214~217 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3：The preparation of N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (I)
40mL toluene is dissolved into 2.968g (10.0mmol) triphosgene, under the conditions of 0 DEG C of magnetic agitation, dropwise addition contains
2.363g (10.0mmol) 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines (II) and 1.012g (10.0mmol) triethylamine
20mL toluene solutions, drip off rear reaction solution and be warmed to room temperature, (course of reaction uses TLC tracing detections, exhibition for back flow reaction 4 hours
It is volume ratio 10 to open agent：1 petroleum ether and ethyl acetate mixture), remove organic solvent under reduced pressure, add 40mL toluene, 0
Under the conditions of DEG C magnetic agitation, the 20mL toluene solutions containing 1.463g (20.0mmol) sec-butylamine are added dropwise, drips off rear reaction solution and rises to
Room temperature, (course of reaction uses TLC tracing detections to back flow reaction, and solvent is volume ratio 10 after 30 hours：1 petroleum ether and second
Acetoacetic ester mixed solution), reaction solution is washed with (50mL × 3), is separated organic phase, after solvent is evaporated off, residue column chromatography, that is, is taken
The 10 milliliters of ethyl acetate solvents of addition of the residue after solvent are evaporated off to be dissolved, obtains lysate, then adds into lysate
Enter 1.0 grams of silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel), after mixing, solvent is evaporated off, obtains dry residual
The mixture of thing and silica gel, mixture is filled into post, then with volume ratio 10：1 petroleum ether and ethyl acetate mixture is to wash
De- agent, elution, (solvent is volume ratio 10 to TLC tracing detections：1 petroleum ether and ethyl acetate mixture), examined according to TLC
Survey and collect the eluent containing the compound shown in formula (I), solvent is evaporated off in the eluent of collection, is dried to obtain faint yellow solid production
Thing, i.e. N- sec-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazine -1- formamides (I), yield 43.6%, fusing point 214
~217 DEG C.1H NMR and IR is the same as embodiment 1.
Embodiment 4：The preparation of N- sec-butyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (I)
20mL toluene is dissolved into 1.484g (5.0mmol) triphosgene, under the conditions of 5 DEG C of magnetic agitations, dropwise addition contains
2.363g (10.0mmol) 3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines (II) and 0.200g (5.0mmol) sodium hydroxide
40mL toluene solutions, drip off rear reaction solution and be warmed to room temperature, (course of reaction uses TLC tracing detections, exhibition for back flow reaction 12 hours
It is volume ratio 5 to open agent：1 petroleum ether and ethyl acetate mixture), remove organic solvent under reduced pressure, add 40mL chloroforms, 0
Under the conditions of DEG C magnetic agitation, the 40mL chloroformic solutions containing 2.926g (40.0mmol) sec-butylamine are added dropwise, drips off rear reaction solution and rises to
Room temperature, (course of reaction uses TLC tracing detections to back flow reaction, and solvent is volume ratio 5 after 20 hours：1 petroleum ether and acetic acid
Ethyl ester mixed solution), reaction solution is washed with (50mL × 3), is separated organic phase, after solvent is evaporated off, residue column chromatography, that is, is taken steaming
Dissolved except the residue after solvent adds 10 milliliters of chloroform solvents, obtain lysate, 1.0 grams are then added into lysate
Silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel), after mixing, is evaporated off solvent, obtains dry residue and silica gel
Mixture, mixture is filled into post, then with volume ratio 5：1 petroleum ether and ethyl acetate mixture is eluant, eluent, elution,
(solvent is volume ratio 5 to TLC tracing detections：1 petroleum ether and ethyl acetate mixture), collected according to TLC detections and contain formula
(I) solvent is evaporated off in the eluent of the compound shown in, the eluent of collection, is dried to obtain faint yellow solid product, i.e. N- Zhong Ding
Base -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazine -1- formamides (I), yield 12.4%, 214~217 DEG C of fusing point.1H
NMR and IR is the same as embodiment 1.
Embodiment 5：Active anticancer testing in vitro
(1) compound (I) made from embodiment 1 people in loop strain HL-60 and human cervical carcinoma have been subjected to
Cell line Siha biological activity tests.As a result it is preferable to show that compound (I) has to people in loop strain HL-60
Active anticancer.
Method of testing：Tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reducing process.
Cell line：People in loop strain HL-60 and human cervical carcinoma cell lines Siha.Above-mentioned tumor cell line purchase
From Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank.
Experimental procedure is as follows：
1) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L with 1000 μ L cell culture
Base dilutes, and it is 50 μ g/mL to make concentration, then with cell culture medium serial dilution to concentration (50 μ g/mL, 5 μ g/mL, 0.5 μ g/
mL)。
2) culture of cell
A) preparation of cell culture medium:Contain 800,000 units of Penicillin, 1.0g chains in per 1000mL culture mediums (RPMI-1640)
Mycin, 10% inactivated fetal bovine serum.
B) culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2Cultivated in incubator, 3~5d
Passage.
C) inhibitory action of the determination sample to growth of tumour cell
Cell is digested with EDTA- pancreatin digestive juice, and with cell culture medium into 1 × 106/ mL, it is thin to be added to 96 holes
In born of the same parents' culture plate, per the μ L of hole 100,37 DEG C are put, 5%CO2Cultivated in incubator.After being inoculated with 24h, sample (sample final concentration is added
Respectively 50 μ g/mL, 5 μ g/mL, 0.5 μ g/mL), per the μ L of hole 100,3 multiple holes, 37 DEG C are put, 5%CO2Cultivated in incubator,
5mg/mL MTT is added after 72h in cell culture well, per the μ L of hole 10,37 DEG C of incubation 3h is put, adds DMSO, per the μ L of hole 150,
Vibrated with oscillator, Shi Jia Za is completely dissolved, with ELIASA under 570nm wavelength colorimetric.With similarity condition with sample is free of, contain
The cell of same concentration DMSO cell culture medium culture calculates IC of the sample to growth of tumour cell as control50.Test
As a result it is as shown in table 1：
The inhibitory action that the compound of table 1 (I) grows to cell line HL-60 and Siha
(2) with reference to embodiment 1, sec-butylamine is substituted with isopropylamine, n-butylamine respectively, has synthesized compound N-isopropyl -3,
6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazine -1- formamides (III), N- normal-butyls -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,
4,5- tetrazine -1- formamides (IV).With 3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines are raw material, respectively with phenyl isocyanide
Acid esters, o-methoxyphenyl isocyanate reaction have obtained N- phenyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- first
Acid amides (V) and N- o-methoxyphenyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1- formamides (VI).
Further according to the above method, obtained compound (III), (IV), (V) and (VI) human promyelocytic leukemia has been subjected to
Cell line HL-60 biological activity test, test result show compound (III), (IV), (V) and (VI) to the early white blood of young grain of people
The equal unobvious of disease cell line HL-60 inhibitions, compound (III), (IV), (V) and (VI) is to people in loop
Strain HL-60 active anticancer can not show a candle to compound (I).Concrete outcome is as shown in table 2：
Inhibitory action of the compound of table 2 (III), (IV), (V) and (VI) to HL-60 cell growths
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (III) of other 4 structures, (IV), (V) and
(VI) to the equal unobvious of inhibitory action of people in loop strain HL-60 growths.Compound (I) is to the early white blood of young grain of people
The inhibitory action of disease cell line HL-60 growths is notable, hence it is evident that better than compound (III), (IV), (V) and (VI).
Claims (10)
1. sec-butyl diphenyl tetrazine benzamide compound shown in a kind of formula (I),
2. the preparation method of sec-butyl diphenyl tetrazine benzamide compound described in a kind of claim 1, it is characterised in that described
Method is：Triphosgene is added in organic solvent A, under -10~12 DEG C of stirring conditions, be added dropwise containing compound shown in formula (II) and
The organic solvent A solution of base catalyst, drip off rear reaction solution and be warmed to room temperature, back flow reaction removes under reduced pressure after 0.5~20 hour
Organic solvent, adds organic solvent B, under -10~12 DEG C of stirring conditions, the organic solvent B solution containing sec-butylamine is added dropwise, drips off
Reaction solution is warmed to room temperature afterwards, and for back flow reaction after 1~50 hour, reaction solution obtains the sec-butyl two shown in formula (I) through isolating and purifying
Phenyl tetrazine benzamide compound；The base catalyst is one of following：Triethylamine, DMAP, pyridine or hydrogen
Sodium oxide molybdena；
3. the preparation method of sec-butyl diphenyl tetrazine benzamide compound as claimed in claim 2, it is characterised in that the formula
(II) the ratio between compound shown in and base catalyst, triphosgene, the amount for the material that feeds intake of sec-butylamine are the ﹕ 1 of 1 ﹕, 0.1~3 ﹕ 0.1~3
~8.
4. the preparation method of sec-butyl diphenyl tetrazine benzamide compound as claimed in claim 2, it is characterised in that described to have
Solvent A is one of following：Dichloromethane, chloroform or toluene；The organic solvent B is one of following：Dichloromethane, chloroform or
Toluene.
5. the preparation method of sec-butyl diphenyl tetrazine benzamide compound as claimed in claim 2, it is characterised in that described anti-
The method for answering liquid to isolate and purify is：After reaction terminates, reaction solution is washed, separates organic phase, after solvent is evaporated off, residue post layer
Analysis obtains sec-butyl diphenyl tetrazine benzamide compound shown in formula (I).
6. the preparation method of sec-butyl diphenyl tetrazine benzamide compound as claimed in claim 5, it is characterised in that the post
Chromatography method is：Take the organic solvent C of the residue after solvent is evaporated off to dissolve, obtain lysate, then added into lysate
The column chromatography silica gel of 1~2 times of amount of residue quality, after mixing, is evaporated off solvent, obtains the mixture of dry residue and silica gel,
Mixture is filled into post loading, then using volume ratio as 0.5~20：1 petroleum ether and ethyl acetate mixture enters for eluant, eluent
Row elution, TLC tracing detections, solvent is volume ratio 0.5~20：1 petroleum ether and ethyl acetate mixture, according to TLC
The eluent containing compound shown in formula (I) is collected in detection, and eluent is concentrated and dried, and obtains sec-butyl diphenyl shown in formula (I)
Tetrazine benzamide compound；The organic solvent C is one of following：Petroleum ether, dichloromethane, chloroform or ethyl acetate.
A kind of 7. the answering in treatment leukemia medicament is prepared of sec-butyl diphenyl tetrazine benzamide compound described in claim 1
With.
8. application as claimed in claim 7, it is characterised in that the medicine is with suppression people in loop strain
The medicine of HL-60 activity.
9. sec-butyl diphenyl tetrazine benzamide compound described in a kind of claim 1 is in treatment human cervical carcinoma's medicine is prepared
Using.
10. application as claimed in claim 9, it is characterised in that the medicine is to be lived with suppression human cervical carcinoma cell lines Siha
The medicine of property.
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| CN201610299007.7A CN105949139B (en) | 2016-05-06 | 2016-05-06 | A kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584734A (en) * | 2011-12-19 | 2012-07-18 | 浙江工业大学 | 3,6-dimethyl-1,2,4,5-tetrazine-1,4-dimethyl amides ramification, preparation method and application |
| CN102702121A (en) * | 2012-04-06 | 2012-10-03 | 浙江工业大学 | New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof |
| CN103145636A (en) * | 2013-03-25 | 2013-06-12 | 台州职业技术学院 | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof |
| CN104098523A (en) * | 2014-05-12 | 2014-10-15 | 浙江工业大学 | 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584734A (en) * | 2011-12-19 | 2012-07-18 | 浙江工业大学 | 3,6-dimethyl-1,2,4,5-tetrazine-1,4-dimethyl amides ramification, preparation method and application |
| CN102702121A (en) * | 2012-04-06 | 2012-10-03 | 浙江工业大学 | New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof |
| CN103145636A (en) * | 2013-03-25 | 2013-06-12 | 台州职业技术学院 | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof |
| CN104098523A (en) * | 2014-05-12 | 2014-10-15 | 浙江工业大学 | 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| N,N′-二取代苯基-3,6-二甲基-1,4-二氢-1,2,4,5-四嗪-1,4-二甲酰胺衍生物的合成及其抗肿瘤活性;蔡志彬，等;《药学学报》;20001231;第35卷(第10期);第793-796页 * |
| Synthesis,X-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines;Guo-Wu Rao, et al;《Bioorg.Med.Chem.Letter.》;20050615;第15卷;第3174-37176页 * |
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