CN105968064B - Two tolyl tetrazine diformamide compounds of one kind and preparation and application - Google Patents
Two tolyl tetrazine diformamide compounds of one kind and preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of two tolyl tetrazine diformamide compounds and preparation and application, provide it is a kind of it is novel, there is preferable anticancer (especially human breast carcinoma and human lung cancer) active tetrazine compound；Provide the preparation method of the tetrazine compound, the preparation method is simple, and easily operated, raw material is easy to get and lower production costs, be suitable for it is practical, be expected to be applied to preparation prevention or treatment tumor disease drug in.
Description
(1) technical field
The present invention relates to N1,N4- two two formyls of tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4-
The application of amine and preparation method thereof and the compound in preparation prevention or tumor.
(2) background technique
Tetrazine kind compound have many preferable physical properties, spectral property and higher reactivity, especially one
The tetrazine derivatives of a little special constructions have apparent antiviral activity, anti-tumor activity, and can be used as pesticide and desinsection
Agent.Such as there are two kind (clofentezine and flufenzines) to list at present for pesticide, (antineoplastic is not for for the existing kind of medicine
Azoles amine) listing.
1978, document report 3,6- hexichol alkynyl-hexahydro -1,2,4,5- tetrazines have anti-tumor activity (refering 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 for the first time
Potential anti-tumor activity.Later, some 1,2,4,5- tetrazine kind compounds are reported successively with anti-tumor activity, such as are had
There are bis- (2'- hydroxyl -5'- the chlorphenyl) -1,2,4,5- tetrazines of the 3,6- of anti-tumor activity (refering to Rao, G.-W.；Hu,W.-
X.Bioorg.Med.Chem.Lett.2006,16(14),3702)、N1,N4- two (aminomethyl phenyl) dimethyl-1,2-3,6-,
4,5- tetrazine -1,4- diformamide is (refering 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 anti-tumor activity.
(3) summary of the invention
The first purpose of this invention is to provide a kind of with anti-human breast cancer and the active novel tetrazine of human lung cancer
Close object --- N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamides.
A second object of the present invention is to provide the N1,N4- two dihydro -1,2 tolyl -3,6- diphenyl -1,4-,
4,5- tetrazines-Isosorbide-5-Nitrae-diformamide preparation method, the preparation method are easy, and easily operated, raw material is easy to get, and production cost compared with
It is low, it is suitable for industrial applications.
Third object of the present invention is to provide the N1,N4- two dihydro -1,2 tolyl -3,6- diphenyl -1,4-,
Application of the 4,5- tetrazine -1,4- diformamide in preparation prevention or treatment human breast carcinoma or human lung cancer drug.
The technical solution adopted in the present invention is illustrated below.
The present invention provides a kind of novel tetrazine compound, i.e. N1,N4- two tolyl -3,6- diphenyl -1,4- dihydros -
1,2,4,5- tetrazine-Isosorbide-5-Nitrae-diformamide, with following structural (I):
The present invention also provides the N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines -
The preparation method of Isosorbide-5-Nitrae-diformamide (I), the preparation method include: that triphosgene is added in organic solvent A, and -10~12 DEG C
Under stirring condition, it is added dropwise containing 3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2 shown in formula (II), 4,5- tetrazines and basic catalyst
Organic solvent A solution drips off rear reaction solution and is warmed to room temperature, and after back flow reaction 0.5~20 hour, removes organic solvent under reduced pressure, then
Organic solvent B is added, under -10~12 DEG C of stirring conditions, the organic solvent B solution containing meta-aminotoluene is added dropwise, drips off rear reaction solution
It is warmed to room temperature, after back flow reaction 1~60 hour, reaction solution is isolated and purified to obtain N shown in formula (I)1,N4- two tolyls-
3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide, the basic catalyst are one of following: three second
Amine, 4-dimethylaminopyridine (DMAP), pyridine or sodium hydroxide；
Preparation N of the present invention1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- two
Shown in for example following reaction equation (a) of the reaction of formamide (I), reaction equation (a) is there is not yet document report:
Further, 3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines (II) and basic catalyst, triphosgene,
The ratio between amount for the substance that feeds intake of meta-aminotoluene is 1 ﹕, 0.1~3 ﹕, 0.1~3 ﹕ 1~8.
Further, the organic solvent A or organic solvent B are selected from one of following: methylene chloride, 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- tetrazine,
Basic catalyst, reaction intermediate, meta-aminotoluene, preferable organic solvent A total volume dosage is with compound shown in formula (II)
The amount of substance is calculated as 6-18mL/mmol, wherein organic solvent A volumetric usage used in dissolution triphosgene is with compound shown in formula (II)
The amount of substance is calculated as 1-10mL/mmol, and organic solvent B total 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 dissolution meta-aminotoluene is calculated as with the amount of combinations of materials shown in formula (II)
1-8mL/mmol。
Further, with TLC tracing detection, (solvent is the petroleum ether and acetic acid second of 0.5~20:1 of volume ratio to reaction process
Ester mixed solution), to determine reaction end, the General reactions time was at 0.5~60 hour.
Further, described to isolate and purify using following steps: after reaction, reaction solution washing separates organic phase, steams
After solvent, residue column chromatographs to obtain N shown in formula (I)1,N4- two dihydro -1,2 tolyl -3,6- diphenyl -1,4-,
4,5- tetrazine -1,4- diformamide.
Further, the operating procedure of column chromatography is specific as follows: taking the residue after solvent is evaporated off in single port bottle
In, organic solvent C is added and is dissolved, lysate is obtained, the column of 1~2 times of residue quality amount is then added into lysate
Chromatographic silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels), after mixing, is evaporated off solvent, obtains dry residual
Mixture is filled column loading by the mixture of object and silica gel, is then mixed with petroleum ether and ethyl acetate that volume ratio is 0.5~20:1
Closing solution is that eluant, eluent is eluted, and (solvent is the petroleum ether and ethyl acetate of 0.5~20:1 of volume ratio to TLC tracing detection
Mixed solution), the eluent containing compound shown in formula (I) is collected according to TLC detection, eluent is concentrated and dried, is obtained formula (I)
Shown compound；The organic solvent C is one of following: petroleum ether, methylene chloride, chloroform or ethyl acetate；It is described organic molten
Agent C dosage 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 to refer to for reacting or column
The organic solvent of chromatography, letter here do not refer in particular to the meaning of certain some organic solvent, and letter is only to facilitate table is answered
It is clear, the organic solvent in different steps is appeared in for distinguishing these.Above-mentioned organic solvent A is same organic solvent, is had
Solvent A, B or C can be same solvent, can also be not homogeneous solvent.
The present invention also provides a kind of N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines -
Application of the Isosorbide-5-Nitrae-diformamide (I) in preparation treatment human breast carcinoma drug, the preferably described drug is to inhibit human breast cancer cell
The strain active drug of MCF-7.
The present invention also provides a kind of N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazines -
Application of the Isosorbide-5-Nitrae-diformamide (I) in preparation treatment human lung cancer drug, the preferably described drug is to inhibit human lung carcinoma cell line A-
549 active drugs.
N of the present invention1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformazans
Amide (I) has significant inhibiting rate to MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549, can be applied to prepare
The drug of prevention or treatment human breast carcinoma or human lung cancer.
The beneficial effects are mainly reflected as follows: (1) provide it is a kind of it is novel, there is preferable anticancer (especially
Human breast carcinoma and human lung cancer) active tetrazine compound；(2) preparation method of the tetrazine compound is provided, the preparation method
Simply, easily operated, raw material is easy to get and lower production costs, be suitable for it is practical, be expected to be applied to preparation prevention or treatment tumour disease
In the drug of disease.
(4) specific embodiment
The present invention is further described in conjunction with specific embodiments, embodiment below illustrate it is of the invention, rather than
It limit the invention in any way.
3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine (II) prepares reference literature (Rao, G.-W.；Hu,W.-
X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702) method is prepared.
Embodiment 1:N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamides
(I) preparation
The chloroform of 10mL 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- tetrazine (II) and 0.122g (1.0mmol) DMAP's
50mL chloroformic solution drips off rear reaction solution and is warmed to room temperature, and (reaction process uses TLC tracing detection, expansion to back flow reaction within 20 hours
Agent is the petroleum ether and ethyl acetate mixture of volume ratio 1:2), it removes organic solvent under reduced pressure, adds 50mL chloroform, -10
Under the conditions of DEG C magnetic agitation, the 10mL chloroformic solution for containing 1.072g (10.0mmol) meta-aminotoluene is added dropwise, drips off rear reaction solution liter
To room temperature, (reaction process uses TLC tracing detection, and solvent is the petroleum ether and second of volume ratio 1:2 after back flow reaction 60 hours
Acetoacetic ester mixed solution), reaction solution is washed with (50mL × 3), separates organic phase, and after solvent is evaporated off, residue column chromatography takes
Residue after solvent is evaporated off is added 10 milliliters of petroleum ether solvents and is dissolved, and obtains lysate, is then added into lysate
1.0 grams of silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel), after mixing, are evaporated off solvent, obtain dry residue
With the mixture of silica gel, mixture is filled into column, is then elution with the petroleum ether of volume ratio 1:2 and ethyl acetate mixture
Agent, elution, TLC tracing detection (petroleum ether and ethyl acetate mixture that solvent is volume ratio 1:2) are detected according to TLC
The eluent containing compound shown in formula (I) is collected, the eluent of collection is evaporated off solvent, is dried to obtain faint yellow solid product, i.e.,
N1,N4- two tolyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydros -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 24.7%
(with 3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2, the meter of 4,5- tetrazine substances, similarly hereinafter), 190~193 DEG C of fusing point.1H NMR
(500MHz,CDCl3)δ:8.470(s,2H),7.592-7.609(m,4H),7.538-7.568(m,2H),7.478-7.507
(m,4H),7.397(s,2H),7.276-7.304(m,2H),7.215-7.246(m,2H),6.949-6.964(m,2H),
2.357(s,6H).IR(KBr,cm-1)ν:3398,3370,2916,2852,1708,1635,1595,1542,1515,1491,
1454,1345,1295,1246,1171,1114,1067,1030,995,918,883,862,781,758,721,711.
Embodiment 2:N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamides
(I) preparation
The methylene chloride of 100mL 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- tetrazine (II) and 2.373g (30.0mmol) pyridine
80mL dichloromethane solution, drip off rear reaction solution and be warmed to room temperature, (reaction process is using TLC tracking inspection for back flow reaction 0.5 hour
Survey, solvent is the petroleum ether and ethyl acetate mixture of volume ratio 20:1), it removes organic solvent under reduced pressure, adds 100mL
Under the conditions of 12 DEG C of magnetic agitations, the 80mL dichloromethane solution for containing 8.572g (80.0mmol) meta-aminotoluene is added dropwise in methylene chloride,
It drips off rear reaction solution to be warmed to room temperature, (reaction process uses TLC tracing detection, and solvent is volume ratio after back flow reaction 1 hour
The petroleum ether and ethyl acetate mixture of 20:1), reaction solution is washed with (50mL × 3), organic phase is separated, after solvent is evaporated off,
Residue column chromatography takes the residue after solvent is evaporated off that 10 milliliters of dichloromethane solvents are added and is dissolved, obtains 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, are evaporated off molten
Agent, obtains the mixture of dry residue and silica gel, mixture is filled column, then with the petroleum ether of volume ratio 20:1 and acetic acid second
Ester mixed solution is eluant, eluent, elution, the TLC tracing detection (petroleum ether and ethyl acetate mixing that solvent is volume ratio 20:1
Solution), the eluent containing compound shown in formula (I) is collected according to TLC detection, the eluent of collection is evaporated off solvent, is dried to obtain
Faint yellow solid product, i.e. N1,N4- two two formyls of tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4-
Amine (I), yield 38.4%, 190~193 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3:N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamides
(I) preparation
The toluene of 40mL 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- tetrazine (II) and 1.012g (10.0mmol) triethylamine
20mL toluene solution, drip off rear reaction solution and be warmed to room temperature, (reaction process uses TLC tracing detection, exhibition for back flow reaction 4 hours
Open the petroleum ether and ethyl acetate mixture that agent is volume ratio 10:1), it removes organic solvent under reduced pressure, adds 40mL toluene, 0
Under the conditions of DEG C magnetic agitation, the 20mL toluene solution for containing 2.143g (20.0mmol) meta-aminotoluene is added dropwise, drips off rear reaction solution liter
To room temperature, after back flow reaction 30 hours (reaction process uses TLC tracing detection, petroleum ether that solvent is volume ratio 10:1 and
Ethyl acetate mixture), reaction solution is washed with (50mL × 3), organic phase is separated, after solvent is evaporated off, residue column chromatography, i.e.,
It takes the residue after solvent is evaporated off that 10 milliliters of ethyl acetate solvents are added to be dissolved, lysate is obtained, then into lysate
1.0 grams of silica gel (300~400 mesh gross porosity (zcx.II) type column chromatography silica gel) is added, after mixing, solvent is evaporated off, obtains dry residual
Mixture is filled column by the mixture for staying object and silica gel, is then with the petroleum ether and ethyl acetate mixture of volume ratio 10:1
Eluant, eluent, elution, TLC tracing detection (petroleum ether and ethyl acetate mixture that solvent is volume ratio 10:1), according to TLC
The eluent containing compound shown in formula (I) is collected in detection, and solvent is evaporated off in the eluent of collection, is dried to obtain faint yellow solid production
Object, i.e. N1,N4- two tolyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydros -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield
22.1%, 190~193 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4:N1,N4- two tolyl -3,6- diphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamides
(I) preparation
The toluene of 20mL 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- tetrazine (II) and 0.200g (5.0mmol) sodium hydroxide
40mL toluene solution, drip off rear reaction solution and be warmed to room temperature, (reaction process uses TLC tracing detection, exhibition for back flow reaction 12 hours
Open the petroleum ether and ethyl acetate mixture that agent is volume ratio 5:1), it removes organic solvent under reduced pressure, adds 40mL chloroform, 0
Under the conditions of DEG C magnetic agitation, the 40mL chloroformic solution for containing 4.286g (40.0mmol) meta-aminotoluene is added dropwise, drips off rear reaction solution liter
To room temperature, (reaction process uses TLC tracing detection, and solvent is the petroleum ether and second of volume ratio 5:1 after back flow reaction 20 hours
Acetoacetic ester mixed solution), reaction solution is washed with (50mL × 3), separates organic phase, and after solvent is evaporated off, residue column chromatography takes
Residue after solvent is evaporated off is added 10 milliliters of chloroform solvents and is dissolved, and obtains 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
Mixture is filled column by the mixture of glue, then using the petroleum ether of volume ratio 5:1 and ethyl acetate mixture as eluant, eluent, is washed
De-, TLC tracing detection (petroleum ether and ethyl acetate mixture that solvent is volume ratio 5:1) is collected according to TLC detection and is 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. N1,N4- two
Between tolyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 18.8%, fusing point 190
~193 DEG C.1H NMR and IR is the same as embodiment 1.
Embodiment 5: anticancer activity testing in vitro
(1) compound made from embodiment 1 (I) MCF-7 cell strainHJ2mm and human lung carcinoma cell line A- have been subjected to
549 biological activity tests.Compound (I) has MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 as the result is shown
Preferable anticancer activity.
Test method: tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reduction method.
Cell strain: MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549.Above-mentioned tumor cell line is purchased from China
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, every 1mg is dissolved with 40 μ L DMSO, takes 2 μ L with 1000 μ L cell culture
Base dilution, makes 50 μ g/mL of concentration, then with cell culture medium serial dilution to using 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 chain in every 1000mL culture medium (RPMI-1640)
Mycin, 10% inactivated fetal bovine serum.
B) culture of cell: by tumor cell inoculation in cell culture medium, 37 DEG C are set, 5%CO2It is cultivated in incubator, 3
~5d passage.
C) inhibiting effect of the measurement sample to growth of tumour cell
Cell EDTA- pancreatin digestive juice is digested, and with cell culture medium at 1 × 106It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, every 100 μ L of hole sets 37 DEG C, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, sample (sample final concentration is added
Respectively 50 μ g/mL, 5 μ g/mL, 0.5 μ g/mL), every 100 μ L of hole, 3 multiple holes set 37 DEG C, 5%CO2It is cultivated in incubator,
MTT, the every 10 μ L of hole of 5mg/mL is added after 72h in cell culture well, sets 37 DEG C of incubation 3h, DMSO, every 150 μ L of hole is added,
Vibrated with oscillator, Shi formazan is completely dissolved, with microplate reader under 570nm wavelength colorimetric.It is used with similarity condition and is free of sample, contained
The cell of the cell culture medium culture of same concentration DMSO calculates sample to the IC of growth of tumour cell as control50.Test
The results are shown in Table 1:
The inhibiting effect that 1 compound of table (I) grows cell strain MCF-7 and A-549
(2) referring to embodiment 1, benzene is substituted with methylamine, o-toluidine, 3,4- dimethylaniline, methylphenylamine respectively
Amine has synthesized compound N1,N4Dimethyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (III),
N1,N4Di-o-tolyl -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (IV), N1,N4- two (3,
4- xylyl) -3,6- diphenyl-Isosorbide-5-Nitrae-dihydro -1,2,4,5- tetrazines-Isosorbide-5-Nitrae-diformamide (V), N1,N4Dimethyl-N1,
N4, 3,6- tetraphenyl -1,4- dihydro -1,2,4,5- tetrazine -1,4- diformamide (VI).
Further according to the above method, compound obtained (III), (IV), (V) and (VI) Breast cancer lines have been subjected to
MCF-7 and human lung cancer cell lines A-549 biological activity test, test result show that compound (III), (IV), (V) and (VI) is right
MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 inhibitory effect are unobvious, compound (III), (IV), (V) and
(VI) compound (I) can not show a candle to the anticancer activity of MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549.Specific knot
Fruit is as shown in table 2:
The inhibiting effect that 2 compound of table (III), (IV), (V) and (VI) grows MCF-7 and A-549 cell
The experiment of above-mentioned anticancer activity testing in vitro shows: the similar compound (III) of other 4 structures, (IV), (V) and
(VI) unobvious to the inhibiting effect of MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 growth.Compound (I)
The inhibiting effect grown to MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 is significant, hence it is evident that is better than compound
(III), (IV), (V) and (VI).
Claims (8)
1. two tolyl tetrazine diformamide compounds shown in a kind of formula (I),
2. the preparation method of two tolyl tetrazine diformamide compounds described in a kind of claim 1, it is characterised in that described
Method are as follows: 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 basic catalyst drips off rear reaction solution and is warmed to room temperature, and after back flow reaction 0.5~20 hour, removes under reduced pressure
Organic solvent, adds organic solvent B, and under -10~12 DEG C of stirring conditions, the organic solvent B solution containing meta-aminotoluene, drop is added dropwise
Reaction solution is warmed to room temperature after complete, and after back flow reaction 1~60 hour, reaction solution is isolated and purified to obtain two first shown in formula (I)
Phenyl tetrazine diformamide compound；The basic catalyst is one of following: triethylamine, 4-dimethylaminopyridine, pyridine or
Sodium hydroxide；Compound shown in the formula (II) is with the ratio between basic catalyst, triphosgene, the amount for the substance that feeds intake of meta-aminotoluene
1 ﹕, 0.1~3 ﹕, 0.1~3 ﹕ 1~8；The organic solvent A is one of following: methylene chloride, chloroform or toluene；The organic solvent
B is one of following: methylene chloride, chloroform or toluene；
3. the preparation method of two tolyls tetrazine diformamide compound as claimed in claim 2, it is characterised in that described anti-
Answer the method that liquid isolates and purifies are as follows: after reaction, reaction solution is washed, separates organic phase, after solvent is evaporated off, residue column layer
Analysis obtains two tolyl tetrazine diformamide compounds shown in formula (I).
4. the preparation method of two tolyls tetrazine diformamide compound as claimed in claim 3, it is characterised in that the column
Chromatography method are as follows: take the organic solvent C of the residue after solvent is evaporated off to dissolve, obtain lysate, be then added into lysate
The column chromatography silica gel of 1~2 times of residue quality amount, after mixing, is evaporated off solvent, obtains the mixture of dry residue and silica gel,
By mixture fill column loading, then using volume ratio be 0.5~20:1 petroleum ether and ethyl acetate mixture as eluant, eluent into
Row elution, TLC tracing detection, solvent is the petroleum ether and ethyl acetate mixture of 0.5~20:1 of volume ratio, according to TLC
The eluent containing compound shown in formula (I) is collected in detection, and eluent is concentrated and dried, and obtains two tolyls four shown in formula (I)
Piperazine diformamide compound；The organic solvent C is one of following: petroleum ether, methylene chloride, chloroform or ethyl acetate.
5. two tolyl tetrazine diformamide compounds described in a kind of claim 1 are in preparation treatment human breast carcinoma drug
Using.
6. application as claimed in claim 5, it is characterised in that the drug is to inhibit MCF-7 cell strainHJ2mm active
Drug.
7. a kind of the answering in preparation treatment human lung cancer drug of two tolyl tetrazine diformamide compounds described in claim 1
With.
8. the use as claimed in claim 7, it is characterised in that the drug is to inhibit the active medicine of human lung cancer cell lines A-549
Object.
Priority Applications (1)
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| CN115286589B (en) * | 2022-07-25 | 2024-04-09 | 浙江工业大学 | Cinnamoyl tetrazine compound, and preparation and application thereof |
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