CN102558081A - N1, N4-disubstituted phenyl-3, 6-dimethyl-1, 2,4, 5-tetrazine-1, 4-dimethyl amide preparation method - Google Patents
N1, N4-disubstituted phenyl-3, 6-dimethyl-1, 2,4, 5-tetrazine-1, 4-dimethyl amide preparation method Download PDFInfo
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Abstract
The invention discloses a preparation method of N1,N4-duel substitution phenyl group-3, 6-dimethyl-1,2,4,5-tetrazine-1,4-dimethyl amide, which comprises the steps of enabling 3, 6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine, duel (trichloromethyl) carbonic ester and basic catalyst to be added in organic solvent, heating, back-flowing and reacting for 4-12 hours after addition, then cooling to reach 4-6 DEG C, leading in nitrogen, adding solution of the organic solvent of amine, using a 'one-pot method' to backflow and react for 12-72 hours after dropping, removing solvent in an evaporating mode after completion of reaction, and conducting recrystallization or column chromatography on residues to obtain compounds. The preparation method is a novel preparation method for tetrazine compound and has good antitumor activity, and the preparation method is simple and convenient, mild in reaction conditions, easy to control, small in pollution, easy in material obtaining and low in production cost and has good application prospect.
Description
(1) technical field
The present invention relates to a kind of N
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4; 5-tetrazine-1, the preparation method of 4-dicarboxylic acid diamides is particularly with 3; 6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine and two (trichloromethyl) carbonic ethers obtain this compounds with substituted-phenyl amine " one kettle way " reaction again after catalyzed reaction under the basic catalyst effect.
(2) background technology
Tetrazine is one type of four nitrogen 6-membered heterocyclic compound.Tetrazine kind compound has many better physical character, spectral quality and high reaction activity and high; In fields such as liquid crystal material and rocket fuels the potential application prospect is arranged; Especially the tetrazine derivatives of some special constructions has tangible antiviral activity, anti-tumor activity, and can be used as agricultural chemicals and sterilant.For example at present existing two kinds (four mite piperazines and the fluorine mite piperazine) listing of agricultural chemicals, an existing kind (antitumour drug TM) listing of medicine.
1,2,4,5-tetrazine structure be know the most at present with the most deep tetrazine compound of research.1978, bibliographical information 3,6-hexichol alkynyl-six hydrogen-1,2,4, the 5-tetrazine has anti-tumor activity and (consults Eremeev, A.V.; Tikhomirova, D.A.; Tyusheva, V.A.; Liepins, F.Khim.Geterotsikl.Soedin, 1978,753), this is 1,2,4, the 5-tetrazine kind compound is in the news first and has the potential anti-tumor activity.Afterwards, reported successively some 3,6-two (2 '-hydroxyl-5 '-chloro-phenyl-)-1,2,4,5-tetrazine, N
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide etc. 1,2,4, the 5-tetrazine kind compound has good antitumor activity and (consults Hu, W.-X.; Rao, G.-W.; Sun, Y.-Q.Bioorg.Med.Chem.Lett.2004,14 (5), 1177.Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702), N for example
1, N
4-two (aminomethyl phenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the 4-diformamide, it has strong restraining effect to people's liver cancer BEL-7402, human breast carcinoma MCF-7 and people's lung cancer A-549.It also has good restraining effect (Lv Yaping, Zhou Yonglie, Hu Weixiao etc., pharmaceutical analysis magazine, 2008,28 (7), 1105 to people's cancer of the stomach AGS, SGC7901 clone and leukemia cell line SHI-1; Zhou Yonglie, Lv Yaping, Hu Weixiao etc., Chinese experimental hematology magazine, 2007,15 (3), 483).
Existing N
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1; The preparation method of 4-dicarboxylic acid diamides mainly is through 3,6-dimethyl--1,6-dihydro-1,2; 4, and 5-tetrazine and this compounds of substituted benzene isocyanic ester catalyzed reaction acquisition (Hu Weixiao, Zhou Mao etc., ZL98121915.2).One of this method raw material is the substituted benzene isocyanic ester, and reaction conditions is harsh, pollutes greatlyyer, and cost of material is higher.Therefore be necessary to study new preparation method.
(3) summary of the invention
The object of the present invention is to provide a kind of N with antitumour activity
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4; 5-tetrazine-1, the novel preparation method of 4-dicarboxylic acid diamides, it is a kind of reasonable to design; The preparation method is easy, and reaction conditions is gentle, easy handling; Pollute few, raw material be easy to get and production cost lower, have the preparation method of the tetrazine kind compound of better popularizing application prospect.
For realizing the object of the invention, the technical scheme that the present invention adopts is following:
N shown in a kind of preparation formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1; The preparation method of 4-dicarboxylic acid diamides, said preparation method carries out as follows: under-10～0 ℃ of condition, with 3 shown in the formula (II), 6-dimethyl--1; 6-dihydro-1,2,4,5-tetrazine, two (trichloromethyl) carbonic ether (TRIPHOSGENE 99.5; BTC), basic catalyst adds in the organic solvent A, after adding, heating reflux reaction 4～12 hours cools to about 5 ℃ then; Normally cool to 4～6 ℃, lead to nitrogen, drip the solution of the organic solvent B of the amine shown in the formula (III) again, after dripping off; " one kettle way " back flow reaction 12～72 hours, reaction finishes, and after steaming desolventizes, residue recrystallization or column chromatography is obtained the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1, the 4-dicarboxylic acid diamides, the R in the described formula (I) is identical with R structure in the formula (III), and R is a substituted-phenyl
X wherein, Y independently are a kind of in hydrogen, methyl, methoxyl group, Cl, trifluoromethyl, nitro, group-4 ethyl formate or the dimethylamino separately; Described basic catalyst is one of following: pyridine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine or 4-pyrrolidyl pyridine;
Preparing method's according to the invention reaction is shown in following reaction formula (1), and reaction formula (1) is that bibliographical information is not arranged.
Of the present invention 3,6-dimethyl--1,6-dihydro-1; 2,4, the feed intake ratio of amount of substance of 5-tetrazine (II) and the amine shown in two (trichloromethyl) carbonic ethers (BTC), basic catalyst, the formula (III) is 1: 0.67～2: 0.1～1: 2～6; The TV consumption of said organic solvent A and organic solvent B is with shown in the formula (II) 3,6-dimethyl--1,6-dihydro-1; 2,4,5-tetrazine quality is counted 13～75ml/g.
The present invention reacts used organic solvent A and organic solvent B and independently is selected from one of following separately: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or THF.
Concrete, preparation method of the present invention recommends to carry out as follows: with shown in organic solvent A 1 dissolution type (II) 3, and 6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine and basic catalyst obtain containing 3,6-dimethyl--1,6-dihydro-1,2; 4, the solution of 5-tetrazine and basic catalyst places reactor drum with two (trichloromethyl) carbonic ethers with organic solvent A 2 ,-10～0 ℃ of stirring down, slowly drips and describedly contains 3; 6-dimethyl--1,6-dihydro-1,2,4, the solution of 5-tetrazine and basic catalyst; Reinforced finishing, reflux 4～12 hours, TLC follows the tracks of detection, and reaction cools to reaction solution about 5 ℃ after finishing, and normally drops to 4～6 ℃; Logical nitrogen drips the solution that amine shown in the formula (III) is dissolved in organic solvent B again, after dripping off, and reflux 12～72 hours; TLC follows the tracks of detection, and reaction finishes, and reaction solution obtains the N shown in the formula (I) with residue recrystallization or column chromatography after steaming and desolventizing
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2; 4; 5-tetrazine-1, the 4-dicarboxylic acid diamides, described organic solvent A 1 is identical organic solvent with organic solvent A 2; Organic solvent B and organic solvent A 1 are identical or different organic solvent, said organic solvent A 1 and with organic solvent A 2 unified be selected from one of following: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or THF; It is one of following that organic solvent B is selected from: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or THF; The TV consumption of said organic solvent A 1 and A2 is with shown in the formula (II) 3,6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine quality is counted 10～50ml/g, and the consumption of said organic solvent A 1 is can dissolve 3,6-dimethyl--1; 6-dihydro-1,2,4,5-tetrazine and basic catalyst get final product; The volumetric usage of said organic solvent B is with shown in the formula (II) 3,6-dimethyl--1, and 6-dihydro-1,2,4,5-tetrazine quality is counted 3～25ml/g.
Residue recrystallization described in the method for the present invention is to carry out as follows: get the residue that steams after desolventizing in reaction flask, add recrystallization solvent, stirring heating; Refluxed 5～10 minutes, filtered while hot is removed insolubles, the filtrating cooling; Separate out solid or crystal; Filter, the filter cake oven dry obtains the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides, said recrystallization solvent are one of following: methyl alcohol, ethanol, sherwood oil, methylene dichloride, chloroform or THF.
Residue column chromatography described in the method for the present invention carries out as follows: get the residue that steams after desolventizing in the single port bottle, add organic solvent C it is dissolved, obtain lysate; In lysate, add the column chromatography silica gel of 1.5～2 times of amounts of residue quality then, behind the mixing, steaming desolventizes; The mixture of exsiccant residue and silica gel, mixture is adorned post, be that 0.5～10: 1 sherwood oil and ethyl acetate mixture are eluent with volume ratio then; Directly carry out wash-out, TLC follows the tracks of detection, detects according to TLC and collects the elutriant that contains the compound shown in the formula (I); Elutriant is dry, the N shown in the acquisition formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides; Said organic solvent C is one of following: methyl alcohol, ethanol, methylene dichloride, chloroform or THF.
Organic solvent A of the present invention (organic solvent A 1 and organic solvent A 2), organic solvent B; The represented organic solvent that is used to react that all is meant; The letter does not here refer in particular to the implication of certain some organic solvent; Letter is just answered clear for the ease of table, be used for distinguishing these organic solvents and appear in the different reactions step.
N shown in the formula of the present invention (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1, the R in the 4-dicarboxylic acid diamides are substituted-phenyl
X wherein, Y independently are a kind of in hydrogen, methyl, methoxyl group, Cl, trifluoromethyl, nitro, group-4 ethyl formate or the dimethylamino separately; Further, the N shown in the formula of the present invention (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1, the 4-dicarboxylic acid diamides is preferably one of compound of structure:
That the inventive method is prepared is one type of preparation method with the active tetrazine kind compound of good anticancer, and document (is consulted Hu, W.-X.; Rao, G.-W.; Sun, Y.-Q.Bioorg.Med.Chem.Lett.2004,14 (5), 1177.) reported the N shown in the formula (I-1) to (I-11)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1, the 4-dicarboxylic acid diamides has than strong inhibitory activity A-549 human lung carcinoma cell or P-388 mouse leukemia cell, for example the N shown in the formula (I-2)
1, N
4-two (aminomethyl phenyl)-3; 6-dimethyl--1,2,4; 5-tetrazine-1; The 4-diformamide, its IC50 to people's liver cancer BEL-7402, human breast carcinoma MCF-7, people's lung cancer A-549 and mouse leukemia cell P-388 is respectively 0.6 μ M, 0.5 μ M, 0.7 μ M, 0.6 μ M, and strong restraining effect is promptly arranged.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: (1) the invention provides a kind of novel preparation method with tetrazine kind compound of good antitumour activity; (2) compare with original isocyanic ester preparation method, the present invention is reasonable in design, and the preparation method is easy, and reaction conditions is gentle, easy handling, pollute few, raw material be easy to get and production cost lower, be preparation method with tetrazine kind compound of better application prospect.
(4) embodiment
The present invention combines specific embodiment to be further described, and following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
3,6-dimethyl--1,6-dihydro-1,2,4, the preparation reference literature of 5-tetrazine (II) (Hu Weixiao, Zhou Mao, Cai Zhibin, Yang Zhongyu, method ZL98121915.2) prepares.
Embodiment 1:N
1, N
4-phenylbenzene-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-1)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine (II) and 2.16 gram (17.8mmol) N, the N-xylidene(s) is dissolved in 50 milliliters of dichloromethane solutions processes preparation solution; Add 20 milliliters of two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and methylene dichloride in 250 milliliters of there-necked flasks successively, stir down, slowly drip preparation solution at 0 ℃; After adding in the 10min, TLC follows the tracks of detection, back flow reaction 4 hours.Be cooled to 5 ℃ then, logical nitrogen drips 6.64 gram (71.3mmol) aniline again and is dissolved in the solution that 20 milliliters of methylene dichloride obtain.After dripping off, TLC follows the tracks of detection, and reflux 12 hours steams reaction solution except that methylene dichloride; The residue column chromatography is about to residue and with 20 ml methanol it is dissolved, and obtains lysate, in lysate, adds 2.50 gram column chromatography silica gels (300～400 order gross porosity (zcx.II) type column chromatography silica gel) then; Behind the mixing, steaming desolventizes, and gets the mixture of exsiccant residue and silica gel, and mixture is adorned post; Be that 1: 1 sherwood oil and ethyl acetate mixture is eluent with volume ratio then, wash-out, TLC follows the tracks of detection, detects according to TLC and collects the elutriant that contains the compound shown in the formula (I-1); Elutriant is dry, obtains white crystal 1.21 gram, i.e. N
1, N
4-phenylbenzene-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-1), yield (with formula (II) 3,6-dimethyl--1,6-dihydro-1,2,4,5-tetrazine amount of substance meter, down together) 19.4%, 183～184 ℃ of fusing points.
1H?NMR(CDCl
3)δ：2.49(s，6H，CH
3)，7.05-7.55(m，10H，C
6H
5)，8.46(s，2H，NH)。
Embodiment 2:N
1, N
4-two (tolyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-2)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2,4,5-tetrazine (II) and 0.98 gram (12.4mmol) pyridine are dissolved in the 10 ml methanol solution processes preparation solution; Add 10 milliliters of two (trichloromethyl) carbonic ether 3.54 grams (11.9mmol) and methyl alcohol in 50 milliliters of there-necked flasks successively, stir down, slowly drip preparation solution at-5 ℃; After 10min added, TLC followed the tracks of detection, back flow reaction 10 hours.Be cooled to 6 ℃ then, logical nitrogen, Dropwise 5 .73 gram (53.5mmol) meta-aminotoluene is dissolved in the solution that 6 milliliters of ethanol obtain again.After dripping off, TLC follows the tracks of detection, reflux 66 hours; Steam and remove methyl alcohol and ethanol, (eluent is a sherwood oil: ETHYLE ACETATE=1: 2 (volume ratio)), residue is with 20 milliliters of dissolve with ethanol for the residue column chromatography; Other operations obtain white solid 0.62 gram, i.e. N with embodiment 1
1, N
4-two (tolyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-2), yield 9.1%, 138～139 ℃ of fusing points.
1H?NMR(CDCl
3)δ：2.349(s，6H，m-CH
3)，2.472(s，6H，CH
3)，6.918-7.350(m，8H，C
6H
4)，8.414(br，2H，NH)。
Embodiment 3:N
1, N
4-two (m-methoxyphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-3)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 0.91 gram (7.4mmol) 4-Dimethylamino pyridine are dissolved in 40 milliliters of chloroformic solutions processes preparation solution, adds 20 milliliters of two (trichloromethyl) carbonic ether 4.30 grams (14.5mmol) and chloroforms in 100 milliliters of there-necked flasks successively; Stir down at-10 ℃, slowly drip preparation solution.After 40min added, TLC followed the tracks of detection, back flow reaction 8 hours, and reaction is cooled to 6 ℃ with reaction solution after finishing, and logical nitrogen drips 4.39 gram (35.6mmol) m-anisidines again and is dissolved in the solution that 10 milliliters of chloroforms obtain.After dripping off, TLC follows the tracks of detection, and reflux 54 hours is steamed and removed chloroform, and residue adds 20 milliliters of ethyl alcohol recrystallization solvents; Stirring heating, the 5～10min that refluxes, filtered while hot is removed insolubles, the filtrating cooling; Filter, filtration cakes torrefaction obtains white solid 1.19 gram, i.e. N
1, N
4-two (m-methoxyphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-3), yield 16.2%, 136～137 ℃ of fusing points.
1H?NMR(CDCl
3)δ：2.46(s，6H，CH
3)，3.79(s，6H，OCH
3)，6.59-7.22(m，8H，C
6H
4)，8.44(s，2H，NH)。
Embodiment 4:N
1, N
4-two (chloro-phenyl-)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-4)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.75 gram (13.5mmol) quinoline are dissolved in 40 milliliters of tetrahydrofuran solutions processes preparation solution, adds 30 milliliters of two (trichloromethyl) carbonic ether 9.06 grams (30.5mmol) and THFs in 250 milliliters of there-necked flasks successively; Stir down at-8 ℃, slowly drip preparation solution.After 30min added, TLC followed the tracks of detection, back flow reaction 12 hours.Be cooled to 4 ℃ then, logical nitrogen drips 11.34 gram (88.9mmol) m-chloro anilines again and is dissolved in the solution that 30 milliliters of chloroforms obtain.After dripping off, TLC follows the tracks of detection, and reflux 42 hours is steamed and removed THF and chloroform, and residue is with 20 ml methanol recrystallizations, and other are operated with embodiment 3, obtains white solid 1.39 gram, i.e. N
1, N
4-two (chloro-phenyl-)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-4), yield 18.6%, 210～211 ℃ of fusing points.
1HNMR(CDCl
3)δ：2.44(s，6H，CH
3)，7.08-8.07(m，8H，C
6H
4)，9.28(s，2H，NH)。
Embodiment 5:N
1, N
4-two (3, the 5-Dimethoxyphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-5)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.29 gram (10.0mmol) quinoline are dissolved in 50 milliliters of dichloromethane solutions processes preparation solution, adds 30 milliliters of two (trichloromethyl) carbonic ether 5.48 grams (18.5mmol) and methylene dichloride in 250 milliliters of there-necked flasks successively; Stir down at-6 ℃, slowly drip preparation solution.After 50min added, TLC followed the tracks of detection, back flow reaction 10 hours.Be cooled to 4 ℃ then, logical nitrogen drips 16.37 gram (106.9mmol) 3 again, and the 5-dimethoxyaniline is dissolved in the solution that 40 milliliters of THFs obtain.After dripping off, TLC follows the tracks of detection, and reflux 38 hours stops to reflux, and steams and removes methylene dichloride and THF, and residue is with 20 milliliters of chloroform recrystallizations, and other are operated with embodiment 3, obtains white solid 1.76 gram, i.e. N
1, N
4-two (3, the 5-Dimethoxyphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-5), yield 21.0%, 230～231 ℃ of fusing points.
Embodiment 6:N
1, N
4-two (3, the 5-dichlorophenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-6)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.39 gram pyridines (17.8mmol) are dissolved in 20 milliliters of toluene solutions processes preparation solution, adds 10 milliliters of two (trichloromethyl) carbonic ether 8.16 grams (27.5mmol) and toluene in 100 milliliters of there-necked flasks successively; Stir down at-4 ℃, slowly drip preparation solution.After 20min added, TLC followed the tracks of detection, back flow reaction 10 hours.Be cooled to 4 ℃ then, logical nitrogen drips 7.23 gram (44.6mmol) 3 again, and the 5-dichlorphenamide bulk powder is dissolved in the solution that 20 milliliters of toluene obtain.After dripping off, TLC follows the tracks of detection, and reflux 28 hours is steamed and removed toluene, and residue is with 20 milliliters of methylene dichloride recrystallizations, and other are operated with embodiment 3, obtains white solid 1.35 gram, i.e. N
1, N
4-two (3, the 5-dichlorophenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-6), yield 15.5%, 235～237 ℃ of fusing points.
Embodiment 7:N
1, N
4-two (3, the 5-xylyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-7)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 0.27 gram (1.8mmol) 4-pyrrolidyl pyridine are dissolved in 20 milliliters of tetrahydrofuran solutions processes preparation solution, adds 20 milliliters of two (trichloromethyl) carbonic ether 7.24 grams (24.4mmol) and THFs in 100 milliliters of there-necked flasks successively; Stir down at-2 ℃, slowly drip preparation solution.After 20min added, TLC followed the tracks of detection, back flow reaction 11 hours.Be cooled to 6 ℃ then, logical nitrogen drips 7.56 gram (62.39mmol) 3 again, and the 5-xylidene(s) is dissolved in the solution that 20 milliliters of THFs obtain.After dripping off, TLC follows the tracks of detection, and reflux 72 hours is steamed and removed THF, and residue is with 20 milliliters of sherwood oil recrystallizations, and other are operated with embodiment 3, obtains white solid 0.83 gram, i.e. N
1, N
4-two (3, the 5-xylyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-7), yield 11.4%, 236～237 ℃ of fusing points.
Embodiment 8:N
1, N
4-two (m-trifluoromethylphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-8)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.60 gram (10.8mmol) 4-pyrrolidyl pyridines are dissolved in 80 milliliters of ethanolic solns processes preparation solution, adds 20 milliliters of two (trichloromethyl) carbonic ether 8.00 grams (27.0mmol) and ethanol in 250 milliliters of there-necked flasks successively; Stir down at 0 ℃, slowly drip preparation solution.After 80min adds, back flow reaction 6 hours.Be cooled to 5 ℃ then, logical nitrogen, Dropwise 5 .75 gram (35.7mmol) m-trifluoromethyl aniline is dissolved in the solution that 40 milliliters of ethanol obtain again.After dripping off, reflux 19 hours is steamed and is removed ethanol, and residue is with 20 milliliters of THF recrystallizations, and other are operated with embodiment 3, obtains white solid 0.88 gram, i.e. N
1, N
4-two (m-trifluoromethylphenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-8), yield 10.1%, 204～206 ℃ of fusing points.
Embodiment 9:N
1, N
4-two (m-nitro bases)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-9)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 0.18 gram (1.78mmol) triethylamine are dissolved in 50 milliliters of toluene solutions processes preparation solution, adds 50 milliliters of two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and toluene in 250 milliliters of there-necked flasks successively; Stir down at-10 ℃, slowly drip preparation solution.After 70min adds, back flow reaction 12 hours.Be cooled to 5 ℃ then, logical nitrogen drips 7.39 gram (53.5mmol) m-nitranilines again and is dissolved in the solution that 50 milliliters of toluene obtain.After dripping off, reflux 12 hours is steamed and is removed toluene, and (eluent is a sherwood oil: ETHYLE ACETATE=10: 1 (volume ratio)), residue dissolves with 20 milliliters of methylene dichloride the residue column chromatography, and other are operated with embodiment 1, obtains white solid 1.72 gram, i.e. N
1, N
4-two (m-nitro bases)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-9), yield 21.9%, 254～255 ℃ of fusing points.
Embodiment 10:N
1, N
4-two (ethyl benzoates-3-yl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-10)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.8 gram (17.8mmol) triethylamines are dissolved in 50 milliliters of toluene solutions processes preparation solution, adds 50 milliliters of two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and toluene in 250 milliliters of there-necked flasks successively; Stir down at 0 ℃, slowly drip preparation solution.After 60min adds, back flow reaction 4 hours.Be cooled to 5 ℃ then, logical nitrogen, Dropwise 5 .88 gram (35.6mmol) gavaculine ethyl ester is dissolved in the solution that 50 milliliters of toluene obtain again.After dripping off, reflux 22 hours is steamed and is removed toluene; (eluent is a sherwood oil: ETHYLE ACETATE=6: 1 (volume ratio)), residue is with 20 milliliters of dissolved in chloroform, and other are operated with embodiment 1 for the residue column chromatography; Obtain white solid 1.13 gram, the i.e. N shown in the formula (I-10)
1, N
4-two (ethyl benzoates-3-yl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-10), yield 12.8%, 172～174 ℃ of fusing points.
Embodiment 11:N
1, N
4-two (m-dimethyl amino phenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1, the preparation of 4-diformamide (I-11)
With 2.00 gram (17.8mmol) 3,6-dimethyl--1,6-dihydro-1; 2; 4,5-tetrazine (II) and 1.75 gram (13.5mmol) quinoline are dissolved in 50 milliliters of toluene solutions processes preparation solution, adds 50 milliliters of two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and toluene in 250 milliliters of there-necked flasks successively; Stir down at 0 ℃, slowly drip preparation solution.After 60min adds, back flow reaction 12 hours.Be cooled to 5 ℃ then, logical nitrogen drips 4.86 gram (35.7mmol) m-dimethyl amino aniline again and is dissolved in the solution that 50 milliliters of toluene obtain.After dripping off, reflux 30 hours is steamed and is removed toluene, and (eluent is a sherwood oil: ETHYLE ACETATE=4: 1 (volume ratio)), residue dissolves with 20 milliliters of THFs the residue column chromatography, and other are operated with embodiment 1, obtains white solid 1.92 gram, i.e. N
1, N
4-two (m-dimethyl amino phenyl)-3,6-dimethyl--1,2,4,5-tetrazine-1,4-diformamide (I-11), yield 24.7%, 170～172 ℃ of fusing points.
Claims (8)
1. one kind prepares the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4; 5-tetrazine-1, the preparation method of 4-dicarboxylic acid diamides is characterized in that, said preparation method carries out as follows: under-10～0 ℃ of condition; With 3 shown in the formula (II), 6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine, two (trichloromethyl) carbonic ether, basic catalyst add in the organic solvent A, after adding, and heating reflux reaction 4～12 hours; Cool to 4～6 ℃ then, lead to nitrogen, drip the solution of the organic solvent B of the amine shown in the formula (III) again, after dripping off; " one kettle way " back flow reaction 12～72 hours, reaction finishes, and after steaming desolventizes, residue recrystallization or column chromatography is obtained the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides;
R in the described formula (I) is identical with R structure in the formula (III); R is wherein X of substituted-phenyl
, and Y independently is a kind of in hydrogen, methyl, methoxyl group, Cl, trifluoromethyl, nitro, group-4 ethyl formate or the dimethylamino separately.
2. preparation method as claimed in claim 1 is characterized in that described organic solvent A and organic solvent B independently are selected from a kind of in methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or the THF separately.
3. preparation method as claimed in claim 1, it is characterized in that described 3,6-dimethyl--1,6-dihydro-1; 2,4, the feed intake ratio of amount of substance of 5-tetrazine (II) and the amine shown in two (trichloromethyl) carbonic ethers, basic catalyst, the formula (III) is 1: 0.67～2: 0.1～1: 2～6; The TV consumption of said organic solvent A and organic solvent B is with shown in the formula (II) 3,6-dimethyl--1,6-dihydro-1; 2,4,5-tetrazine quality is counted 13～75ml/g.
4. preparation method as claimed in claim 1 is characterized in that described method is: with shown in organic solvent A 1 dissolution type (II) 3, and 6-dimethyl--1,6-dihydro-1,2; 4,5-tetrazine and basic catalyst obtain containing 3,6-dimethyl--1,6-dihydro-1,2; 4, the solution of 5-tetrazine and basic catalyst places reactor drum with two (trichloromethyl) carbonic ethers with organic solvent A 2 ,-10～0 ℃ of stirring down, slowly drips and describedly contains 3; 6-dimethyl--1,6-dihydro-1,2,4, the solution of 5-tetrazine and basic catalyst; Reinforced finishing, reflux 4～12 hours, TLC follows the tracks of detection, and reaction cools to 4～6 ℃ with reaction solution after finishing; Logical nitrogen drips the solution that amine shown in the formula (III) is dissolved in organic solvent B again, after dripping off, and reflux 12～72 hours; TLC follows the tracks of detection, and reaction finishes, and reaction solution obtains the N shown in the formula (I) with residue recrystallization or column chromatography after steaming and desolventizing
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2; 4; 5-tetrazine-1, the 4-dicarboxylic acid diamides, described organic solvent A 1 is identical organic solvent with organic solvent A 2; Organic solvent B and organic solvent A 1 are identical or different organic solvent, and it is one of following that said organic solvent A 1 and organic solvent B independently are selected from separately: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or THF; The TV consumption of said organic solvent A 1 and A2 is with shown in the formula (II) 3,6-dimethyl--1, and 6-dihydro-1,2,4,5-tetrazine quality is counted 10～50ml/g; The volumetric usage of said organic solvent B is with shown in the formula (II) 3,6-dimethyl--1, and 6-dihydro-1,2,4,5-tetrazine quality is counted 3～25ml/g.
5. like claim 1 or 4 described preparing methods, it is characterized in that described basic catalyst is one of following: pyridine, triethylamine, quinoline, N, N-xylidene(s), 4-Dimethylamino pyridine or 4-pyrrolidyl pyridine.
6. like claim 1 or 4 described preparing methods, it is characterized in that the used solvent of described residue recrystallization is one of following: methyl alcohol, ethanol, sherwood oil, methylene dichloride, chloroform or THF, described recrystallization are to carry out as follows: get the residue that steams after desolventizing in reaction flask; Add recrystallization solvent, stirring heating refluxed 5～10 minutes; Filtered while hot is removed insolubles; Solid or crystal are separated out in the filtrating cooling, filter; The filter cake oven dry obtains the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides.
7. like claim 1 or 4 described methods, it is characterized in that described residue column chromatography carries out as follows: get the residue that steams after desolventizing in the single port bottle, add organic solvent C it is dissolved; Obtain lysate, in lysate, add the column chromatography silica gel of 1.5～2 times of amounts of residue quality then, behind the mixing; Steaming desolventizes, and gets the mixture of exsiccant residue and silica gel, and mixture is adorned post; Be that 0.5～10: 1 sherwood oil and ethyl acetate mixture are eluent with volume ratio then; Directly carry out wash-out, TLC follows the tracks of detection, detects according to TLC and collects the elutriant that contains the compound shown in the formula (I); Elutriant is dry, the N shown in the acquisition formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides; Said organic solvent C is one of following: methyl alcohol, ethanol, methylene dichloride, chloroform or THF.
8. like claim 1 or 4 described preparing methods, it is characterized in that the N shown in the formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1, the R in the 4-dicarboxylic acid diamides are substituted-phenyl
X wherein, Y independently are a kind of in hydrogen, methyl, methoxyl group, Cl, trifluoromethyl, nitro, group-4 ethyl formate or the dimethylamino separately, the N shown in the described formula (I)
1, N
4-di-substituted-phenyl-3,6-dimethyl--1,2,4,5-tetrazine-1,4-dicarboxylic acid diamides are one of following compounds:
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949140A (en) * | 2016-05-06 | 2016-09-21 | 浙江工业大学 | Diphenyl tetrazine dicarboamide compound, preparation and application |
| CN105968064A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(m-methylphenyl) tetrazine dicarboxamide compound as well as preparation and application thereof |
| CN105968063A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(sec-butyl) diphenyl tetrazine dicarboxamide compound as well as preparation and application thereof |
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| CN1223259A (en) * | 1998-09-26 | 1999-07-21 | 杭州民生凯普医药化工有限公司 | Anti-cancer medicine 3,6-dimethyl 1,4-dihydro 1,2,4,5-tetrazine-1,4-dimethyl amides compound and preparation process thereof |
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| CN1223259A (en) * | 1998-09-26 | 1999-07-21 | 杭州民生凯普医药化工有限公司 | Anti-cancer medicine 3,6-dimethyl 1,4-dihydro 1,2,4,5-tetrazine-1,4-dimethyl amides compound and preparation process thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949140A (en) * | 2016-05-06 | 2016-09-21 | 浙江工业大学 | Diphenyl tetrazine dicarboamide compound, preparation and application |
| CN105968064A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(m-methylphenyl) tetrazine dicarboxamide compound as well as preparation and application thereof |
| CN105968063A (en) * | 2016-05-06 | 2016-09-28 | 浙江工业大学 | Bis(sec-butyl) diphenyl tetrazine dicarboxamide compound as well as preparation and application thereof |
| CN105968064B (en) * | 2016-05-06 | 2019-02-01 | 浙江工业大学 | Two tolyl tetrazine diformamide compounds of one kind and preparation and application |
| CN105968063B (en) * | 2016-05-06 | 2019-02-01 | 浙江工业大学 | A kind of di-sec-butyl diphenyl tetrazine diformamide compound and preparation and application |
| CN105949140B (en) * | 2016-05-06 | 2019-05-31 | 浙江工业大学 | A kind of diphenyl tetrazine diformamide compound and preparation and application |
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