CN104098523B - 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application - Google Patents

1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application Download PDF

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CN104098523B
CN104098523B CN201410198215.9A CN201410198215A CN104098523B CN 104098523 B CN104098523 B CN 104098523B CN 201410198215 A CN201410198215 A CN 201410198215A CN 104098523 B CN104098523 B CN 104098523B
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tetrazine
dihydro
phenyl
nitrae
isobutyryl
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CN104098523A (en
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饶国武
倪嘉斌
沈依婷
邹佳琪
李晓敏
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Xuancheng Youdu Technology Service Co Ltd
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Jiang University Of Technology
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/08Six-membered rings

Abstract

The invention discloses 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application, described 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the structure of 2,4,5-tetrazine is suc as formula shown in (I). described 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, the preparation method of 5-tetrazine comprises: by 3-phenyl-1 shown in formula (II), 4-dihydro-1, 2, 4, 5-tetrazine adds in organic solvent A, add again base catalyst, under 0~12 DEG C of condition, drip isobutyric anhydride or isobutyryl chloride, drip off rear room temperature reaction, reactant liquor obtains 1-isobutyryl-3-phenyl-1 shown in formula (I) through separation and purification after completion of the reaction, 4-dihydro-1, 2, 4, 5-tetrazine, described base catalyst is one of following: triethylamine, N, accelerine, NaOH, or potassium hydroxide. the present invention also provides described 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the application of 2,4,5-tetrazine in preparation prevention or treatment human breast carcinoma or people's lung-cancer medicament.

Description

1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application
(1) technical field
The present invention relates to 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation method thereof, Yi JisuoState the application of compound in the medicine of preparation prevention or treatment tumor disease.
(2) background technology
Tetrazine kind compound has many good physical propertys, spectral quality and higher reactivity,Especially the tetrazine derivatives of some special constructions has obvious antiviral activity, antitumor activity, Yi JikeBe used as agricultural chemicals and pesticide. At present existing two kinds (clofentezine and the fluorine mite piperazine) listing of for example agricultural chemicals, medicineAn existing kind (antineoplastic Temozolomide) listing.
1978, bibliographical information 3,6-hexichol alkynyl-six hydrogen-1,2,4,5-tetrazine has antitumor activity and (consultsEremeev,A.V.;Tikhomirova,D.A.;Tyusheva,V.A.;Liepins,F.Khim.Geterotsikl.Soedin, 1978,753), this is that 1,2,4,5-tetrazine kind compound is in the news first and may has potential antitumor workProperty. Afterwards, reported successively some 1,2,4,5-tetrazine kind compound has antitumor activity, for example, have anti-3 of tumor promotion, two (the 2'-hydroxyl-5'-chlorphenyls)-1,2,4 of 6-, 5-tetrazine (is consulted Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16(14),3702)、N1,N4-bis-(aminomethyl phenyl)-3,6-dimethyl-1,2,4,5-tetrazine-Isosorbide-5-Nitrae-diformamide (is consulted Rao, G.-W.; Guo, Y.-M.; Hu, W.-X.ChemMedChem, 2012,7 (6), 973) etc. Certainly great majority 1,2,4,5-tetrazine kind compound does not have anti-Tumor promotion.
(3) summary of the invention
First object of the present invention is to provide a kind of novel four of anti-human breast cancer and people's lung cancer activity that havePiperazine compound---1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine.
Second object of the present invention is to provide described 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazinePreparation method, this preparation method is easy, easy operating, raw material is easy to get, and production cost is lower, is suitable forIndustrial applications.
The 3rd object of the present invention is to provide described 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazineApplication in preparation prevention or treatment human breast carcinoma or people's lung-cancer medicament.
Below the technical solution adopted in the present invention is illustrated.
The invention provides a kind of novel tetrazine compound, i.e. 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-Tetrazine, it has following structural (I):
The present invention also provides described 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)Method, described preparation method comprises: by 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 shown in formula (II), 2,4,5-tetrazine addsIn organic solvent A, then add base catalyst, under 0~12 DEG C of condition, drip isobutyric anhydride or isobutyryl chloride,Drip off rear room temperature reaction, reactant liquor obtains the 1-isobutyryl-3-shown in formula (I) through separation and purification after completion of the reactionPhenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine, described base catalyst is one of following: triethylamine, N, N-diformazanBase aniline, NaOH or potassium hydroxide;
Preparation 1-isobutyryl-3-of the present invention phenyl-Isosorbide-5-Nitrae-dihydro-1, the reaction of 2,4,5-tetrazine (I) is as followingShown in reaction equation (a), reaction equation (a) does not have bibliographical information:
Further, described 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II) and base catalyst, isobutyric acidThe molar ratio of acid anhydride or isobutyryl chloride is 1 ﹕ 0.1~3 ﹕ 1~4.
Further, described organic solvent A is selected from one of following: carrene, chloroform or toluene. DescribedOrganic solvent A consumption to be can dissolve 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine, base catalyst and isobutyric acidAcid anhydride (or isobutyryl chloride).
Further, with TLC tracking detection, (solvent is the benzinum of volume ratio 0.5~10:1 to course of reactionAnd ethyl acetate mixture), to determine reaction end, the general reaction time was at 0.5~10 hour.
Further, described separation and purification adopts following steps: reactant liquor washes with water, separates organic phase, steamsAfter desolventizing, residue recrystallization or column chromatography obtain the 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro shown in formula (I)-1,2,4,5-tetrazine.
Further, recrystallization solvent is one of following: ethanol, chloroform or acetone.
Further, the operating procedure of described column chromatography is specific as follows: get the residue that steams after desolventizing inIn single port bottle, add organic solvent B to be dissolved, obtain lysate, then residual to adding in lysateThe column chromatography silica gel of 1~2 times of amount of amount, after mixing, steaming desolventizes, and obtains dry residue and silica gelMixture, mixture is filled to post loading, then the benzinum taking volume ratio as 0.5~10:1 and ethyl acetateMixed solution is eluant, eluent, directly carries out wash-out, and TLC follows the tracks of detection, and (solvent is volume ratio 0.5~10:1Benzinum and ethyl acetate mixture), detect and collect containing the compound shown in formula (I) according to TLCEluent, collects liquid concentrate drying, the compound shown in acquisition formula (I); Described organic solvent B be following itOne: ethanol, carrene or ethyl acetate; Described organic solvent B consumption is with can dissolution residual substance.
Organic solvent A of the present invention, organic solvent B, represented all refers to for reaction or column chromatographyOrganic solvent, the letter here does not refer in particular to the implication of certain some organic solvent, letter is just for justAnswer clearly in table, be used for distinguishing these and appear at the organic solvent in different steps.
1-isobutyryl-3-of the present invention phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (I) is thin to human breast carcinomaBorn of the same parents' strain MCF-7 has significant inhibiting rate, and human lung cancer cell lines A-549 is also had to certain inhibiting rate, canBe applied to the medicine of preparation prevention or treatment human breast carcinoma or people's lung cancer.
Beneficial effect of the present invention is mainly reflected in: (1) provide a kind of novel, have anticancer preferablyThe tetrazine compound that (especially human breast carcinoma or people's lung cancer) is active; (2) provide this tetrazine compoundPreparation method, this preparation method is simple, easy operating, raw material be easy to get and production cost lower, be suitable for practicality,Be expected to be applied in the medicine of preparation prevention or treatment tumor disease.
(4) detailed description of the invention
The present invention is further described in conjunction with specific embodiments, and following embodiment is that explanation is of the present invention,Instead of limit by any way the present invention.
Embodiment 1:3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (II)
3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II) prepare reference literature (Bohle, M.ScienceofSynthesis, 2004,17,585 and Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702) method prepares by following reaction scheme (b),
In the there-necked flask of 100mL, add the formamidine acetate of 1.030g, 1.25mL benzonitrile, 0.066gSulphur powder and 4mL methyl alcohol, condition of ice bath lower magnetic force stirs, and starts to drip 80% hydrazine hydrate of 2mL-3 DEG C time,2min drips end, and reaction temperature is 0 DEG C, continues magnetic agitation, and yellow solid is separated out recession deicing and bathed,After room temperature reaction 22h, cooling, to filter, washing, is dried to obtain 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II).
Embodiment 2:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With chloroform dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 20mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 1.09g (10.8mmol) triethylamine, condition of ice bath lower magnetic force stirsMix, 12 DEG C start to drip 0.63g (4mmol) isobutyric anhydride, and 2min drips end, and temperature is 9 DEG C,Remove ice bath, after room temperature reaction 4h, (course of reaction adopts TLC to follow the tracks of and detects, the oil that solvent is 1:2Ether and ethyl acetate mixture), reactant liquor is washed with 13mL, separates organic phase, after steaming desolventizes,Residue column chromatography, gets the residue steaming after desolventizing and adds 15 milliliters of alcohol solvents to be dissolved, and obtainsLysate then adds 2.5 grams of silica gel (300~400 order gross porosity (zcx.II) type column chromatography silicon in lysateGlue), after mixing, steaming desolventizes, and obtains dry residue and the mixture of silica gel, and mixture is filled to post,Then taking the benzinum of volume ratio 1:2 and ethyl acetate mixture as eluant, eluent, wash-out, TLC follows the tracks of inspectionSurvey (benzinum that solvent is 1:1 and ethyl acetate mixture), detect and collect containing formula (I) according to TLCThe eluent of shown compound, collects liquid steaming and desolventizes, dry solid product, i.e. the 1-isobutyryl-3-of obtainingPhenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (I), yield 55.5% (with 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine materialAmount meter, lower with), 124~125 DEG C of fusing points.1HNMR(500MHz,CDCl3)δ:1.234(d,6H,J=6.9Hz,CH3),3.330-3.385(m,H,CH),7.037(s,H,NH),7.476-7.511(m,3H),7.546-7.576(m,H),7.682-7.705(m,2H).IR(KBr,cm-1)ν:3321,2977,1661,1466,1443,1407,1360,1090,1032,958,916.
Embodiment 3:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With carrene dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 30mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 0.022g (0.4mmol) potassium hydroxide, condition of ice bath lower magnetic forceStir, 0 DEG C starts to drip 2.41g (15.3mmol) isobutyric anhydride, and 8min drips end, and temperature is 5 DEG C,Remove ice bath, after room temperature reaction 1h, (course of reaction adopts TLC to follow the tracks of and detects, the oil that solvent is 10:1Ether and ethyl acetate mixture), reactant liquor is washed with 20mL, separates organic phase, after steaming desolventizes,Residue adds 15 milliliters of ethanol, agitating heating, and the 5~10min that refluxes, removes by filter insoluble matter while hot,Filtrate is cooling, separates out solid, filters, and is dried and obtains solid product, i.e. 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-bis-Hydrogen-1,2,4,5-tetrazine (I), yield 56.8%, 124~125 DEG C of fusing points.1HNMR and IR are with embodiment 2.
Embodiment 4:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With toluene dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 30mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 1.45g (12mmol) DMA, under condition of ice bathMagnetic agitation, 10 DEG C start to drip 2.53g (16mmol) isobutyric anhydride, and 10min drips end, temperatureBe 8 DEG C, remove ice bath, after room temperature reaction 2h (course of reaction adopts TLC to follow the tracks of and detects, and solvent is 10:1 benzinum and ethyl acetate mixture), reactant liquor is washed with 20mL, separates organic phase, steams except moltenAfter agent, residue adds 15 milliliters of chloroforms, agitating heating, and the 5~10min that refluxes, removes by filter not while hotMolten thing, filtrate is cooling, separates out solid, filters, dry solid product, i.e. the 1-isobutyryl-3-phenyl of obtaining-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (I), yield 50.1%, 124~125 DEG C of fusing points.1HNMR and IR are with realExecute example 2.
Embodiment 5:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With toluene dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 30mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 1.45g (12mmol) DMA, under condition of ice bathMagnetic agitation, 6 DEG C start to drip 1.70g (16mmol) isobutyryl chloride, and 10min drips end, and temperature is4 DEG C, remove ice bath, after room temperature reaction 0.5h, (course of reaction adopts TLC to follow the tracks of and detects, and solvent is 10:1Benzinum and ethyl acetate mixture), reactant liquor is washed with 20mL, separates organic phase, steams except moltenAfter agent, residue adds 15 milliliters of acetone, agitating heating, and the 5~10min that refluxes, removes by filter not while hotMolten thing, filtrate is cooling, separates out solid, filters, dry solid product, i.e. the 1-isobutyryl-3-phenyl of obtaining-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (I), yield 52.4%, 124~125 DEG C of fusing points.1HNMR and IR are with realExecute example 2.
Embodiment 6:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With chloroform dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 20mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 0.016g (0.4mmol) NaOH, condition of ice bath lower magnetic forceStir, 4 DEG C start to drip 0.43g (4mmol) isobutyryl chloride, and 4min drips end, and temperature is 2 DEG C,Remove ice bath, after room temperature reaction 10h, (course of reaction adopts TLC to follow the tracks of and detects, the stone that solvent is 10:1Oil ether and ethyl acetate mixture), reactant liquor is washed with 13mL, separates organic phase, after steaming desolventizes,Residue column chromatography (eluant, eluent is benzinum: ethyl acetate=10:1 (volume ratio)), residue is with 15 millilitersCarrene dissolves, and other operate with embodiment 2, obtain solid product, i.e. 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-Dihydro-1,2,4,5-tetrazine (I), yield 51.8%, 124~125 DEG C of fusing points.1HNMR and IR are with embodiment 2.
Embodiment 7:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With carrene dissolving 0.64g (4mmol) 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 of 30mL, 2,4,5-tetrazine (II),Be transferred in the there-necked flask of 50mL, add 0.40g (4mmol) triethylamine, condition of ice bath lower magnetic force stirs,2 DEG C start to drip 0.43g (4mmol) isobutyryl chloride, and 4min drips end, and temperature is 3 DEG C, removes ice bath,After room temperature reaction 8h, (course of reaction adopts TLC to follow the tracks of and detects, the benzinum that solvent is 6:1 and acetic acidEthyl ester mixed solution), reactant liquor is washed with 20mL, separates organic phase, after steaming desolventizes, residue postChromatography (eluant, eluent is benzinum: ethyl acetate=6:1 (volume ratio)), 15 milliliters of ethyl acetate for residueDissolve, other operate with embodiment 2, obtain solid product, i.e. 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (I), yield 53.6%, 124~125 DEG C of fusing points.1HNMR and IR are with embodiment 2.
Embodiment 8: active anticancer testing in vitro
(1) compound (I) embodiment 2~7 being made has carried out human breast carcinoma and human lung carcinoma cell line biologyActive testing. Result shows that compound (I) has good active anticancer to human breast cancer cell strain MCF-7.
Method of testing: tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reducing process.
Cell line: human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549. Above-mentioned tumor cell linePurchased 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, every 1mg dissolves with 40 μ LDMSO, gets 1000 μ L for 2uLNutrient solution dilution, making concentration is 50 μ g/mL, then uses nutrient solution serial dilution to working concentration.
2) cultivation of cell
A) preparation of culture medium: contain 800,000 unit penicillin, 1.0g streptomysin, 10% in every 1000mL culture mediumInactivated fetal bovine serum.
B) cultivation of cell: tumor cell inoculation, in culture medium, is put to 37 DEG C, 5%CO2In incubator, trainSupport, 3~5d goes down to posterity.
C) inhibitory action of working sample to growth of tumour cell
By EDTA-trypsinization liquid digestion for cell, and be diluted to 1 × 10 with culture medium6/ mL, is added to 96 holesIn Tissue Culture Plate, every hole 100uL, puts 37 DEG C, 5%CO2In incubator, cultivate. After inoculation 24h, addWith the sample of culture medium dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubatorCultivate, add the MTT of 5mg/mL after 72h in cell culture hole, every hole 10 μ L, put 37 DEG C and hatch 3h,Add DMSO, every hole 150 μ L, with oscillator vibration, Shi Jia Za dissolves completely, uses ELIASA at 570nmColorimetric under wavelength. With not containing sample, contain the cell work of the medium culture of same concentration DMSO with similarity conditionFor contrast, the IC of calculation sample to growth of tumour cell50
The result of test is as shown in table 1:
The inhibitory action of table 1 compound (I) to MCF-7 and A-549 growth of cancer cells
(2) according to embodiment 1 and 2, substitute isobutyric anhydride with acetic anhydride, other operate with embodiment 1 He2, synthesize compound 1-acetyl group-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (III). With reference to embodiment 2, withIsosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine is raw material, reacts and has obtained 1-respectively with acetic anhydride, propionic andydride, isobutyric anhydrideAcetyl group-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (IV), 1-propiono-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (V), 1-isobutyrylBase-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (VI). According to said method, by the compound making (III), (IV), (V)(VI) carried out human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549 biological activity test, surveysTest result shows that compound (III), (IV), (V) and (VI) are thin to human breast cancer cell strain MCF-7 and people's lung cancerBorn of the same parents' strain A-549 inhibition is all poor, and compound (III), (IV), (V) and (VI) are to human breast cancer cell strainThe active anticancer of MCF-7 can not show a candle to compound (I). Concrete outcome is as shown in table 2 and table 3:
The inhibitory action of table 2 compound (III) to MCF-7 and A-549 growth of cancer cells
Table 3 compound (IV), (V) and (VI) inhibitory action to MCF-7 and A-549 growth of cancer cells
Above-mentioned active anticancer testing in vitro experiment shows: other 4 similar compounds of structure (III), (IV), (V)(VI) is all not clear to the inhibitory action of human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549 growthAobvious. Compound (I) is remarkable to the inhibitory action of human breast cancer cell strain MCF-7 growth, to human lung carcinoma cellThe inhibitory action of strain A-549 growth is not obvious, but is obviously better than compound (III) and (VI).

Claims (7)

1.1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine, it has following structural (I):
2. 1-isobutyryl-3-as claimed in claim 1 phenyl-Isosorbide-5-Nitrae-dihydro-1, the system of 2,4,5-tetrazinePreparation Method, described preparation method comprises: by 3-phenyl-Isosorbide-5-Nitrae-dihydro-1 shown in formula (II), 2,4,5-tetrazine addsEnter in organic solvent A, then add base catalyst, under 0~12 DEG C of condition, drip isobutyric anhydride or isobutyryl chloride,Drip off rear room temperature reaction, reactant liquor obtains the 1-isobutyryl-3-shown in formula (I) through separation and purification after completion of the reactionPhenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine, described base catalyst is one of following: triethylamine, N, N-diformazanBase aniline, NaOH or potassium hydroxide; It is one of following that described organic solvent A is selected from: carrene,Chloroform or toluene;
3. preparation method as claimed in claim 2, is characterized in that: described 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II) is 1 ﹕ 0.1~3 with the molar ratio of base catalyst, isobutyric anhydride or isobutyryl chloride﹕1~4。
4. preparation method as claimed in claim 2, is characterized in that described separation and purification adopts following stepRapid: reactant liquor washes with water, separate organic phase, after steaming desolventizes, residue recrystallization or column chromatography obtain formula (I)Shown 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine.
5. preparation method as claimed in claim 4, is characterized in that: recrystallization solvent is one of following:Ethanol, chloroform or acetone.
6. preparation method as claimed in claim 4, is characterized in that: the operating procedure of described column chromatographySpecific as follows: to get the residue steaming after desolventizing in single port bottle, add organic solvent B to be dissolved, obtainLysate, then to the column chromatography silica gel that adds 1~2 times of amount of residue quality in lysate, after mixing,Steaming desolventizes, and obtains dry residue and the mixture of silica gel, mixture is filled to post loading, then with volumeBe eluant, eluent than the benzinum and the ethyl acetate mixture that are 0.5~10:1, directly carry out wash-out, TLCFollow the tracks of and detect, detect 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro of collecting containing shown in formula (I) according to TLC-1, the eluent of 2,4,5-tetrazine, collects liquid concentrate drying, the 1-isobutyryl-3-phenyl shown in acquisition formula (I)-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine; Described organic solvent B is one of following: ethanol, carrene or acetic acid secondEster.
7. 1-isobutyryl-3-as claimed in claim 1 phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine is pre-in preparationApplication in the medicine of anti-or treatment human breast carcinoma.
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