CN104098523A - 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof - Google Patents
1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- JFOPWNBZUKGVQT-UHFFFAOYSA-N 2-methyl-1-(6-phenyl-1h-1,2,4,5-tetrazin-2-yl)propan-1-one Chemical compound N1=CN(C(=O)C(C)C)NC(C=2C=CC=CC=2)=N1 JFOPWNBZUKGVQT-UHFFFAOYSA-N 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 16
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 201000005202 lung cancer Diseases 0.000 claims abstract description 12
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 12
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 49
- OVFJHQBWUUTRFT-UHFFFAOYSA-N 1,2,3,4-tetrahydrotetrazine Chemical compound C1=CNNNN1 OVFJHQBWUUTRFT-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 238000010025 steaming Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 201000008275 breast carcinoma Diseases 0.000 claims description 6
- 239000006166 lysate Substances 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 235000014666 liquid concentrate Nutrition 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 claims 1
- 238000001514 detection method Methods 0.000 claims 1
- QMOBTWKKNMWQIX-UHFFFAOYSA-N 3-phenyl-1,4-dihydro-1,2,4,5-tetrazine Chemical compound N1C=NNC(C=2C=CC=CC=2)=N1 QMOBTWKKNMWQIX-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 abstract 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 21
- 239000000243 solution Substances 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000000452 restraining effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000012265 solid product Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- -1 tetrazine compound Chemical class 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000005907 cancer growth Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000005654 Clofentezine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- UXADOQPNKNTIHB-UHFFFAOYSA-N clofentezine Chemical compound ClC1=CC=CC=C1C1=NN=C(C=2C(=CC=CC=2)Cl)N=N1 UXADOQPNKNTIHB-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/08—Six-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof, wherein the structure of the 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine is as shown in formula (I). The preparation method of the 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine is as follows: adding 3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine as shown in formula (II) into an organic solvent A, then adding an alkaline catalyst, dropwise adding isobutyric anhydride or isobutyryl chloride at 0 to 12 DEG C, after addition of the isobutyric anhydride or isobutyryl chloride is completed, reacting at room temperature, after the reaction is completed, separating and purifying the reaction liquid to obtain the 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine as shown in the formula (I). The alkaline catalyst is one of the following substances: triethylamine, N, N-dimethyl aniline, sodium hydroxide or potassium hydroxide. The invention also provides the application of the 1-isobutyryl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine in preparation of drugs for prevention or treatment of human breast cancer or lung cancer.
Description
(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, and the application of described compound in the medicine of preparation prevention or treatment tumor disease.
(2) background technology
Tetrazine kind compound has many good physical propertiess, spectral quality and higher reactive behavior, and especially the tetrazine derivatives of some special constructions has obvious antiviral activity, anti-tumor activity, and can be used as agricultural chemicals and sterilant.For example at present existing two kinds (clofentezine and the fluorine mite piperazine) listing of agricultural chemicals, an existing kind (antitumour drug Temozolomide) listing of medicine.
1978, bibliographical information 3,6-hexichol alkynyl-six hydrogen-1,2,4,5-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 that 1,2,4,5-tetrazine kind compound is in the news first and may has potential anti-tumor activity.Afterwards, reported successively some 1,2,4,5-tetrazine kind compound has anti-tumor activity, for example, have 3 of anti-tumor activity, two (the 2'-hydroxyl-5'-chloro-phenyl-s)-1,2,4 of 6-, 5-tetrazine (is consulted Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702), N
1, N
4-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 activity.
(3) summary of the invention
First object of the present invention is to provide a kind of novel tetrazine compound with anti-human mammary cancer and people's lung cancer activity---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, the preparation method of 2,4,5-tetrazine, and this preparation method is easy, easy handling, raw material is easy to get, and production cost is lower, is suitable for industrial applications.
The 3rd object of the present invention is to provide 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.
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-1, 4-dihydro-1, 2, 4, the preparation method of 5-tetrazine (I), described preparation method comprises: by 3-phenyl-1 shown in formula II, 4-dihydro-1, 2, 4, 5-tetrazine adds in organic solvent A, add again basic catalyst, under 0～12 ℃ of condition, drip isobutyric anhydride or isobutyryl chloride, drip off rear room temperature reaction, reaction solution 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 basic catalyst is one of following: triethylamine, N, accelerine, sodium hydroxide, 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 shown in following reaction formula (a), and reaction formula (a) does not have bibliographical information:
Further, described 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II) is 1 ﹕ 0.1～3 ﹕ 1～4 with the molar ratio of basic catalyst, isobutyric anhydride or isobutyryl chloride.
Further, described organic solvent A is selected from one of following: methylene dichloride, chloroform or toluene.Described organic solvent A consumption to be can dissolve 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine, basic catalyst and isobutyric anhydride (or isobutyryl chloride).
Further, reaction process is followed the tracks of and is detected (developping agent is sherwood oil and the ethyl acetate mixture of volume ratio 0.5～10:1) with TLC, and to determine reaction end, the general reaction times was at 0.5～10 hour.
Further, described separation and purification adopts following steps: reaction solution washes with water, separates organic phase, and after steaming desolventizes, residue recrystallization or column chromatography obtain 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1 shown in formula I, 2,4,5-tetrazine.
Further, recrystallization solvent is one of following: ethanol, chloroform or acetone.
Further, the operation steps of described column chromatography is specific as follows: get the residue that steams after desolventizing in single port bottle, add organic solvent B to be dissolved, obtain lysate, then to the column chromatography silica gel that adds 1～2 times of amount of residue quality in lysate, after mixing, steaming desolventizes, residue that must be dry and the mixture of silica gel, mixture is filled to post loading, then the sherwood oil that the volume ratio of take is 0.5～10:1 and ethyl acetate mixture are eluent, directly carry out wash-out, TLC follows the tracks of and detects (developping agent is sherwood oil and the ethyl acetate mixture of volume ratio 0.5～10:1), according to TLC, detect the elutriant of collecting containing the compound shown in formula I, collect liquid concentrate drying, obtain the compound shown in formula I, described organic solvent B is one of following: ethanol, methylene dichloride 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 referring to for reacting or the organic solvent of column chromatography, the letter here does not 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 and appear at the organic solvent in different steps.
1-isobutyryl-3-of the present invention phenyl-1; 4-dihydro-1; 2; 4; 5-tetrazine (I) has significant inhibiting rate to human breast cancer cell strain MCF-7; human lung cancer cell lines A-549 is also had to certain inhibiting rate, can be applicable 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, there is anticancer (especially human breast carcinoma or people's lung cancer) active tetrazine compound preferably; (2) provide the preparation method of this tetrazine compound, this preparation method is simple, easy handling, 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) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment is that explanation is of the present invention, rather than limits 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.Science ofSynthesis, 2004,17,585 and Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702) method by following reaction scheme (b), prepare,
The FORMAMIDINE ACETATE that adds 1.030g in the there-necked flask of 100mL, 1.25mL cyanobenzene, 0.066g sulphur powder and 4mL methyl alcohol, condition of ice bath lower magnetic force stirs, and starts to drip 80% hydrazine hydrate of 2mL in the time of-3 ℃, and 2min drips end, temperature of reaction is 0 ℃, continues magnetic agitation, and yellow solid is separated out recession deicing and bathed, after room temperature reaction 22h, cooling, 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 the chloroform of 20mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 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 stirs, 12 ℃ start to drip 0.63g (4mmol) isobutyric anhydride, 2min drips end, temperature is 9 ℃, remove ice bath, after room temperature reaction 4h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 1:2), reaction solution is washed with 13mL, separate organic phase, after steaming desolventizes, residue column chromatography, getting the residue steaming after desolventizing adds 15 milliliters of alcohol solvents to be dissolved, obtain lysate, then in lysate, add 2.5 grams of silica gel (300～400 order gross porosity (zcx.II) type column chromatography silica gel), after mixing, steaming desolventizes, residue that must be dry and the mixture of silica gel, mixture is filled to post, then sherwood oil and the ethyl acetate mixture of volume ratio 1:2 of take is eluent, wash-out, TLC follows the tracks of and detects (sherwood oil that developping agent is 1:1 and ethyl acetate mixture), according to TLC, detect the elutriant of collecting containing the compound shown in formula I, collecting liquid steaming desolventizes, the dry solid product that obtains, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 55.5% is (with 3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine amount of substance meter, lower same), 124～125 ℃ of fusing points.
1H?NMR(500MHz,CDCl
3)δ:1.234(d,6H,J＝6.9Hz,CH
3),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 the methylene dichloride of 30mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 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 force stirs, 0 ℃ starts to drip 2.41g (15.3mmol) isobutyric anhydride, 8min drips end, temperature is 5 ℃, remove ice bath, after room temperature reaction 1h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 10:1), reaction solution is washed with 20mL, separate organic phase, after steaming desolventizes, residue adds 15 milliliters of ethanol, stirring heating, 5～10min refluxes, filtered while hot is removed insolubles, filtrate is cooling, separate out solid, filter, the dry solid product that obtains, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 56.8%, 124～125 ℃ of fusing points.
1h NMR 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 the toluene of 30mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (II), be transferred in the there-necked flask of 50mL, add 1.45g (12mmol) N, accelerine, condition of ice bath lower magnetic force stirs, 10 ℃ start to drip 2.53g (16mmol) isobutyric anhydride, 10min drips end, temperature is 8 ℃, remove ice bath, after room temperature reaction 2h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 10:1), reaction solution is washed with 20mL, separate organic phase, after steaming desolventizes, residue adds 15 milliliters of chloroforms, stirring heating, 5～10min refluxes, filtered while hot is removed insolubles, filtrate is cooling, separate out solid, filter, the dry solid product that obtains, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 50.1%, 124～125 ℃ of fusing points.
1h NMR and IR are with embodiment 2.
Embodiment 5:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With the toluene of 30mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (II), be transferred in the there-necked flask of 50mL, add 1.45g (12mmol) N, accelerine, condition of ice bath lower magnetic force stirs, 6 ℃ start to drip 1.70g (16mmol) isobutyryl chloride, 10min drips end, temperature is 4 ℃, remove ice bath, after room temperature reaction 0.5h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 10:1), reaction solution is washed with 20mL, separate organic phase, after steaming desolventizes, residue adds 15 milliliters of acetone, stirring heating, 5～10min refluxes, filtered while hot is removed insolubles, filtrate is cooling, separate out solid, filter, the dry solid product that obtains, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 52.4%, 124～125 ℃ of fusing points.
1h NMR and IR are with embodiment 2.
Embodiment 6:1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1, the preparation of 2,4,5-tetrazine (I)
With the chloroform of 20mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (II), be transferred in the there-necked flask of 50mL, add 0.016g (0.4mmol) sodium hydroxide, condition of ice bath lower magnetic force stirs, 4 ℃ start to drip 0.43g (4mmol) isobutyryl chloride, 4min drips end, temperature is 2 ℃, remove ice bath, after room temperature reaction 10h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 10:1), reaction solution is washed with 13mL, separate organic phase, after steaming desolventizes, residue column chromatography (eluent is sherwood oil: ethyl acetate=10:1 (volume ratio)), residue dissolves with 15 milliliters of methylene dichloride, other operations are with embodiment 2, obtain solid product, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 51.8%, 124～125 ℃ of fusing points.
1h NMR 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 the methylene dichloride of 30mL, dissolve 0.64g (4mmol) 3-phenyl-1, 4-dihydro-1, 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 ℃ start to drip 0.43g (4mmol) isobutyryl chloride, 4min drips end, temperature is 3 ℃, remove ice bath, after room temperature reaction 8h, (reaction process adopts TLC to follow the tracks of and detects, developping agent is sherwood oil and the ethyl acetate mixture of 6:1), reaction solution is washed with 20mL, separate organic phase, after steaming desolventizes, residue column chromatography (eluent is sherwood oil: ethyl acetate=6:1 (volume ratio)), 15 milliliters of acetic acid ethyl dissolutions for residue, other operations are with embodiment 2, obtain solid product, it is 1-isobutyryl-3-phenyl-1, 4-dihydro-1, 2, 4, 5-tetrazine (I), yield 53.6%, 124～125 ℃ of fusing points.
1h NMR and IR are with embodiment 2.
Embodiment 8: antitumour activity vitro test
(1) compound embodiment 2～7 being made (I) has carried out human breast carcinoma and human lung carcinoma cell line biological activity test.Result shows that compound (I) has good antitumour activity to human breast cancer cell strain MCF-7.
Testing method: tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reduction method.
Cell strain: human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549.Above-mentioned tumor cell line is purchased 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 L DMSO, gets 2uL and dilutes with 1000 μ L nutrient solutions, and making concentration is 50 μ g/mL, then uses nutrient solution serial dilution to working concentration.
2) cultivation of cell
A) preparation of substratum: contain 80Wan unit's penicillin, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum in every 1000mL substratum.
B) cultivation of cell: tumor cell inoculation, in substratum, is put to 37 ℃, 5%CO
2in incubator, cultivate, 3～5d goes down to posterity.
C) restraining effect of working sample to growth of tumour cell
By EDTA-trysinization liquid digestion for cell, and be diluted to 1 * 10 with substratum
6/ mL, is added in 96 porocyte culture plates, and every hole 100uL, puts 37 ℃, 5%CO
2in incubator, cultivate.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 ℃, 5%CO
2in incubator, cultivate, add the MTT of 5mg/mL after 72h in cell cultures hole, every hole 10 μ L, put 37 ℃ and hatch 3h, add DMSO, every hole 150 μ L, and with vibrator vibration, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the cell of the culture medium culturing of same concentration DMSO in contrast, the IC of calculation sample to growth of tumour cell
50.
The result of test is as shown in table 1:
The restraining effect of table 1 compound (I) to MCF-7 and A-549 growth of cancer cells
(2) according to embodiment 1 and 2, with diacetyl oxide, substitute isobutyric anhydride, other operate with embodiment 1 and 2, have synthesized compound 1-ethanoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (III).With reference to embodiment 2, with Isosorbide-5-Nitrae-dihydro-1,2; 4,5-tetrazine is raw material, reacts and has obtained 1-ethanoyl-Isosorbide-5-Nitrae-dihydro-1 respectively with diacetyl oxide, propionic anhydride, isobutyric anhydride; 2,4,5-tetrazine (IV), 1-propionyl-1; 4-dihydro-1,2,4; 5-tetrazine (V), 1-isobutyryl-Isosorbide-5-Nitrae-dihydro-1; 2,4,5-tetrazine (VI).According to aforesaid method, the compound making (III), (IV), (V) and (VI) have been carried out to human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549 biological activity test, test result shows that compound (III), (IV), (V) and (VI) are all poor to human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549 inhibition, and compound (III), (IV), (V) and (VI) can not show a candle to compound (I) to the antitumour activity of human breast cancer cell strain MCF-7.Concrete outcome is as shown in table 2 and table 3:
The restraining effect of table 2 compound (III) to MCF-7 and A-549 growth of cancer cells
Table 3 compound (IV), (V) and (VI) restraining effect to MCF-7 and A-549 growth of cancer cells
The experiment of above-mentioned antitumour activity vitro test shows: the restraining effect that the compound of other 4 similar (III), (IV), (V) and (VI) are grown to human breast cancer cell strain MCF-7 and human lung cancer cell lines A-549 is all not obvious.Compound (I) is remarkable to the restraining effect of human breast cancer cell strain MCF-7 growth, not obvious to the restraining effect of human lung cancer cell lines A-549 growth, but is obviously better than compound (III) and (VI).
Claims (9)
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-1, 4-dihydro-1, 2, 4, the preparation method of 5-tetrazine, described preparation method comprises: by 3-phenyl-1 shown in formula II, 4-dihydro-1, 2, 4, 5-tetrazine adds in organic solvent A, add again basic catalyst, under 0～12 ℃ of condition, drip isobutyric anhydride or isobutyryl chloride, drip off rear room temperature reaction, reaction solution 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 basic catalyst is one of following: triethylamine, N, accelerine, sodium hydroxide, or potassium hydroxide,
3. preparation method as claimed in claim 2, is characterized in that: described organic solvent A is selected from one of following: methylene dichloride, chloroform or toluene.
4. preparation method as claimed in claim 2 or claim 3, is characterized in that: described 3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (II) is 1 ﹕ 0.1～3 ﹕ 1～4 with the molar ratio of basic catalyst, isobutyric anhydride or isobutyryl chloride.
5. preparation method as claimed in claim 2; it is characterized in that described separation and purification adopts following steps: reaction solution washes with water; separate organic phase; after steaming desolventizes; residue recrystallization or column chromatography obtain 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1 shown in formula I, 2; 4,5-tetrazine.
6. preparation method as claimed in claim 5, is characterized in that: recrystallization solvent is one of following: ethanol, chloroform or acetone.
7. preparation method as claimed in claim 5, it is characterized in that: the operation steps of described column chromatography is specific as follows: get the residue that steams after desolventizing in single port bottle, add organic solvent B to be dissolved, obtain lysate, then to the column chromatography silica gel that adds 1～2 times of amount of residue quality in lysate, after mixing, steaming desolventizes, residue that must be dry and the mixture of silica gel, mixture is filled to post loading, then the sherwood oil that the volume ratio of take is 0.5～10:1 and ethyl acetate mixture are eluent, directly carry out wash-out, TLC follows the tracks of detection, according to TLC, detect 1-isobutyryl-3-phenyl-1 of collecting containing shown in formula I, 4-dihydro-1, 2, 4, the elutriant of 5-tetrazine, collect liquid concentrate drying, obtain 1-isobutyryl-3-phenyl-1 shown in formula I, 4-dihydro-1, 2, 4, 5-tetrazine, described organic solvent B is one of following: ethanol, methylene dichloride or ethyl acetate.
8. 1-isobutyryl-3-as claimed in claim 1 phenyl-Isosorbide-5-Nitrae-dihydro-1, the application of 2,4,5-tetrazine in the medicine of preparation prevention or treatment human breast carcinoma or people's lung cancer.
9. application as claimed in claim 8, is characterized in that: described medicine is the medicine of prevention or treatment human breast carcinoma.
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