CN101153041B - 1,2,3-triazolo 1,3-diaza heterocyclic compound and its preparation method and application - Google Patents
1,2,3-triazolo 1,3-diaza heterocyclic compound and its preparation method and application Download PDFInfo
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- CN101153041B CN101153041B CN200610113451A CN200610113451A CN101153041B CN 101153041 B CN101153041 B CN 101153041B CN 200610113451 A CN200610113451 A CN 200610113451A CN 200610113451 A CN200610113451 A CN 200610113451A CN 101153041 B CN101153041 B CN 101153041B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- -1 nitro, cyano , amino Chemical group 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 150000000177 1,2,3-triazoles Chemical class 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 241000534944 Thia Species 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 8
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
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- 239000003814 drug Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- 125000004076 pyridyl group Chemical group 0.000 claims description 6
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- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 4
- JSLZUBLGGPEVQN-DIPNUNPCSA-N (2r)-4-methyl-2-propan-2-yl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazin-1-yl]butoxy]phenyl]-1,4-benzothiazin-3-one Chemical compound COC1=C(OC)C(OC)=CC(CCN2CCN(CCCCOC=3C(=CC=CC=3)[C@@]3(C(N(C)C4=CC=CC=C4S3)=O)C(C)C)CC2)=C1 JSLZUBLGGPEVQN-DIPNUNPCSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229950001891 iprotiazem Drugs 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
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- 125000001207 fluorophenyl group Chemical group 0.000 claims 4
- PNBRACSSFLTMRS-UHFFFAOYSA-N 1-propan-2-yl-2-propylhydrazine Chemical compound CCCNNC(C)C PNBRACSSFLTMRS-UHFFFAOYSA-N 0.000 claims 2
- 230000001093 anti-cancer Effects 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 32
- 239000002994 raw material Substances 0.000 abstract description 12
- 125000003435 aroyl group Chemical group 0.000 abstract description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 abstract 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
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- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 abstract 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 32
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 29
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- 239000000047 product Substances 0.000 description 29
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 27
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- VGYLMOJQAHXYCK-UHFFFAOYSA-N 1-methylimidazolidine Chemical compound CN1CCNC1 VGYLMOJQAHXYCK-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
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- SANQECZWBCESOD-UHFFFAOYSA-N phenyl(2h-triazol-4-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CNN=N1 SANQECZWBCESOD-UHFFFAOYSA-N 0.000 description 6
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- AQUKDMANPBWYSE-UHFFFAOYSA-N (4-fluorophenyl)-(2h-triazol-4-yl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=NNN=C1 AQUKDMANPBWYSE-UHFFFAOYSA-N 0.000 description 5
- NCAGJVFMWWIKNF-UHFFFAOYSA-N (4-phenylphenyl)-(2H-triazol-4-yl)methanone Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1C(=O)C=1C=NNN=1 NCAGJVFMWWIKNF-UHFFFAOYSA-N 0.000 description 5
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- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 4
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- FNEBPDNAUCTTNF-UHFFFAOYSA-N 2h-triazol-4-yl-[4-(trifluoromethyl)phenyl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1C(=O)C1=NNN=C1 FNEBPDNAUCTTNF-UHFFFAOYSA-N 0.000 description 3
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- VBIBPGNOHRGVRR-UHFFFAOYSA-N thiophen-2-yl(2H-triazol-4-yl)methanone Chemical compound C=1C=CSC=1C(=O)C=1C=NNN=1 VBIBPGNOHRGVRR-UHFFFAOYSA-N 0.000 description 3
- MEGPCWYKTKUKEG-UHFFFAOYSA-N 1-(2h-triazol-4-yl)ethanone Chemical compound CC(=O)C=1C=NNN=1 MEGPCWYKTKUKEG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
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- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 2
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- BABJTMNVJXLAEX-UHFFFAOYSA-N Triamiphos Chemical compound N1=C(N)N(P(=O)(N(C)C)N(C)C)N=C1C1=CC=CC=C1 BABJTMNVJXLAEX-UHFFFAOYSA-N 0.000 description 1
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- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention discloses a 1, 2, 3-triazole combined with 1, 3-two-nitrogen heterocyclic compound, a preparation method and application thereof. The 1, 2, 3-triazole combined with 1, 3-two-nitrogen heterocyclic compound provided by the present invention has a structure as shown in formula I; wherein, Y is O or NR'; R' is hydrogen, halogen, nitro, cyano , amino, C1-8 alkyl, C1-8 alkyla, C1-8acyl, aroyl, viscous aroyl, aryl, viscous aryl, cycloalkyl, aryl alkyl, oxa alkyl, oxa acyl, thia alkyl or thia acyl; n is equal to 1, 2 or 3; R1 is aryl, heterocyclic aryl or alkyl. In the present invention, the compound of heterocyclicketene shrinking amine category and p-methyl benzenesulfonyl azide are used as raw materials to prepare a series of 1, 2, 3-triazole combined with 1, 3-two-nitrogen heterocyclic compound of a novel structure; the synthesis is convenient; the reaction conditions are mild and easy to control; the production rate is high; the present invention is in particular suitable for industrial production; and the cost is low. The compound of the present invention has good bactericidal activity, anti-tumor activity and wide application prospects.
Description
Technical field
The present invention relates to 1,2,3-triazoles compounds and preparation method thereof and application, particularly relate to 1,2,3-triazoles and 1,3-diazacyclo compound and preparation method thereof and application.
Background technology
Triazole class compounds has important value at drug development and initiative field.Wherein, many triazole bactericidal agents because of its broad spectrum, long-lasting and high efficiency in the extended familys of sterilant in occupation of important one seat, as triamiphos, triazolone, butrizol etc.But up to now, the research of relevant triazole bactericidal agent concentrates on 1,2 mostly, and the 4-triazole class compounds is less relatively for the research of 1,2,3-triazoles compound, come into operation at present only with the U.S. different azoles of fluorine be representative a few.
Summary of the invention
The purpose of this invention is to provide a class 1,2,3-triazoles and 1,3-diazacyclo compound and preparation method thereof.
1,2,3-triazoles provided by the present invention and 1,3-diazacyclo compound, structure is suc as formula I,
Wherein, Y is O or NR ', and R ' is hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl, oxa alkyl, oxa-acyl group, thia alkyl or thia acyl group;
N=1,2 or 3; R
1Be aryl, heterocyclic aryl or alkyl.
And, as n=1 or 2 and during Y=NH, R
1Be not phenyl, rubigan, p-methylphenyl and p-methoxyphenyl.
Wherein, preferred, R
1Be phenyl, pyridyl, indyl, oxazolyl, thiazolyl, imidazolyl, naphthyl, anthryl, benzo pyridyl, benzimidazolyl-, benzothiazolyl or 2, the 6-dimethyl-4-tertiary butyl-3,5-dinitrophenyl; Perhaps; be the phenyl that replaces; pyridyl; indyl; oxazolyl; thiazolyl; imidazolyl; naphthyl; anthryl; the benzo pyridyl; benzimidazolyl-or benzothiazolyl; its substituting group is selected from fluorine; chlorine; bromine; iodine; nitro; cyano group; amido; methyl; ethyl; propyl group; sec.-propyl; normal-butyl; isobutyl-; the tertiary butyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; n-butoxy; isobutoxy; tert.-butoxy; methylamino; ethylamino-; Propylamino; isopropylamine base; n-butylamine-based; isobutyl amine; the TERTIARY BUTYL AMINE base; methylthio group; ethylmercapto group; the rosickyite base; the iprotiazem base; positive butylthio; the isobutyl sulfenyl; uncle's butylthio; formyl radical; ethanoyl; propionyl; different propionyl; positive butyryl radicals; isobutyryl; uncle's butyryl radicals; methoxycarbonyl; ethoxycarbonyl; the third oxygen carbonyl; the different third oxygen carbonyl; positive butoxy carbonyl; isobutyl boc; tertbutyloxycarbonyl; N; the N dimethyl amido; N; N-diethyl amido; N, N-dipropyl amido; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; adamantyl; phenyl; trifluoromethyl.
1,2,3-triazoles of the present invention and 1, the preparation method of 3-diazacyclo compound is that the heterocycle ketene peptide aminated compounds of formula II structure and the Methyl benzenesulfonyl nitrine of formula III structure are reacted, and obtains described 1,2,3-triazoles and 1,3-diazacyclo compound.
In the above-mentioned reaction, the solvent of reaction is selected from acetonitrile, tetrahydrofuran (THF), trichloromethane, methylene dichloride, 1,2-ethylene dichloride, 1,4-dioxane, toluene, ethyl acetate.The temperature of reaction is 0-160 ℃.The mol ratio of formula II compound and formula III compound is 0.8-2.0: 0.8-2.0.
Another object of the present invention provides 1,2,3-triazoles of the present invention and 1, the purposes of 3-diazacyclo compound.
The inventor confirms by experiment, the present invention 1,2,3-triazolo 1,3-diazacyclo compound has excellent bactericidal activity, simultaneously, find that also this compounds has good inhibition effect to some cancer cells (stomach cancer cell and breast cancer cell), can on preparation sterilant and cancer therapy drug (cancer of the stomach and mammary cancer), be widely used.
In the present invention, the heterocycle ketene peptide aminated compounds is mixed with sulfonyl azide compounds equivalent, heat a few hours, TLC detects, have to unique product point after raw material reaction is complete, after of the method separation purification of this product with easy recrystallization (indivedual products are still needed and passed through column chromatography for separation), prove conclusively this product by means of testing such as nucleus magnetic resonance, mass spectrum, infrared spectra and ultimate analyses and be target product---1,2,3-triazolo 1,3-diazacyclo compound, productive rate majority are more than 80%, and what have surpasses 90%.
The present invention with the heterocycle ketene peptide aminated compounds and to the Methyl benzenesulfonyl nitrine be feedstock production a series of novel structures 1,2,3-triazoles and 1,3-diazacyclo compound, synthetic convenient, the reaction conditions gentleness is easy to control, the productive rate height is suitable for suitability for industrialized production especially, and cost is low.Active testing experiment showed, that The compounds of this invention has good biological activity, and its anti-breast cancer is active and fungicidal activity is particularly outstanding, has broad application prospects.
Description of drawings
Figure 1A and Figure 1B are respectively DMSO group (blank) and the Compound I-photo of j group effect cancer of the stomach BGC-823 cell after 72 hours;
Fig. 2 A and Fig. 2 B are respectively DMSO group (blank) and the Compound I-photo of n group effect mammary cancer Bcap-37 cell after 72 hours.
Embodiment
First part's 1,2,3-triazoles and 1,3-diazacyclo compound synthetic
The present invention synthesizes 1,2,3-triazoles and 1 by reaction between heterocycle ketene peptide aminated compounds and the p-toluene sulfonyt azide, 3-diazacyclo compound, and reaction equation is as follows:
(formula I)
The reaction mechanism of above-mentioned reaction process is:
Wherein:
Y is O, NR '; Wherein, R ' is hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, aroyl, thick aroyl, aryl, thick aryl, cycloalkyl, aralkyl, oxa alkyl, oxa-acyl group, thia alkyl, thia acyl group;
N=1,2 or 3;
R
1Be aryl, heterocyclic aryl or alkyl; Wherein, R
1Be preferably phenyl, pyridyl, indyl, oxazolyl, thiazolyl, imidazolyl, naphthyl, anthryl, benzo pyridyl, benzimidazolyl-, benzothiazolyl, 2, the 6-dimethyl-4-tertiary butyl-3,5-dinitrophenyl; Perhaps; the phenyl that replaces; pyridyl; indyl; oxazolyl; thiazolyl; imidazolyl; naphthyl; anthryl; the benzo pyridyl; benzimidazolyl-or benzothiazolyl; its substituting group can be selected from fluorine; chlorine; bromine; iodine; nitro; cyano group; amido; methyl; ethyl; propyl group; sec.-propyl; normal-butyl; isobutyl-; the tertiary butyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; n-butoxy; isobutoxy; tert.-butoxy; methylamino; ethylamino-; Propylamino; isopropylamine base; n-butylamine-based; isobutyl amine; the TERTIARY BUTYL AMINE base; methylthio group; ethylmercapto group; the rosickyite base; the iprotiazem base; positive butylthio; the isobutyl sulfenyl; uncle's butylthio; formyl radical; ethanoyl; propionyl; different propionyl; positive butyryl radicals; isobutyryl; uncle's butyryl radicals; methoxycarbonyl; ethoxycarbonyl; the third oxygen carbonyl; the different third oxygen carbonyl; positive butoxy carbonyl; isobutyl boc; tertbutyloxycarbonyl; N; the N-dimethyl amido; N; N-diethyl amido; N; N-dipropyl amido; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; adamantyl; phenyl; trifluoromethyl; situation about replacing can be single replacement; also can be polysubstituted, or even full the replacement.
In above-claimed cpd, as n=1 or 2 and during Y=NH, R
1Can not be phenyl, rubigan, p-methylphenyl and p-methoxyphenyl.
In the present invention, the compound that used reaction raw materials heterocycle ketene peptide aminated compounds [formula II] has structural performance as a class, its special structure is given its special reaction property, has a plurality of reaction site, is good parent-1,3-dipole body.Synthesizing of heterocyclic ketene semiamine (formula II): (a) Huang, Z.-T. by wide coverage, for example; Liu, Z.-R.Synth.Commun.1989,19,943. (b) Wang, H.-T.; Wang, X.-J.; Huang, Z.-T.Chem.Ber.1990,122,2141. (c) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T.Tetrahedron 2002,58, and 1309.
The organic nitrine compounds is as a kind of typical 1, and 3-dipole body has important application in the synthesizing heterocyclic compounds.Wherein, p-toluene sulfonyt azide (formula III) is easy to synthesize, and is convenient to preserve, and with multiple close 1, the reactive behavior of 3-dipole body is all very high.Sulfonyl azide compounds synthetic quite ripe already mainly can obtain corresponding sulfonyl azide compounds by azido-takes place between corresponding SULPHURYL CHLORIDE compounds and the sodiumazide to the substitution reaction of chlorine.In the present invention, sulfonyl azide partly is only key point, and no matter how the substituting group on the phenyl ring changes, and all will reset with the form of corresponding benzsulfamide via Dimroth in reaction process and slough.So, obtain to take into account raw material economics and be easy to get on the basis of target compound guaranteeing, be easy to factors such as preparation and preservation, used sulfonyl azide compounds is chosen to be p-toluene sulfonyt azide.
Below with specific embodiment the synthetic of The compounds of this invention is described.
Embodiment 1, synthetic 4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (among the formula I, n=1, Y=NH, R
1=4-fluorophenyl) (Compound I-a)
In 50 milliliters round-bottomed flask, add exsiccant acetonitrile (20 milliliters); 2-(4-fluoro benzoyl) methylene radical imidazolidine (1.0 mmole) and to Methyl benzenesulfonyl nitrine (1.0 mmole); under induction stirring, heat; this moment, raw material dissolved fully; reaction system is a red tan solution; TLC detects sustained reaction until raw material completely dissolve, and has only a product point.Remove solvent under reduced pressure, with pale brown look solid crude product with common organic solvent recrystallization, pale yellow crystals, this is target product 4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (Compound I-a), productive rate: 81.3%; Product fusing point: 199-200 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.58 (dd, 2H, aryl H), and 7.20-7.14 (m, 2H, aryl H), 5.22 (s, 1H, NH), 4.52-4.45 (m, 4H, CH
2-CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 183.16,167.34,163.97,155.64,132.99,132.87,132.80,126.80,115.55,115.26,52.98,44.80;
Mass spectrum (EI): m/z 233 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 24.26, and C 56.79, and H 3.88;
Theoretical value (%): N.24.13, C 56.89, and H 3.91.
Embodiment 2, synthetic 4-(4-trifluoromethyl benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (among the formula I, n=1, Y=NH, R
1=4-trifluoromethyl) (Compound I-b)
In 50 milliliters round-bottomed flask, add the exsiccant acetonitrile and make solvent; the 2-of equivalent (4-trifluoromethyl benzoyl) methylene radical imidazolidine and to the Methyl benzenesulfonyl nitrine; heating is dissolved raw material fully under induction stirring; reaction system is a red tan solution; TLC detects sustained reaction until raw material completely dissolve, and has only a product point.Remove solvent under reduced pressure, pale brown look solid crude product with common organic solvent recrystallization, is got pale yellow crystals, this is target product 4-(4-trifluoromethyl benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (I-b), productive rate: 80.4%; Product fusing point: 201-203 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.58 (d, 2H, aryl H), and 7.76 (d, 2H, aryl H), 5.16 (s, 1H, NH), 4.57-4.46 (m, 4H, CH
2-CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 183.51,155.74,139.40,133.65,130.51,126.59,125.29,125.24,63.05,44.81;
Mass spectrum (EI): m/z 283 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 20.03, and C 50.85, and H 3.12;
Theoretical value (%): N.19.85, C 51.07, and H 3.21.
Embodiment 3, synthetic 4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (among the formula I, n=1, Y=NH, R
1=4-phenyl) (Compound I-c)
With 2-(4-fluoro benzoyl) the methylene radical imidazolidine among 2-(4-phenyl benzoyl) the methylene radical imidazolidine replacement embodiment 1, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (Compound I-c), productive rate: 93.0%; Fusing point: 239-240 ℃.
Embodiment 4, synthetic 4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (among the formula I, n=2, Y=NH, R
1=4-fluorophenyl) (Compound I-d)
In 50 milliliters round-bottomed flask, add the exsiccant acetonitrile and make solvent; the 2-of equivalent (4-fluoro benzoyl) methylene radical hexahydropyrimidine and to the Methyl benzenesulfonyl nitrine; under induction stirring, heat; this moment, raw material dissolved fully; reaction system is a red tan solution; TLC detects and continues sustained reaction until raw material completely dissolve, and has only a product point.Remove solvent under reduced pressure, with pale brown look solid crude product with common organic solvent recrystallization, pale yellow crystals, this is target product 4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (Compound I-d), productive rate: 82.8%; Fusing point: 167-168 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.60 (dd, 2H, aryl H), and 7.20-7.10 (m, 2H, aryl H), 6.69 (s, 1H, NH), 4.40 (m, 2H, CH
2), 3.56-3.49 (m, 2H, CH
2), 2.28-2.18 (m, 2H, CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 183.93,167.10,163.74,146.16,133.47,133.43,132.74,132.61,128.46,115.42,115.13,43.21,38.65,20.58;
Mass spectrum (EI): m/z 247 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 22.60, and C 58.28, and H 4.56;
Theoretical value (%): N.22.75, C 58.53, and H 4.50.
Embodiment 5, synthetic 4-(4-trifluoromethyl benzoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (among the formula I, n=2, Y=NH, R
1=4-trifluoromethyl) (Compound I-e)
With 2-(4-fluoro benzoyl) the methylene radical hexahydropyrimidine among 2-(4-trifluoromethyl benzoyl) the methylene radical hexahydropyrimidine replacement embodiment 4; under same condition; with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-trifluoromethyl benzoyl)-[1; 2; 3] triazole [1; 5-e] and hexahydropyrimidine (Compound I-e), productive rate: 76.4%, fusing point: 190-191 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.59-8.56 (m, 2H, aryl H), and 7.77-7.74 (m, 2H, aryl H), 6.73 (s, 1H, NH), 4.41-4.37 (m, 2H, CH
2), 3.57-3.52 (m, 2H, CH
2), 2.24-2.20 (m, 2H, CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 184.17,146.28,140.08,133.68,133.25,130.21,128.48,125.67,125.20,125.15,125.10,43.21,38.67,20.49;
Mass spectrum (EI): m/z 297 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 18.74, and C 52.74, and H 3.64;
Theoretical value (%): N 18.91, and C 52.71, and H 3.74.
Embodiment 6, synthetic 4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (among the formula I, n=2, Y=NH, R
1=4-phenyl) (Compound I-f)
With 2-(4-fluoro benzoyl) the methylene radical hexahydropyrimidine in 2-(4-phenyl benzoyl) the methylene radical hexahydropyrimidine replacement embodiment 4, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (Compound I-f), productive rate: 82.7%; Fusing point: 165-166 ℃.
Embodiment 7, synthetic 4-(4-anisoyl)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=4-p-methoxy-phenyl) (Compound I-g)
In 50 milliliters round-bottomed flask, add acetonitrile, (N-methyl) [2-(4-chlorobenzene formacyl) methylene radical] imidazolidine and to the Methyl benzenesulfonyl nitrine, under induction stirring, heat, TLC detects sustained reaction until raw material completely dissolve. remove solvent under reduced pressure, with pale brown look solid crude product with common organic solvent crystallization, get pale yellow crystals, this is target product 4-(4-anisoyl)-[1,2,3] triazole [1,5-e] and also (N-methyl imidazolidine) (Compound I-g), productive rate: 81.5%; Fusing point: 108-109 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.56 (d, 2H, aryl H), and 7.00 (d, 2H, aryl H), 5.26 (s, 1H, NH), 4.54-4.41 (m, 4H, CH
2-CH
2), 3.89 (s, 3H, OCH
3);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 183.41,63.38, and 155.54,132.57,129.49,127.19,113.58,77.22,55.46,52.92,44.78;
Mass spectrum (ESI): m/z 398 (M++H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 21.33, and C 54.70, and H 4.22;
Theoretical value (%): N 21.33, and C 54.87, and H 4.22.
Embodiment 8, synthetic synthetic 4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=4-fluoro benzoyl) (Compound I-h)
With (N-methyl) [2-(4-chlorobenzene formacyl) methylene radical] imidazolidine among (N-methyl) [2-(4-fluoro benzoyl) methylene radical] imidazolidine replacement embodiment 7; under same condition; with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-fluoro benzoyl)-[1; 2; 3] triazole [1; 5-e] and also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=4-fluorophenyl) (Compound I-h).Productive rate: 70.8%; Fusing point: 105-106 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.35 (d.2H, aryl H), 7.76 (d, 2H, aryl H), 4.52-4.44 (t, 2H, CH
2), 4.22-4.18 (t, 2H, CH
2), 3.36 (s, 3H, CH
3);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 184.53,155.54,140.70,130.53,126.19,125.09,125.04,59.89,44.48,36.35;
Mass spectrum (EI): m/z 297 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 18.93, and C 52.54, and H 3.75;
Theoretical value (%): N 18.91, and C 52.71, and H 3.74.
Embodiment 9, synthetic 4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=3,5-two trifluoromethyls) (Compound I-i)
[2-(3 with (N-methyl); 5-two trifluoromethyl benzoyls) methylene radical] imidazolidine replaces (N-methyl) [2-(4-chlorobenzene formacyl) methylene radical] imidazolidine among the embodiment 7; under same condition; with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(3,5-two trifluoromethyl benzoyls)-[1,2; 3] triazole [1; 5-e] and also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=3,5-two trifluoromethyls) (Compound I-i), productive rate: 70.8%; Fusing point: 113-114 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.78 (s, 2H, aryl H), 8.15 (s, 1H, aryl H), 4.54-4.46 (t, 2H, CH
2), 4.26-4.20 (t, 2H, CH
2), 3.38 (s, 3H, CH
3);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 182.01,155.73,139.28,131.75,131.31,130.53,125.72,125.38,125.33,125.28,124.98,121.37,59.88,44.49,36.23;
Mass spectrum (EI): m/z 365 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 15.32, and C 46.23, and H 2.82;
Theoretical value (%): N 15.38, and C 46.16, and H 2.77.
Embodiment 10, synthetic 4-(2,6-dimethyl-3,5 dinitrobenzenes-4-tert.-butylbenzene formyl radical)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (among the formula I, n=1, Y=N-CH
3, R
1=2,6-dimethyl-3,5 dinitrobenzenes-4-tert-butyl-phenyl) (Compound I-j)
[2-(2 with (1-methyl), 6-dimethyl-3,5 dinitrobenzenes-4-tert.-butylbenzene formyl radical) methylene radical] imidazolidine replaces (1-methyl) [2-(4-1 chlorobenzene formacyl) methylene radical] imidazolidine in the embodiment 15, under same condition, can get target product 4-(2 with the Methyl benzenesulfonyl nitrine is reacted, 6-dimethyl-3,5 dinitrobenzenes-4-tert.-butylbenzene formyl radical)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (I-j), productive rate: 85.1%; Fusing point: 216-217 ℃.
Ultimate analysis (Flash EA 1112): experimental value (%): N 20.64, and C 54.03, and H 5.41;
Theoretical value (%): N 20.88, and C 53.73, and H 5.51.
Embodiment 11, synthetic 4-(4-chlorobenzene formacyl)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=4-chlorobenzene formacyl) (Compound I-k)
Add an amount of acetonitrile in 50 milliliters round-bottomed flask, (1-methyl) (2-benzoyl methylene radical) hexahydropyrimidine and to the Methyl benzenesulfonyl nitrine heats under induction stirring, and TLC detects and continues sustained reaction to raw material completely dissolve.Remove solvent under reduced pressure, pale brown look solid crude product with common organic solvent recrystallization, is got pale yellow crystals, this is target product 4-(4-chlorobenzene formacyl)-[1,2,3] triazole [1,5-e] and also (N-methyl hexahydropyrimidine) (Compound I-k), productive rate: 75.6%; Fusing point: 103-104 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.56 (d, 2H, aryl H), and 7.00 (d, 2H, aryl H), 5.26 (s, 1H, NH), 4.54-4.41 (m, 4H, CH
2-CH
2), 3.89 (s, 3H, OCH
3);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 183.41,63.38, and 155.54,132.57,129.49,127.19,113.58,77.22,55.46,52.92,44.78;
Mass spectrum (ESI): m/z 398 (M++H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 23.23, and C 64.33, H5.78;
Theoretical value (%): N 23.13, and C 64.45, and H 5.82.
Embodiment 12, synthetic 4-(4-anisoyl)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=4-p-methoxy-phenyl) (Compound I-l)
With (1-methyl) (the 2-benzoyl methylene radical) hexahydropyrimidine among (1-methyl) [2-(4-phenyl benzoyl) methylene radical] hexahydropyrimidine replacement embodiment 11; under same condition; with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-anisoyl)-[1; 2; 3] triazole [1; 5-e] and also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=4-phenyl) (Compound I-l), productive rate: 93.9%; Fusing point: 137-138 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.16 (dd, 2H, aryl H), 6.96 (dd, 2H, aryl H), 4.37-4.33 (m, 2H, CH
2), 3.88 (s, 3H, OCH
3), 3.38-3.34 (m, 2H, CH
2), 3.23 (s, 3H, NCH
3), 2.25-2.21 (m, 2H, CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 185.25,162.97,145.73,132.80,131.36,129.40,113.32,55.46,49.30,43.63,40.48,21.01;
Mass spectrum (EI): m/z 273 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 20.38, and C 61.52, and H 5.94:
Theoretical value (%): N 20.58, and C 61.75, and H 5.92.
Embodiment 13, synthetic 4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=4-phenyl) (Compound I-m)
With (1-methyl) (the 2-benzoyl methylene radical) hexahydropyrimidine among (1-methyl) [2-(4-phenyl benzoyl) methylene radical] hexahydropyrimidine replacement embodiment 11; under same condition; with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-phenyl benzoyl)-[1; 2; 3] triazole [1; 5-e] and also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=4-phenyl) (Compound I-m), productive rate: 72.7%; Fusing point: 117-118 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AY 300 instrument) is at room temperature measured: δ 8.20 (d, 2H, aryl H), 7.71-7.64 (m, 4H, aryl H), 7.49-7.36 (m, 3H, aryl H), 4.36-4.32 (m, 2H, CH
2), 3.39-3.35 (m, 2H, CH
2), 3.27 (s, 3H, NCH
3), 2.26-2.19 (m, 2H, CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 186.05,145.91,144.83,140.45,137.47,131.05,129.45,128.88,127.91,127.35,126.78,49.30,43.63,40.58,20.97;
Mass spectrum (EI): m/z 319 (M+H).
Ultimate analysis (Flash EA 1112): experimental value (%): N 17.57, and C 71.63, and H 5.66;
Theoretical value (%): N 17.60, and C 71.68, and H 5.70.
Embodiment 14, synthetic 4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (among the formula I, n=2, Y=N-CH
3, R
1=3,5-two trifluoromethyls) (Compound I-n)
[2-(3 with (1-methyl), 5-two trifluoromethyl benzoyls) methylene radical] hexahydropyrimidine replaces (1-methyl) (the 2-benzoyl methylene radical) hexahydropyrimidine among the embodiment 11, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] and also (N-methyl hexahydropyrimidine) (Compound I-n), productive rate: 72.7%; Fusing point: 101-102 ℃.
Embodiment 15, synthetic 4-(4-chlorobenzene formacyl)-[1,2,3] triazole [1,5-e] also (1, the 3-Diazesuberane) (among the formula I, n=3, Y=NH, R
1=4-chloro-phenyl-) (Compound I-o)
With 2-(4-fluoro benzoyl) the methylene radical imidazolidine among 2-(4-chlorobenzene formacyl) the methylene radical hexahydropyrimidine replacement embodiment 1, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(4-chlorobenzene formacyl)-[1,2,3] triazole [1,5-e] and also (1, the 3-Diazesuberane) (Compound I-o), productive rate: 71.0%; Fusing point: 158-160 ℃.
Proton nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: δ 8.45 (d, 2H, aryl H), and 7.48 (d, 2H, aryl H), 7.40 (m, 1H, NH), 4.48-4.40 (m, 2H, CH
2), 3.36-3.32 (m, 2H, CH
2), 2.04-1.98 (m, 4H, CH
2-CH
2);
Carbon-13 nmr spectra (deuterochloroform is a solvent, Bruker AV 300 instrument) is at room temperature measured: 185.14,152.18,138.84,135.56,131.72,130.64,128.50,50.82,46.29,29.66,26.37;
Embodiment 16, synthetic 4-ethanoyl-[1,2,3] triazole [1,5-e] and imidazolidine (among the formula I, n=2, Y=NH, R
1=methyl) (Compound I-p)
With 2-(4-fluoro benzoyl) the methylene radical imidazolidine among the 2-ethanoyl methylene radical imidazolidine replacement embodiment 1, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-ethanoyl-[1,2,3] triazole [1,5-e] and imidazolidine (Compound I-p), productive rate: 65.0%; Fusing point: 162-164 ℃.
Embodiment 17, synthetic 4-benzoyl-[1,2,3] triazole [1, and 5-e] Bing oxazolidine (among the formula I, n=2, Y=O, R
1=phenyl) (Compound I-q)
With 2-(4-fluoro benzoyl) the methylene radical imidazolidine among the 2-benzoyl methylene radical oxazolidine replacement embodiment 1, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-benzoyl-[1,2,3] triazole [1,5-e] Bing oxazolidine (Compound I-q), productive rate: 77.5%; Fusing point: 182-184 ℃.
Embodiment 18, synthetic 4-benzoyl-[1,2,3] triazole [1,5-e] also (1,3-oxazine alkane) (among the formula I, n=2, Y=O, R
1=phenyl) (Compound I-r)
With 2-benzoyl methylene radical-1,3-oxazine alkane replaces 2-(4-fluoro benzoyl) the methylene radical hexahydropyrimidine among the embodiment 4, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-benzoyl-[1,2,3] triazole [1,5-e] also (1,3-oxazine alkane) (Compound I-r), productive rate: 80.2%; Fusing point: 194-195 ℃.
Embodiment 19, synthetic 4-(2-Thenoyl)-[1,2,3] triazole [1,5-e] and imidazolidine (among the formula I, n=2, Y=NH, R
1=thienyl) (Compound I-s)
With 2-(4-fluoro benzoyl) the methylene radical imidazolidine among 2-(2-Thenoyl) the methylene radical imidazolidine replacement embodiment 1, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-benzoyl-[1,2,3] triazole [1,5-e] and imidazolidine (Compound I-s), productive rate: 82.5%; Fusing point: 201-203 ℃.
Embodiment 20, synthetic 4-(2-Thenoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (among the formula I, n=3, Y=NH, R
1=phenyl) (Compound I-t)
With 2-(4-fluoro benzoyl) the methylene radical hexahydropyrimidine among 2-(2-Thenoyl) the methylene radical hexahydropyrimidine replacement embodiment 4, under same condition, with being reacted, the Methyl benzenesulfonyl nitrine can get target product 4-(2-Thenoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine (Compound I-t), productive rate: 86.3%; Fusing point: 210-212 ℃.
Above-mentioned institute synthetic 1,2, the structural formula of 3-three substituted triazole compounds is as shown in table 1:
The structural formula table of table 1 The compounds of this invention
Second section 1,2,3-triazoles and 1, the determination of activity of 3-diazacyclo compound
(Compound I-a) is to the prevention effect of rice sheath blight disease for embodiment 21:4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] and imidazolidine
4-with 1% (4-fluoro benzoyl)-[1; 2; 3] triazole [1; 5-e] and imidazolidine (Compound I-a) is made into the solution of 500mg/L; draw the Erlenmeyer flask of 2ml to sterilization; add the PDA substratum 18ml about 50 degree; pour the plate of 2 diameter 9cm after shaking up into; make 2 toxic PDA substratum that contain 50mg/L concentration. with cultured rice sheath blight disease pathogenic bacteria; punch tool with diameter 5mm breaks into the bacterium piece at colony edge; the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance with inoculating needle; placing then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times. said preparation is 80.46%. to rice sheath blight disease pathogenic bacteria colony growth inhibiting rate
Embodiment 22:4-(4-fluoro benzoyl)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (Compound I-h) is to the prevention effect of wheat scab
4-with 1% (4-fluoro benzoyl)-[1; 2; 3] triazole [1; 5-e] also (N-methyl imidazolidine) (Compound I-h) is made into the solution of 500mg/L; draw the Erlenmeyer flask of 2ml to sterilization; add the PDA substratum 18ml about 50 degree, pour the plate of 2 diameter 9cm after shaking up into, make 2 toxic PDA substratum that contain 50mg/L concentration.With cultured wheat scab pathogenic bacteria, break into the bacterium piece with the punch tool of diameter 5mm at colony edge, with inoculating needle the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance, place then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times.Said preparation is 87.76% to wheat scab pathogenic bacteria colony growth inhibiting rate.
Embodiment 23:4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (Compound I-i) is to the prevention effect of gray mold of cucumber
4-(3 with 1%; 5-two trifluoromethyl benzoyls)-[1; 2; 3] triazole [1; 5-e] also (N-methyl imidazolidine) (Compound I-i) is made into the solution of 500mg/L, draws the Erlenmeyer flask of 2ml to sterilization, adds the PDA substratum 18ml about 50 degree; pour the plate of 2 diameter 9cm after shaking up into, make 2 toxic PDA substratum that contain 50mg/L concentration.With cultured gray mold of cucumber pathogenic bacteria, break into the bacterium piece with the punch tool of diameter 5mm at colony edge, with inoculating needle the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance, place then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times.Said preparation is 86.22% to gray mold of cucumber pathogenic bacteria colony growth inhibiting rate.
Embodiment 24:4-(4-phenyl benzoyl)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (Compound I-m) is to the prevention effect of ring rot of apple
4-with 1% (4-phenyl benzoyl)-[1; 2; 3] triazole [1; 5-e] also (N-methyl hexahydropyrimidine) (Compound I-m) is made into the solution of 500mg/L; draw the Erlenmeyer flask of 2ml to sterilization; add the PDA substratum 18ml about 50 degree, pour the plate of 2 diameter 9cm after shaking up into, make 2 toxic PDA substratum that contain 50mg/L concentration.With cultured ring rot of apple pathogenic bacteria, break into the bacterium piece with the punch tool of diameter 5mm at colony edge, with inoculating needle the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance, place then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times.Said preparation is 87.27% to ring rot of apple pathogenic bacteria colony growth inhibiting rate.
Embodiment 25:4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (Compound I-n) is to the prevention effect of rice sheath blight disease
4-(3 with 1%; 5-two trifluoromethyl benzoyls)-[1; 2; 3] triazole [1; 5-e] also (N-methyl hexahydropyrimidine) (Compound I-n) is made into the solution of 500mg/L, draws the Erlenmeyer flask of 2ml to sterilization, adds the PDA substratum 18ml about 50 degree; pour the plate of 2 diameter 9cm after shaking up into, make 2 toxic PDA substratum that contain 50mg/L concentration.With cultured rice sheath blight disease pathogenic bacteria, break into the bacterium piece with the punch tool of diameter 5mm at colony edge, with inoculating needle the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance, place then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times.Said preparation is 81.97% to rice sheath blight disease pathogenic bacteria colony growth inhibiting rate.
(Compound I-t) is to the prevention effect of early blight of tomato for embodiment 26:4-(2-Thenoyl)-[1,2,3] triazole [1,5-e] and hexahydropyrimidine
4-with 1% (2-Thenoyl)-[1; 2; 3] triazole [1; 5-e] and hexahydropyrimidine (Compound I-t) is made into the solution of 500mg/L; draw the Erlenmeyer flask of 2ml to sterilization; add the PDA substratum 18ml about 50 degree; pour the plate of 2 diameter 9cm after shaking up into; make 2 toxic PDA substratum that contain 50mg/L concentration. with cultured early blight of tomato pathogenic bacteria; punch tool with diameter 5mm breaks into the bacterium piece at colony edge; the bacterium piece is moved to the toxic PDA substratum central authorities that are mixed with in advance with inoculating needle; placing then in the 25 degree left and right sides incubators and cultivate, handle for every kind and repeat 2 times. said preparation is 83.65%. to early blight of tomato pathogenic bacteria colony growth inhibiting rate
Embodiment 27:4-(2,6-dimethyl-3,5-dinitrobenzene-4-tert.-butylbenzene formyl radical)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (Compound I-j) is to the vitro inhibition activity of stomach cancer cell (BGC-823)
Screening conditions: the inoculating cell number is 2000/hole, and compound medicine concentration is 5 μ M, and each sample is established 6 multiple holes.
Material: 1640 substratum, foetal calf serum, MTT etc.
Screening method: mtt assay
Under above-mentioned test conditions, record 4-(2,6-dimethyl-3,5-dinitrobenzene-4-tert.-butylbenzene formyl radical)-[1,2,3] triazole [1,5-e] also (N-methyl hexahydropyrimidine) (Compound I-j) extracorporeal inhibiting rate to stomach cancer cell (BGC-823) is 80.3%.
DMSO group (blank) and the Compound I-photo of j group effect cancer of the stomach BGC-823 cell after 72 hours is respectively shown in Figure 1A and Figure 1B, and the result shows that Compound I-j has good inhibition effect to stomach cancer cell BGC-823.
[1, (Compound I-q) is to the vitro inhibition activity of stomach cancer cell (BGC-823) for 5-e] Bing oxazolidine for embodiment 28:4-benzoyl-[1,2,3] triazole
Screening conditions: the inoculating cell number is 2000/hole, and compound medicine concentration is 5 μ M, and each sample is established 6 multiple holes.
Material: 1640 substratum, foetal calf serum, MTT etc.
Screening method: mtt assay
Under above-mentioned test conditions, [1, (Compound I-q) extracorporeal inhibiting rate to stomach cancer cell (BGC-823) is 78.9% to 5-e] Bing oxazolidine to record 4-benzoyl-[1,2,3] triazole.
Embodiment 29:4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] is (N-methyl hexahydropyrimidine) (Compound I-n) mammary cancer Bcap-37 cells in vitro is suppressed active also
Screening conditions: the inoculating cell number is 2000/hole, and compound medicine concentration is 5 μ M, and each sample is established 6 multiple holes.
Material: 1640 substratum, foetal calf serum, MTT etc.
Screening method: mtt assay
Under above-mentioned test conditions, record 4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (3-methyl hexahydropyrimidine) (Compound I-n) is 89.6% to mammary cancer Bcap-37 cells in vitro inhibiting rate.
DMSO group (blank) and the Compound I-photo of n group effect mammary cancer Bcap-37 cell after 72 hours is respectively shown in Fig. 2 A and Fig. 2 B, and the result shows that Compound I-n has good inhibition effect to mammary cancer Bcap-37 cell.
Embodiment 30:4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] is (N-methyl imidazolidine) (Compound I-i) mammary cancer Bcap-37 cells in vitro is suppressed active also
Screening conditions: the inoculating cell number is 2000/hole, and compound medicine concentration is 5 μ M, and each sample is established 6 multiple holes.
Material: 1640 substratum, foetal calf serum, MTT etc.
Screening method: mtt assay
Under above-mentioned test conditions, record 4-(3,5-two trifluoromethyl benzoyls)-[1,2,3] triazole [1,5-e] also (N-methyl imidazolidine) (Compound I-i) is 83.8% to mammary cancer Bcap-37 cells in vitro inhibiting rate.
Claims (9)
1. the 1,2,3-triazoles of formula I structure and 1,3-diazacyclo compound,
Wherein, Y is O or NR '; R ' is hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, oxa alkyl, oxa-acyl group, thia alkyl or thia acyl group;
N=1,2 or 3;
R
1Be indyl, oxazolyl, thiazolyl, imidazolyl, naphthyl, benzo pyridyl, benzimidazolyl-or benzothiazolyl; Perhaps, be the phenyl that replaces, the pyridyl of replacement, indyl, replacement De oxazolyl, the thiazolyl of replacement, the imidazolyl of replacement, the naphthyl of replacement, the benzo pyridyl of replacement, the benzimidazolyl-of replacement or the benzothiazolyl of replacement of replacement; Described substituting group is selected from fluorine, chlorine, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, N, the N-dimethyl amido, N, N-diethyl amido, N, N-dipropyl amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl;
And, as n=1 or 2 and during Y=NH, R
1Be not phenyl, to fluorophenyl, rubigan, p-methylphenyl and p-methoxyphenyl; As n=2 and Y=N-CH
3The time, R
1Be not to fluorophenyl.
2. 1,2,3-triazoles according to claim 1 and 1,3-diazacyclo compound is characterized in that: the phenyl of described replacement is 2, the 6-dimethyl-4-tertiary butyl-3,5-dinitrophenyl.
3. 1,2,3-triazoles according to claim 1 and 1,3-diazacyclo compound is characterized in that: described compound is:
4. the described 1,2,3-triazoles of claim 1 and 1, the preparation method of 3-diazacyclo compound is that the heterocycle ketene peptide aminated compounds of formula II structure and the Methyl benzenesulfonyl nitrine of formula III structure are reacted, and obtains described 1,2,3-triazolo 1,3-diazacyclo compound;
Wherein, Y is O or NR '; R ' is hydrogen, halogen, nitro, cyano group, amido, C
1～8Alkyl, C
1～8Alkylamino radical, C
1～8Alkyloyl, oxa alkyl, oxa-acyl group, thia alkyl or thia acyl group;
N=1,2 or 3;
R
1Be indyl, oxazolyl, thiazolyl, imidazolyl, naphthyl, benzo pyridyl, benzimidazolyl-or benzothiazolyl; Perhaps, be the phenyl that replaces, the pyridyl of replacement, indyl, replacement De oxazolyl, the thiazolyl of replacement, the imidazolyl of replacement, the naphthyl of replacement, the benzo pyridyl of replacement, the benzimidazolyl-of replacement or the benzothiazolyl of replacement of replacement; Described substituting group is selected from fluorine, chlorine, bromine, iodine, nitro, cyano group, amido, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, methylamino, ethylamino-, Propylamino, isopropylamine base, n-butylamine-based, isobutyl amine, the TERTIARY BUTYL AMINE base, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, positive butylthio, the isobutyl sulfenyl, uncle's butylthio, formyl radical, ethanoyl, propionyl, different propionyl, positive butyryl radicals, isobutyryl, uncle's butyryl radicals, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, N, the N-dimethyl amido, N, N-diethyl amido, N, N-dipropyl amido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl;
And, as n=1 or 2 and during Y=NH, R
1Be not phenyl, to fluorophenyl, rubigan, p-methylphenyl and p-methoxyphenyl; As n=2 and Y=N-CH
3The time, R
1Be not to fluorophenyl.
5. preparation method according to claim 4 is characterized in that: the solvent of described reaction is selected from acetonitrile, tetrahydrofuran (THF), trichloromethane, methylene dichloride, 1,2-ethylene dichloride, 1,4-dioxane, toluene, ethyl acetate.
6. preparation method according to claim 4 is characterized in that: the temperature of reaction is 0-160 ℃.
7. preparation method according to claim 4 is characterized in that: the mol ratio of formula II compound and formula III compound is 0.8-2.0: 0.8-2.0.
8. the described 1,2,3-triazoles of claim 1 and 1, the application of 3-diazacyclo compound on the preparation sterilant.
9. the described 1,2,3-triazoles of claim 1 and 1, the application of 3-diazacyclo compound on anti-cancer of the stomach of preparation and anti-breast cancer medicines.
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Non-Patent Citations (6)
| Title |
|---|
| bo liu,mei-xiang wang, li-ben wang等.the reaction of aroyl-substituted heterocyclic ketene aminalswith aryl azides.Heteroatom chemistry11 (6).2000,11((6)),387-391. |
| bo liu,mei-xiang wang,li-ben wang等.the reaction of aroyl-substituted heterocyclic ketene aminalswith aryl azides.Heteroatom chemistry11 (6).2000,11((6)),387-391. * |
| qiang yang, zhan-jiang li, xiao-min chen等.the reaction of heteraroyl-substituted heterocyclic keteneaminals with 2,3,4,6-tetra-O-acetyl -b-glucopyranosyl azide.heteroatom chemistry13 (3).2002,13((3)),242-246. |
| qiang yang,zhan-jiang li,xiao-min chen等.the reaction of heteraroyl-substituted heterocyclic keteneaminals with 2,3,4,6-tetra-O-acetyl-b-glucopyranosyl azide.heteroatom chemistry13 (3).2002,13((3)),242-246. * |
| zhi-tang huang, mei-xiang wang.the reaction of benzoyl-substitutde heterocyclic ketenaminalswith aryl azides.journal of organic chemistry57 (1).1992,57((1)),184-190. |
| zhi-tang huang, mei-xiang wang.the reaction of benzoyl-substitutde heterocyclic ketenaminalswith aryl azides.journal of organic chemistry57 (1).1992,57((1)),184-190. * |
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