CN102408386A - Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives - Google Patents
Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives Download PDFInfo
- Publication number
- CN102408386A CN102408386A CN2011102120521A CN201110212052A CN102408386A CN 102408386 A CN102408386 A CN 102408386A CN 2011102120521 A CN2011102120521 A CN 2011102120521A CN 201110212052 A CN201110212052 A CN 201110212052A CN 102408386 A CN102408386 A CN 102408386A
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- CN
- China
- Prior art keywords
- triazole
- formula
- acetate
- replacement
- propyl
- Prior art date
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- -1 2,4-disubstituted-2H-1, 2, 3-triazole Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 239000004327 boric acid Substances 0.000 claims description 31
- 239000003960 organic solvent Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 20
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 20
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 20
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 20
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 15
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical compound C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 claims description 10
- UHOPWFKONJYLCF-UHFFFAOYSA-N 2-(2-sulfanylethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCS)C(=O)C2=C1 UHOPWFKONJYLCF-UHFFFAOYSA-N 0.000 claims description 10
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 10
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 10
- YEJCDKJIEMIWRQ-UHFFFAOYSA-N Linopirdine Chemical compound O=C1N(C=2C=CC=CC=2)C2=CC=CC=C2C1(CC=1C=CN=CC=1)CC1=CC=NC=C1 YEJCDKJIEMIWRQ-UHFFFAOYSA-N 0.000 claims description 10
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 10
- 229940022663 acetate Drugs 0.000 claims description 10
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 10
- 229940043232 butyl acetate Drugs 0.000 claims description 10
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 10
- 239000000194 fatty acid Substances 0.000 claims description 10
- 229930195729 fatty acid Natural products 0.000 claims description 10
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 10
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 10
- 229940117955 isoamyl acetate Drugs 0.000 claims description 10
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 229940017219 methyl propionate Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 10
- TWSRVQVEYJNFKQ-UHFFFAOYSA-N pentyl propanoate Chemical compound CCCCCOC(=O)CC TWSRVQVEYJNFKQ-UHFFFAOYSA-N 0.000 claims description 10
- 229940090181 propyl acetate Drugs 0.000 claims description 10
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 10
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000638 solvent extraction Methods 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 7
- KNVJTCKKCLWSII-UHFFFAOYSA-L O1CCCC1.[Cl-].[Li+].[Cl-].C(C)(C)[Mg+] Chemical compound O1CCCC1.[Cl-].[Li+].[Cl-].C(C)(C)[Mg+] KNVJTCKKCLWSII-UHFFFAOYSA-L 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 5
- 235000011089 carbon dioxide Nutrition 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910021536 Zeolite Inorganic materials 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000005621 boronate group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical group O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 18
- ZOYCSDVMNWQTGB-UHFFFAOYSA-N 2-bromotriazole Chemical compound BrN1N=CC=N1 ZOYCSDVMNWQTGB-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- ZAFJCESPRXTGMG-UHFFFAOYSA-N 4-bromo-2-[(3-methoxyphenyl)methyl]triazole Chemical compound COc1cccc(Cn2ncc(Br)n2)c1 ZAFJCESPRXTGMG-UHFFFAOYSA-N 0.000 description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- PUVQVJPJOFGBFT-UHFFFAOYSA-N 4-bromo-2-ethyltriazole Chemical compound CCN1N=CC(Br)=N1 PUVQVJPJOFGBFT-UHFFFAOYSA-N 0.000 description 3
- IKEWONYTNWDSND-UHFFFAOYSA-N Brc1cnn(n1)C1CCCC1 Chemical compound Brc1cnn(n1)C1CCCC1 IKEWONYTNWDSND-UHFFFAOYSA-N 0.000 description 3
- LSFUZMLRQMWUEI-UHFFFAOYSA-N C(C1=CC=CC=C1)N1N=CC(=N1)Br Chemical compound C(C1=CC=CC=C1)N1N=CC(=N1)Br LSFUZMLRQMWUEI-UHFFFAOYSA-N 0.000 description 3
- RMSNIWSLKWSSBP-UHFFFAOYSA-N CCCn1ncc(Br)n1 Chemical compound CCCn1ncc(Br)n1 RMSNIWSLKWSSBP-UHFFFAOYSA-N 0.000 description 3
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- KTSIELCAQWRVAI-UHFFFAOYSA-N 2-cyclopentyltriazole-4-carboxylic acid Chemical compound OC(=O)c1cnn(n1)C1CCCC1 KTSIELCAQWRVAI-UHFFFAOYSA-N 0.000 description 2
- FEUUHWYUKDPCKU-UHFFFAOYSA-N 2-ethyltriazole-4-carboxylic acid Chemical compound CCN1N=CC(C(O)=O)=N1 FEUUHWYUKDPCKU-UHFFFAOYSA-N 0.000 description 2
- CFKZTQWMLBGDDA-UHFFFAOYSA-N 2-propyltriazole-4-carboxylic acid Chemical compound CCCN1N=CC(C(O)=O)=N1 CFKZTQWMLBGDDA-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- QSLKCCSCWWCKAQ-UHFFFAOYSA-N 2-[(3-methoxyphenyl)methyl]triazole-4-carboxylic acid Chemical compound COC1=CC=CC(CN2N=C(C=N2)C(O)=O)=C1 QSLKCCSCWWCKAQ-UHFFFAOYSA-N 0.000 description 1
- GFFNQCSTALBIGY-UHFFFAOYSA-N 2-benzyl-4-(trifluoromethoxy)triazole Chemical compound FC(OC1=NN(N=C1)CC1=CC=CC=C1)(F)F GFFNQCSTALBIGY-UHFFFAOYSA-N 0.000 description 1
- PXGCUTZOOVBRHV-UHFFFAOYSA-N 2-benzyl-4-methyltriazole Chemical compound N1=C(C)C=NN1CC1=CC=CC=C1 PXGCUTZOOVBRHV-UHFFFAOYSA-N 0.000 description 1
- YOBRSSKXKOZDKM-UHFFFAOYSA-N 2-benzyl-5-(trifluoromethyl)triazole-4-carboxylic acid Chemical compound FC(F)(F)C=1C(=NN(N1)CC1=CC=CC=C1)C(=O)O YOBRSSKXKOZDKM-UHFFFAOYSA-N 0.000 description 1
- BCKOLQGUEQNBOG-UHFFFAOYSA-N 2-benzyl-5-chlorotriazole-4-carboxylic acid Chemical compound N1=C(Cl)C(C(=O)O)=NN1CC1=CC=CC=C1 BCKOLQGUEQNBOG-UHFFFAOYSA-N 0.000 description 1
- UVYYSORXDVRFRI-UHFFFAOYSA-N 2-benzyltriazole-4-carboxylic acid Chemical compound N1=C(C(=O)O)C=NN1CC1=CC=CC=C1 UVYYSORXDVRFRI-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- GFNZYOVVRMWTOF-UHFFFAOYSA-N 2-methyltriazole-4-carboxylic acid Chemical compound CN1N=CC(C(O)=O)=N1 GFNZYOVVRMWTOF-UHFFFAOYSA-N 0.000 description 1
- MEEKMZNPDDHRHE-UHFFFAOYSA-N 5-bromo-2-methyltriazole-4-carboxylic acid Chemical compound CN1N=C(Br)C(C(O)=O)=N1 MEEKMZNPDDHRHE-UHFFFAOYSA-N 0.000 description 1
- GMQYLNVVAMYICZ-UHFFFAOYSA-N CC1=NN(CC2=CC=CC=C2)N=C1C(O)=O Chemical compound CC1=NN(CC2=CC=CC=C2)N=C1C(O)=O GMQYLNVVAMYICZ-UHFFFAOYSA-N 0.000 description 1
- ZZXJLTSLKHDXJM-UHFFFAOYSA-N CN1N=CC(=N1)C(=O)O.FC1=CC=CC=C1 Chemical compound CN1N=CC(=N1)C(=O)O.FC1=CC=CC=C1 ZZXJLTSLKHDXJM-UHFFFAOYSA-N 0.000 description 1
- JIPYZFCNCDAGBI-UHFFFAOYSA-N CN1N=CC=N1.FC1=CC=CC=C1 Chemical compound CN1N=CC=N1.FC1=CC=CC=C1 JIPYZFCNCDAGBI-UHFFFAOYSA-N 0.000 description 1
- OKCRGENEZFTYKD-UHFFFAOYSA-N COc1ccc(C[n](nc2)nc2Br)cc1 Chemical compound COc1ccc(C[n](nc2)nc2Br)cc1 OKCRGENEZFTYKD-UHFFFAOYSA-N 0.000 description 1
- IZWBTEMIDFFIPC-UHFFFAOYSA-N COc1ccc(C[n](nc2Br)nc2Br)cc1 Chemical compound COc1ccc(C[n](nc2Br)nc2Br)cc1 IZWBTEMIDFFIPC-UHFFFAOYSA-N 0.000 description 1
- PQEIOSUFZMWYSZ-UHFFFAOYSA-N COc1cccc(C[n]2nc(B(O)O)cn2)c1 Chemical compound COc1cccc(C[n]2nc(B(O)O)cn2)c1 PQEIOSUFZMWYSZ-UHFFFAOYSA-N 0.000 description 1
- WHILOWIJXVRQLR-UHFFFAOYSA-N N1=C(Cl)C=NN1CC1=CC=CC=C1 Chemical compound N1=C(Cl)C=NN1CC1=CC=CC=C1 WHILOWIJXVRQLR-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 2,4-disubstituted-2H-1,2,3-triazole derivatives and particularly relates to a preparation method of 2-substituted-2H-1,2,3-triazole-4-carboxylic acid compounds and 2-substituted-2H-1,2,3-triazole-4-boric acid compounds. The preparation method is simple and feasible and the obtained compounds have high yield.
Description
Technical field
The present invention relates to the organic synthesis intermediate preparing technical field, relate in particular to new compound 2,4-two replacement-2H-1,2,3-triazole verivate and preparation method thereof.Further, the present invention relates to new compound 2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1,2,3-triazole-4-boric acid and preparation method thereof.
Background technology
2,4-two replacement-2H-1,2,3-triazole verivate is one type of novel compound with huge exploitation value.The compound that with the triazole is parent nucleus has potential widely using value, is the important intermediate of present many medicines, weedicide and agrochemical compound, also is pharmacophoric group main in a lot of drug molecules.
2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1,2,3-triazole-4-boric acid is novel active intermediate, can be used as very important active precursor, in organic synthesis, is applied.
Summary of the invention
Goal of the invention: the object of the present invention is to provide a kind of novel 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate; Further, the present invention provides 2-replacement-2H-1, and 2; 3-triazole-4-carboxylic acid and 2-replacement-2H-1,2, the preparation method of 3-triazole-4-boric acid.
Technical scheme: in order to realize the foregoing invention purpose, the technical scheme that the present invention adopts is following:
2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate is characterized in that: 2,4-two replacement-2H-1,2,3-triazole verivate has following structure:
Formula I
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl; R2 representes carboxyl or boronate.
When R2 is carboxyl, described 2,4-two replacement-2H-1,2,3-triazole verivate is 2-replacement-2H-1,2,3-triazole-4-carboxylic acid (formula II);
Formula II
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
When R2 is boronate, described 2,4-two replacement-2H-1,2,3-triazole verivate is 2-replacement-2H-1,2,3-triazole-4-boric acid (formula III).
Formula III
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound II of the present invention can be prepared by compound VIII.
Formula VIII
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound VIII has had detailed description in applicant's No. 201110166067.9 patented claim.
Compound VIII of the present invention is dissolved in mass volume ratio 1: 1～100, in preferred 1: 5～20 the organic solvent, adds 0.1～50%, the metal catalyst of preferred 0.5～10% weight ratio; Feed hydrogen, keep pressure 1～100atm, preferred 1～10atm; At 0～200 ℃, preferred 10～50 ℃, reacted 1～50 hour; At room temperature filter, be evaporated to driedly, enriched material obtains compound II through recrystallization;
Described organic solvent is the mixing of one or more arbitrary proportions in alcohols or the fatty acid ester; Comprise the mixing of one or more arbitrary proportions in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and the amyl propionate, ethyl acetate, methyl alcohol;
Described metal catalyst is that in palladium metal, ruthenium, the platinum one or more are carried on the charge capacity of processing on gac, aluminum oxide or the Zeolite support is 1～10% catalyzer, preferred 5～10% palladium charcoal.
Reaction formula is as follows:
Compound I of the present invention can also be prepared by compound VI.
Formula VI
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound VI of the present invention is dissolved in mass volume ratio 1: 2～20 ether, THF or 1, the 4-dioxane is cooled to-20～30 ℃; Add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour, be cooled to-50～20 ℃; Fed dioxide gas about 10～30 minutes, and be warming up to room temperature, regulate pH=1～5 with hydrochloric acid after; Use organic solvent extraction; Through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying, be evaporated to driedly, enriched material obtains compound II through recrystallization;
Compound VI of the present invention is dissolved in mass volume ratio 1: 2～20 ether, THF or 1, the 4-dioxane is cooled to-20～30 ℃; Add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour, be cooled to-50～20 ℃; Add compound boric acid ester (formula IX), stirred 0.1～2 hour, be warming up to room temperature; After regulating pH=1～5 with hydrochloric acid, use organic solvent extraction, through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying; Be evaporated to driedly, enriched material obtains the compound formula III through recrystallization;
Formula IX
Wherein, R3 representes the straight or branched alkyl of C1～C5, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl.
The mol ratio of compound VI of the present invention and isopropylmagnesium chloride-lithium chloride mixture is 1: 0.8～2.0, preferred 1: 1.2～1.5; The mol ratio of compound VI and boric acid ester (formula IX) or carbonic acid gas is 1: 1～10, preferred 1: 1.2～2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers; Comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE, ethyl acetate, MTBE.
Compound VI and grignard reagent isopropylmagnesium chloride-lithium chloride mixture generation format exchange reaction generates compound VII.
Compound VII need not separate, and directly formats reaction with carbonic acid gas or boric acid ester again, generates compound II or compound formula III.
Reaction formula is as follows:
Isopropylmagnesium chloride of the present invention-lithium chloride mixture is the tetrahydrofuran solution of its different volumetric molar concentrations, and commercially available concentration is generally 1.0～1.3 mol.
Compound VI of the present invention is prepared by compound IV.
Formula IV
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound IV has had detailed description in applicant's No. 201110166067.9 patented claim.
Compound IV of the present invention is dissolved in mass volume ratio 1: 2～20 ether, THF or 1, the 4-dioxane is cooled to-78～0 ℃; Add isopropylmagnesium chloride, stirred 0.1～2 hour, add the water of mass ratio 1: 1～20; After regulating pH=1～5 with hydrochloric acid, use organic solvent extraction, through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying; Be evaporated to driedly, obtain compound VI.
The mol ratio of compound IV of the present invention and isopropylmagnesium chloride is 1: 0.8～1.2, preferred 1: 1～1.1; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers; Comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE, ethyl acetate, MTBE.
Compound IV and the reaction of grignard reagent isopropylmagnesium chloride generation format exchange generate compound V.Compound V, direct and water reaction through aftertreatment, obtains compound VI.
Reaction formula is as follows:
Isopropylmagnesium chloride of the present invention is tetrahydrofuran solution, 2-methyltetrahydrofuran solution or the diethyl ether solution of its different volumetric molar concentrations, and commercially available concentration is generally 1.0～2.0 mol.
Compound I of the present invention also can be prepared by compound IV one kettle way, and midbody compound formula VI need not separate.Operation steps is following: compound IV is dissolved in mass volume ratio 1: 2～20 ether, THF or 1, and the 4-dioxane is cooled to-78～0 ℃, adds isopropylmagnesium chloride; Stirred 0.1～2 hour, and slowly added C1～C4 lower alcohol, stirred 0.5～1 hour; Under-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour; Be cooled to-50～20 ℃, feed about 10～30 minutes of dioxide gas or add compound boric acid ester (formula IX), stirred 0.1～2 hour; Be warming up to room temperature, regulate pH=1～5 with hydrochloric acid after, use organic solvent extraction; Through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying, be evaporated to driedly, enriched material obtains compound I through recrystallization.
The mol ratio of compound IV of the present invention and C1～C4 lower alcohol is 1: 0.8～1.2, preferred 1: 1～1.1; The lower alcohol of described C1～C4 comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of described compound IV and 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8～2.0, preferred 1: 1.2～1.5; The mol ratio of compound IV and boric acid ester (formula IX) or carbonic acid gas is 1: 1～10, preferred 1: 1.2～2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers; Comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE, ethyl acetate, MTBE.
One kettle way of the present invention prepares compound I, compares with the method for fractional steps, and total recovery can improve 3～10%.
The method of recrystallization of the present invention may further comprise the steps, and presses mass volume ratio 1: 1～100, preferred 1: 2～20 enriched material to be added in the organic solvent, and at-20～50 ℃, preferred 0～25 ℃ was stirred 0.5～24 hour, filtered, and vacuum-drying obtains pure article.
The used organic solvent of recrystallization of the present invention is the mixing of one or more arbitrary proportions in fatty acid ester, ketone, ethers and the hydro carbons; Comprise ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, acetone, 2-butanone, ketopentamethylene and pimelinketone, ether, propyl ether, isopropyl ether, MTBE and THF, 1; The mixing of one or more arbitrary proportions in 4-dioxane, sherwood oil, normal hexane, hexanaphthene, methylcyclohexane and the normal heptane, the mixed solvent of ethyl acetate or MTBE and normal hexane arbitrary proportion.
Of the present invention 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate is simple, and the compound yield of acquisition is high.
Embodiment
Below in conjunction with specific embodiment the present invention is done further explanation.
Embodiment 1:
With 10g (41.5mmol) 2-methyl-4,5-two bromo-2H-1,2, the 3-triazole is dissolved in the 100ml THF, is cooled to-15～-5 ℃, slowly adds 22.4ml (44.8mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finishes, and continues reaction 0.5 hour.Slowly add 10ml water, temperature＜-10 ℃, extract with the 100ml MTBE to pH=1～2 with the 1.0M hcl acidifying again; Organic layer is through anhydrous sodium sulfate drying, is evaporated to driedly, obtains 4-bromo-2-methyl-2H-1; 2,3-triazole 5.85g, yield 87%.
1H?NMR(CDCl
3，500MHz)：δ7.52(s，1H)，4.18(s，3H)；
13C?NMR(CDCl
3，500MHz)：δ135.4，42.3。
Embodiment 2:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 10.6g (41.5mmol) 2-ethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-ethyl-2H-1,2,3-triazole 6.94g, yield 95%.
1H?NMR(CDCl
3，400MHz)：δ7.52(s，1H)，4.44(t，J＝7.2Hz，2H)，1.55(t，J＝7.2Hz，3H)；
13C?NMR(CDCl
3，400MHz)：δ135.1，121.4，50.8，14.7。
Embodiment 3:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 11.16g (41.5mmol) 2-n-propyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-n-propyl-2H-1,2,3-triazole 7.57g, yield 96%.
1H?NMR(CDCl
3，400MHz)：δ7.52(s，1H)，4.35(t，J＝7.2Hz，2H)，2.01-1.92(m，2H)，0.92(t，J＝7.4Hz，3H)；
13CNMR(CDCl
3，400MHz)：δ135.0，121.4，57.3，23.0，11.0。
Embodiment 4:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 12.24g (41.5mmol) 2-cyclopentyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-cyclopentyl-2H-1,2,3-triazole 8.6g, yield 96%.
1H?NMR(CDCl
3，400MHz)：δ7.50(s，1H)，4.99-4.93(m，1H)，2.18-2.13(m，4H)，1.90-1.86(m，2H)，1.71-1.68(m，2H)；
13C?NMR(CDCl
3，400MHz)：δ134.7，121.1，66.9，32.7，24.3。
Embodiment 5:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 13.1g (41.5mmol) 2-phenmethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-phenmethyl-2H-1,2,3-triazole 9.48g, yield 96%.
1H?NMR(CDCl
3，400MHz)：δ7.56(s，1H)，7.267.38-7.32(m，5H)，5.55(s，2H)；
13C?NMR(CDCl
3，400MHz)：δ135.8，134.5，128.9，128.6，128.2，122.2，59.4。
Embodiment 6:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 13.7g (41.5mmol) 2-to methylbenzyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-to methylbenzyl-2H-1,2,3-triazole 10.25g, yield 98%.
1H?NMR(CDCl
3，400MHz)：δ7.53(s，1H)，7.23(ABq，J＝8.0Hz，2H)，7.15(ABq，J＝8.0Hz，2H)，5.69(s，2H)，2.32(s，3H)；
13C?NMR(CDCl
3，400MHz)：δ138.5，135.7，131.5，129.6，128.3，122.0，59.2，21.2。
Embodiment 7:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 14.4g (41.5mmol) 2-meta-methoxy phenmethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-meta-methoxy phenmethyl-2H-1,2,3-triazole 10.78g, yield 97%.
1H?NMR(CDCl
3，400MHz)：δ7.56(s，1H)，7.26(t，J＝8.0Hz，1H)，6.92-6.87(m，2H)，6.85(s，1H)，5.52(s，2H)，3.79(s，3H)；
13C?NMR(CDCl
3，400MHz)：δ159.9，135.9，135.8，130.0，122.2，120.4，114.1，113.7，59.3，55.3。
Embodiment 8:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 14.4g (41.5mmol) 2-to mehtoxybenzyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-to mehtoxybenzyl-2H-1,2,3-triazole 10.78g, yield 97%.
1H?NMR(CDCl
3，500MHz)：δ7.54(s，1H)，7.30(ABq，J＝8.2Hz，2H)，6.88(ABq，J＝8.2Hz，2H)，5.48(s，2H)，3.79(s，3H)；
13C?NMR(CDCl
3，500MHz)：δ159.9，135.6，129.8，126.6，122.0，114.2，59.0，55.3。
Embodiment 9:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 13.9g (41.5mmol) 2-to fluorobenzene methyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-to fluorobenzene methyl-2H-1,2,3-triazole 10.2g, yield 96%.
1H?NMR(CDCl
3，500MHz)：δ7.56(s，1H)，7.33(dd，J＝5.7，8.2Hz，2H)，7.03(dd，J＝8.2，9.0Hz，2H)，5.51(s，2H)；
13C?NMR(CDCl
3，500MHz)：δ162.8(d，J＝246.0Hz)，135.9，130.3(d，J＝3.3Hz)，130.2(d，J＝8.3Hz)，122.3，115.9(d，J＝21.6Hz)，58.6。
Embodiment 10:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 14.58g (41.5mmol) 2-to chlorophenylmethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-to chlorophenylmethyl-2H-1,2,3-triazole 10.5g, yield 93%.
1H?NMR(CDCl
3，400MHz)：δ7.56(s，1H)，7.32(ABq，J＝8.8Hz，2H)，7.26(ABq，J＝8.8Hz，2H)，5.51(s，2H)；
13C?NMR(CDCl
3，400MHz)：δ136.0，135.2，132.9，129.6，129.1，122.4，58.6。
Embodiment 11:
Working method is with embodiment 1, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 16.64g (41.5mmol) 2-to trifluoromethoxy phenmethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 4-bromo-2-to trifluoromethoxy phenmethyl-2H-1,2,3-triazole 12.8g, yield 96%.
1H?NMR(CDCl
3，400MHz)：δ7.58(s，1H)，7.36(ABq，J＝8.6Hz，2H)，7.20(ABq，J＝8.6Hz，2H)，5.55(s，2H)；
13C?NMR(CDCl
3，400MHz)：δ149.4，136.0，133.1，129.8，122.5，121.3，120.4(q，J＝256.0Hz)，58.5。
Embodiment 12:
With 3.24g (20mmol) 4-bromo-2-methyl-2H-1,2, the 3-triazole is dissolved in the 50ml THF, at 10～20 ℃, slowly adds 18.5ml (24mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution.Finish, continue reaction 2 hours.Be cooled to below 0 ℃, fed dioxide gas about 10～30 minutes, temperature＜15 ℃.At room temperature, to pH=1～2, with the extraction of 100ml MTBE, organic layer is evaporated to dried through anhydrous sodium sulfate drying again with the 1.0M hcl acidifying.Residual solid is dissolved in 5ml ETHYLE ACETATE, drips the 20ml normal hexane under the room temperature, continue to stir 1 hour, filter, room temperature vacuum-drying obtains 2-methyl-2H-1, and 2,3-triazole-4-carboxylic acid 1.78g, yield 70%.
1H?NMR(CD
3COCD
3，500MHz)：δ8.07(s，1H)，4.26(s，3H)；
13CNMR(CD
3COCD
3，500MHz)：δ161.7，141.0，137.4，42.6。
Embodiment 13:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 3.52g (20mmol) 4-bromo-2-ethyl-2H-1,2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid 2.1g, yield 74%.
1H?NMR(CDCl
3，400MHz)：δ11.57(bs，1H)，8.17(s，1H)，4.62(t，J＝7.2Hz，2H)，1.64(t，J＝7.2Hz，2H)；
13C?NMR(CDCl
3，400MHz)δ165.3，138.9，137.4，51.1，14.6。
Embodiment 14:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 3.8g (20mmol) 4-bromo-2-n-propyl-2H-1,2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid 2.45g, yield 79%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.12(s，1H)，4.49(t，J＝7.0Hz，2H)，2.03-1.96(m，2H)，0.92(t，J＝7.4Hz，3H)；
13C?NMR(CD
3COCD
3，400MHz)δ161.9，140.8，137.6，57.7，23.6，11.2。
Embodiment 15:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 4.3g (20mmol) 4-bromo-2-cyclopentyl-2H-1,2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid 3.1g, yield 85%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.09(s，1H)，5.15-5.09(m，1H)，2.24-2.14(m，4H)，1.90-1.86(m，2H)，1.78-1.74(m，2H)；
13C?NMR(CD
3COCD
3，400MHz)：δ161.9，140.5，137.4，67.5，33.4，24.9。
Embodiment 16:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 4.76g (20mmol) 4-bromo-2-phenmethyl-2H-1,2,3-triazole.Obtain 2-phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 3.7g, yield 91%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.14(s，1H)，7.39-7.33(m，5H)，5.67(s，2H)；
13C?NMR(CD
3COCD
3，400MHz)：δ165.3，139.3，138.1，133.9，129.0，128.8，128.4，59.7。
Embodiment 17:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.06g (20mmol) 4-bromo-2-to methylbenzyl-2H-1, and 2, the 3-triazole.Obtain 2-to methylbenzyl-2H-1,2,3-triazole-4-carboxylic acid 3.82g, yield 88%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.11(s，1H)，7.28(ABq，J＝8.0Hz，2H)，7.19(ABq，J＝8.0Hz，2H)，5.66(s，2H)，2.30(s，3H)；
13C?NMR(CD
3COCD
3，400MHz)：δ161.7，141.3，139.0，138.0，133.1，130.2，129.1，59.6，21.1。
Embodiment 18:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.4g (20mmol) 4-bromo-2-meta-methoxy phenmethyl-2H-1,2,3-triazole.Obtain 2-meta-methoxy phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 3.82g, yield 82%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.13(s，1H)，7.29(t，J＝8.0Hz，1H)，6.95-6.90(m，3H)，5.69(s，2H)，3.78(s，3H)；
13C?NMR(CD
3COCD
3，400MHz)：δ161.7，160.9，141.4，138.1，137.5，130.7，121.1，114.8，114.5，59.7，55.6。
Embodiment 19:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.4g (20mmol) 4-bromo-2-to mehtoxybenzyl-2H-1, and 2, the 3-triazole.Obtain 2-to mehtoxybenzyl-2H-1,2,3-triazole-4-carboxylic acid 4.2g, yield 90%.
1H?NMR(CD
3COCD
3，500MHz)：δ8.10(s，1H)，7.35(ABq，J＝8.5Hz，2H)，6.92(ABq，J＝8.5Hz，2H)，5.63(s，2H)，3.78(s，3H)；
13C?NMR(CD
3COCD
3，500MHz)：δ161.7，160.8，141.2，138.0，130.7，128.0，114.9，59.4，55.6。
Embodiment 20:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.1g (20mmol) 4-bromo-2-to fluorobenzene methyl-2H-1, and 2, the 3-triazole.Obtain 2-to fluorobenzene methyl-2H-1,2,3-triazole-4-carboxylic acid 3.76g, yield 85%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.13(s，1H)，7.46(dd，J＝5.7，8.2Hz，2H)，7.16(dd，J＝8.2，9.0Hz，2H)，5.72(s，2H)；
13C?NMR(CD
3COCD
3，400MHz)：δ163.6(d，J＝244.0Hz)，141.4，138.1，132.3(d，J＝3.0Hz)，131.4(d，J＝8.0Hz)，122.3，116.3(d，J＝21.0Hz)，59.0。
Embodiment 21:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.45g (20mmol) 4-bromo-2-to chlorophenylmethyl-2H-1, and 2, the 3-triazole.Obtain 2-to chlorophenylmethyl-2H-1,2,3-triazole-4-carboxylic acid 2.62g, yield 55%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.14(s，1H)，7.42(s，4H)，5.74(s，2H)；
13C?NMR(CD
3COCD
3，400MHz)：δ165.9，145.8，142.6，142.4，139.3，135.2，134.0，63.2。
Embodiment 22:
Working method is with embodiment 12, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 6.45g (20mmol) 4-bromo-2-to trifluoromethyl phenmethyl-2H-1, and 2, the 3-triazole.Obtain 2-to trifluoromethyl phenmethyl-2H-1,2,3-triazole-4-carboxylic acid 4.65g, yield 81%.
1H?NMR(CD
3COCD
3，400MHz)：δ8.15(s，1H)，7.54(ABq，J＝8.4Hz，2H)，7.36(ABq，J＝8.4Hz，2H)，5.79(s，2H)；
13C?NMR(CD
3COCD
3，400MHz)：δ161.6，149.9，141.6，138.2，135.4，131.1，122.2，121.4(q，J＝254.0Hz)，58.8。
Embodiment 23:
With 3.24g (20mmol) 4-bromo-2-methyl-2H-1,2, the 3-triazole is dissolved in the 50ml THF, at 10～20 ℃, slowly adds 18.5ml (24mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finishes, and continues reaction 2 hours.Be cooled to below-20 ℃, add trimethyl borate 3.5ml (30mmol), continue reaction 0.5～2 hour.At room temperature, to pH=1～2, use the 100ml ethyl acetate extraction with the 1.0M hcl acidifying again, organic layer is evaporated to dried through anhydrous sodium sulfate drying.Resistates is dissolved in the 20ml MTBE, drips the 30ml normal hexane under the room temperature, is cooled to 0～5 ℃, stirs 1 hour, and filtration, room temperature vacuum-drying obtain 2-methyl-2H-1, and 2,3-triazole-4-boric acid 1.6g, yield 63%.
1H?NMR(DMSO-d6，400MHz)：δ7.93(s，1H)，4.19(s，3H)；
13C?NMR(DMSO-d6，400MHz)：δ142.0，41.0。
Embodiment 24:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 3.52g (20mmol) 4-bromo-2-ethyl-2H-1,2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-boric acid 1.0g, yield 72%.
1H?NMR(DMSO-d6，400MHz)：δ7.92(s，1H)，4.46(t，J＝7.2Hz，2H)，1.45(t，J＝7.2Hz，3H)；
13C?NMR(DMSO-d6，400MHz)δ140.6，49.0，14.7。
Embodiment 25:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 3.8g (20mmol) 4-bromo-2-n-propyl-2H-1,2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-boric acid 2.66g, yield 86%.
1H?NMR(DMSO-d6，400MHz)：δ7.94(s，1H)，4.40(t，J＝6.8Hz，2H)，1.92-1.86(m，2H)，0.83(t，J＝7.4Hz，3H)；
13C?NMR(DMSO-d6，400MHz)δ141.6，140.6，55.4，22.7，10.9。
Embodiment 26:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 4.3g (20mmol) 4-bromo-2-cyclopentyl-2H-1,2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-boric acid 3.08g, yield 85%.
1H?NMR(DMSO-d6，400MHz)：δ7.92(s，1H)，5.09-5.02(m，1H)，2.14-2.03(m，4H)，1.984-1.78(m，2H)，1.69-1.66(m，2H)；
13C?NMR(DMSO-d6，400MHz)：δ141.5(bs)，140.4，64.9，32.4，23.9。
Embodiment 27:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 4.76g (20mmol) 4-bromo-2-phenmethyl-2H-1,2,3-triazole.Obtain 2-phenmethyl-2H-1,2,3-triazole-4-boric acid 3.53g, yield 87%.
1H?NMR(DMSO-d6，400MHz)：δ7.99(s，1H)，7.37-7.24(m，5H)，5.68(s，2H)；
13C?NMR(DMSO-d6，400MHz)：δ142.1，141.1，137.1，133.0，129.0，127.6，57.2，20.6。
Embodiment 28:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.06g (20mmol) 4-bromo-2-to methylbenzyl-2H-1, and 2, the 3-triazole.Obtain 2-to methylbenzyl-2H-1,2,3-triazole-4-boric acid 3.81g, yield 88%.
1H?NMR(DMSO-d6，400MHz)：δ7.96(s，1H)，7.15(s，4H)，5.62(s，2H)，2.27(s，3H)；
13C?NMR(DMSO-d6，400MHz)：δ142.0，141.1?136.0，128.5，127.8，127.6，57.4。
Embodiment 29:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.4g (20mmol) 4-bromo-2-meta-methoxy phenmethyl-2H-1,2,3-triazole.Obtain 2-meta-methoxy phenmethyl-2H-1,2,3-triazole-4-boric acid 3.82g, yield 82%.
1H?NMR(DMSO-d6，400MHz)：δ8.37(bs，2H)，7.96(s，1H)，7.26(t，J＝8.0Hz，1H)，6.87(d，J＝8.0Hz，1H)，6.80(s，1H)，6.79(d，J＝8.0Hz，1H)，5.63(s，2H)，3.72(s，3H)；
13C?NMR(DMSO-d6，400MHz)：δ159.2，141.1，138.1，137.5，129.6，119.6，113.3，113.1，57.2，55.0。
Embodiment 30:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.4g (20mmol) 4-bromo-2-to mehtoxybenzyl-2H-1, and 2, the 3-triazole.Obtain 2-to mehtoxybenzyl-2H-1,2,3-triazole-4-boric acid 3.77g, yield 81%.
1H?NMR(CD
3COCD
3，400MHz)：δ7.90(s，1H)，7.27(ABq，J＝8.6Hz，2H)，6.89(ABq，J＝8.6Hz，2H)，5.58(s，2H)，3.77(s，3H)；
13C?NMR(CD
3COCD
3，400MHz)：δ160.5，141.7，130.3，129.0，114.8，58.4，55.6。
Embodiment 31:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.1g (20mmol) 4-bromo-2-to fluorobenzene methyl-2H-1, and 2, the 3-triazole.Obtain 2-to fluorobenzene methyl-2H-1,2,3-triazole-4-boric acid 3.1g, yield 70%.
1H?NMR(DMSO-d6，400MHz)：δ7.97(s，1H)，7.46(dd，J＝5.7，8.6Hz，2H)，7.19(dd，J＝8.6，9.0Hz，2H)，5.67(s，2H)；
13C?NMR(DMSO-d6，400MHz)：δ161.7(d，J＝243.0Hz)，141.1，132.2(d，J＝3.0Hz)，129.9(d，J＝9.0Hz)，115.4(d，J＝22.0Hz)，56.5。
Embodiment 32:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 5.45g (20mmol) 4-bromo-2-to chlorophenylmethyl-2H-1, and 2, the 3-triazole.Obtain 2-to chlorophenylmethyl-2H-1,2,3-triazole-4-boric acid 2.45g, yield 52%.
1H?NMR(DMSO-d6，400MHz)：δ7.99(s，1H)，7.42(ABq，J＝8.4Hz，2H)，7.27(ABq，J＝8.4Hz，2H)，5.69(s，2H)；
13C?NMR(DMSO-d6，400MHz)δ141.2，135.0，132.5，129.5，128.5，128.4，56.6。
Embodiment 33:
Working method is with embodiment 23, with 4-bromo-2-methyl-2H-1, and 2, the 3-triazole replaces with 6.45g (20mmol) 4-bromo-2-to trifluoromethyl phenmethyl-2H-1, and 2, the 3-triazole.Obtain 2-to trifluoromethyl phenmethyl-2H-1,2,3-triazole-4-boric acid 3.79g, yield 66%.
1H?NMR(DMSO-d6，400MHz)：δ8.00(s，1H)，7.39(ABq，J＝9.2Hz，2H)，7.36(ABq，J＝9.2Hz，2H)，5.74(s，2H)；
13C?NMR(DMSO-d6，400MHz)：δ147.9(d，J＝2.0Hz)，141.3，135.5，129.7，121.3，119.9(q，J＝245.0Hz)，56.5。
Embodiment 34:
With 5g (20.7mmol) 2-methyl-4,5-two bromo-2H-1,2, the 3-triazole is dissolved in the 40ml THF, is cooled to-15～-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finishes, and continues reaction 0.5 hour.Slowly add 0.88ml (21.74mmol) methyl alcohol, be warming up to 5～15 ℃, add 17.3ml (22.4mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, continue reaction 2 hours under the room temperature.Be cooled to below 0 ℃, fed dioxide gas about 10～30 minutes, temperature＜15 ℃, with the 1.0M hcl acidifying to pH=1～2; Again with 100ml MTBE extraction, organic layer is through anhydrous sodium sulfate drying, is evaporated to driedly, and residual solid is dissolved in 5ml ETHYLE ACETATE; Drip the 20ml normal hexane under the room temperature, continue to stir 1 hour, filter room temperature vacuum-drying; Obtain 2-methyl-2H-1,2,3-triazole-4-carboxylic acid 1.74g, yield 66%.
Embodiment 35:
Working method is with embodiment 34, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid 2.34g, yield 80%.
Embodiment 36:
Working method is with embodiment 34, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid 2.66g, yield 83%.
Embodiment 37:
Working method is with embodiment 34, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid 3.3g, yield 88%.
Embodiment 38:
With 5g (20.7mmol) 2-methyl-4,5-two bromo-2H-1,2, the 3-triazole is dissolved in the 40ml THF, is cooled to-15～-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finishes, and continues reaction 0.5 hour.Slowly add 0.88ml (21.74mmol) methyl alcohol, be warming up to 5～15 ℃, add 17.3ml (22.4mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, continue reaction 2 hours under the room temperature.Be cooled to below-20 ℃, add trimethyl borate 3.6ml (31mmol), continue reaction 0.5～2 hour, with the 1.0M hcl acidifying to pH=1～2, temperature＜15 ℃; Use the 100ml ethyl acetate extraction again, organic layer is through anhydrous sodium sulfate drying, is evaporated to driedly, and resistates is dissolved in the 10ml MTBE; Drip the 30ml normal hexane under the room temperature, be cooled to 0～5 ℃, stirred 1 hour, filtration, room temperature vacuum-drying; Obtain 2-methyl-2H-1,2,3-triazole-4-boric acid 1.97g, yield 75%.
Embodiment 39:
Working method is with embodiment 38, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-ethyl-2H-1,2,3-triazole-4-boric acid 2.54g, yield 87%.
Embodiment 40:
Working method is with embodiment 38, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-n-propyl-2H-1,2,3-triazole-4-boric acid 2.95g, yield 92%.
Embodiment 41:
Working method is with embodiment 38, with 2-methyl-4, and 5-two bromo-2H-1,2, the 3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4,5-two bromo-2H-1,2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-boric acid 3.37g, yield 90%.
Embodiment 42:
With 5g (24.27mmol) 5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylic acid is dissolved in 100ml ETHYLE ACETATE, adds 0.25g 5% palladium charcoal, feeds hydrogen, keeps pressure 1～3atm, room temperature reaction 20～24 hours.Reaction finishes, and filters, and filtrate decompression is concentrated into dried.Residual solid is dissolved in 10ml ETHYLE ACETATE, and Dropwise 5 0ml normal hexane under the room temperature continues to stir 1 hour, filters, and room temperature vacuum-drying obtains 2-methyl-2H-1, and 2,3-triazole-4-carboxylic acid 2.9g, yield 95%.
Claims (11)
1.2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate, this 2,4-two replacement-2H-1,2,3-triazole verivate has following structure:
Formula I
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl; R2 representes carboxyl or boronate;
It is characterized in that, comprise step:
With formula IV compound be dissolved in mass volume ratio 1: 2～20 ether, THF or 1, the 4-dioxane is cooled to-78～0 ℃, adds isopropylmagnesium chloride; Stirred 0.1～2 hour, and slowly added C1～C4 lower alcohol, stirred 0.5～1 hour, under-20～30 ℃; Add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour, be cooled to-50～20 ℃, feed the compound boric acid ester of about 10～30 minutes of dioxide gas or adding formula IX; Stirred 0.1～2 hour, and be warming up to room temperature, regulate pH=1～5 with hydrochloric acid after, use organic solvent extraction; Through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying, be evaporated to driedly, enriched material obtains 2 of formula I through recrystallization, 4-two replacement-2H-1; 2,3-triazole verivate
Formula IV
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl;
Formula IX
Wherein, R3 representes the straight or branched alkyl of C1～C5, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl.
2. according to claim 12,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate is characterized in that, the mol ratio of described formula IV compound and lower alcohol is 1: 0.8～1.2; The lower alcohol of described C1～C4 comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of described compound IV and 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8～2.0; The mol ratio of formula IV compound and formula IX boric acid ester or carbonic acid gas is 1: 1～10; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers, comprises the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE.
3.2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate, this 2,4-two replacement-2H-1,2,3-triazole verivate has following structure:
Formula I
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl; R2 representes carboxyl or boronate;
It is characterized in that, comprise step:
With formula IV compound be dissolved in mass volume ratio 1: 2～20 ether, THF or 1, the 4-dioxane is cooled to-78～0 ℃, adds isopropylmagnesium chloride; Stirred 0.1～2 hour, and added the water of mass ratio 1: 1～20, regulate pH=1～5 with hydrochloric acid after, use organic solvent extraction; Through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying, be evaporated to driedly, obtain formula VI compound, formula VI compound further converts 2 of formula I into; 4-two replacement-2H-1,2,3-triazole verivate
Formula IV
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl;
Formula VI
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
4. according to claim 32,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate is characterized in that, the mol ratio of said formula IV compound and isopropylmagnesium chloride is 1: 0.8～1.2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers, comprises the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE.
5. according to claim 1 or 3 described 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate; It is characterized in that, when R2 is carboxyl, described 2 among the formula I, 4-two replacement-2H-1; 2,3-triazole verivate is the 2-replacement-2H-1 of formula II, 2, and 3-triazole-4-carboxylic acid;
Formula II
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl;
Said 2-replacement-2H-1,2,3-triazole-4-carboxylic acid prepares through following method: with said formula VI compound be dissolved in mass volume ratio 1: 2～20 ether, THF or 1,4-dioxane; Be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour, be cooled to-50～20 ℃; Fed dioxide gas about 10～30 minutes, and be warming up to room temperature, regulate pH=1～5 with hydrochloric acid after; Use organic solvent extraction,, be evaporated to dried through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying; Enriched material obtains said 2-replacement-2H-1 through recrystallization, and 2,3-triazole-4-carboxylic acid.
6. according to claim 1 or 3 described 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate; It is characterized in that, when R2 is carboxyl, described 2 among the formula I, 4-two replacement-2H-1; 2,3-triazole verivate is the 2-replacement-2H-1 of formula II, 2, and 3-triazole-4-carboxylic acid;
Formula II
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl;
Said 2-replacement-2H-1,2,3-triazole-4-carboxylic acid prepares through following method: in formula VIII compound is dissolved in mass volume ratio 1: 1～100 the organic solvent, add the metal catalyst of 0.1～50% weight ratio; Feed hydrogen, keep pressure 1～100atm,, reacted 1～50 hour at 0～200 ℃; At room temperature filter, be evaporated to driedly, enriched material obtains said 2-replacement-2H-1 through recrystallization; 2,3-triazole-4-carboxylic acid
Formula VIII
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
7. according to claim 62; 4-two replacement-2H-1; 2; The preparation method of 3-triazole verivate; It is characterized in that; Described organic solvent is the mixing of one or more arbitrary proportions in alcohols or the fatty acid ester, comprises the mixing of one or more arbitrary proportions in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and the amyl propionate; Described metal catalyst is that in palladium metal, ruthenium, the platinum one or more are carried on the charge capacity of processing on gac, aluminum oxide or the Zeolite support is 1～10% catalyzer.
8. according to claim 1 or 3 described 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate; It is characterized in that: when R2 is boronate, described 2 among the formula I, 4-two replacement-2H-1,2; 3-triazole verivate is the 2-replacement-2H-1 of formula III, 2, and 3-triazole-4-boric acid
Formula III
Wherein, R1 representes alkyl, aryl, aralkyl, naphthenic base, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl;
Said 2-replacement-2H-1,2,3-triazole-4-boric acid prepares through following method: with said compound VI be dissolved in mass volume ratio 1: 2～20 ether, THF or 1,4-dioxane; Be cooled to-20～30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stirred 0.5～5 hour, be cooled to-50～20 ℃; Adding formula IX compound boric acid ester stirred 0.1～2 hour, was warming up to room temperature, regulate pH=1～5 with hydrochloric acid after; Use organic solvent extraction,, be evaporated to dried through SODIUM SULPHATE ANHYDROUS 99PCT or anhydrous magnesium sulfate drying; Enriched material obtains said 2-replacement-2H-1 through recrystallization, and 2,3-triazole-4-boric acid.
9. according to claim 6 or 8 described 2,4-two replacement-2H-1,2, the preparation method of 3-triazole verivate is characterized in that, the mol ratio of described compound VI and isopropylmagnesium chloride-lithium chloride mixture is 1: 0.8～2.0; The mol ratio of formula VI compound and formula IX boric acid ester or carbonic acid gas is 1: 1～10; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or the ethers, comprises the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ether, propyl ether, isopropyl ether, the MTBE.
10. according to each is described 2 in the claim 1,5,6,8,4-two replacement-2H-1,2; The preparation method of 3-triazole verivate is characterized in that the method for described recrystallization may further comprise the steps; By mass volume ratio 1: 1～100 enriched material is added in the organic solvent, stirred 0.5～24 hour, filter at-20～50 ℃; Vacuum-drying obtains pure article.
11. according to claim 10 2; 4-two replacement-2H-1; 2; The preparation method of 3-triazole verivate; It is characterized in that; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester, ketone, ethers and the hydro carbons, comprises ethyl formate, propyl formate, butyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, acetone, 2-butanone, ketopentamethylene and pimelinketone, ether, propyl ether, isopropyl ether, MTBE and THF, 1, the mixing of one or more arbitrary proportions in 4-dioxane, sherwood oil, normal hexane, hexanaphthene, methylcyclohexane and the normal heptane.
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| CN102786485A (en) * | 2012-08-24 | 2012-11-21 | 苏州雅本化学股份有限公司 | 2-substituted-2H-1,2,3-triazole derivative and preparation method thereof |
| CN103073513A (en) * | 2012-12-14 | 2013-05-01 | 雅本化学股份有限公司 | 1-substituted-5-chlorine-2H-1, 2, 3-triazole-4-carboxylic acid derivative and preparation method thereof |
| CN104311586A (en) * | 2014-09-28 | 2015-01-28 | 南京中电熊猫液晶显示科技有限公司 | Triazole-containing compound and synthesis method thereof |
| WO2016062175A1 (en) * | 2014-10-23 | 2016-04-28 | 上海雅本化学有限公司 | Preparation method for 1-substituted-1h-1,2,3-triazole-4-carboxylic acid |
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| GB0603891D0 (en) * | 2006-02-27 | 2006-04-05 | Syngenta Ltd | Novel herbicides |
| SA08290245B1 (en) * | 2007-04-23 | 2012-02-12 | استرازينيكا ايه بي | Novel n- (8-Heteroaryltetrahydronaphtalene-2-Y1) or N- (5- Heteroarylchromane-3-Y1) Carboxamide Derivatives for the Treatment of Pain |
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| CN102786485A (en) * | 2012-08-24 | 2012-11-21 | 苏州雅本化学股份有限公司 | 2-substituted-2H-1,2,3-triazole derivative and preparation method thereof |
| CN102786485B (en) * | 2012-08-24 | 2014-11-26 | 雅本化学股份有限公司 | 2-substituted-2H-1,2,3-triazole derivative and preparation method thereof |
| CN103073513A (en) * | 2012-12-14 | 2013-05-01 | 雅本化学股份有限公司 | 1-substituted-5-chlorine-2H-1, 2, 3-triazole-4-carboxylic acid derivative and preparation method thereof |
| CN103073513B (en) * | 2012-12-14 | 2015-12-02 | 雅本化学股份有限公司 | 1-replaces the chloro-2H-1 of-5-, 2,3-triazole-4-carboxylic acid derivative and preparation method thereof |
| CN104311586A (en) * | 2014-09-28 | 2015-01-28 | 南京中电熊猫液晶显示科技有限公司 | Triazole-containing compound and synthesis method thereof |
| WO2016062175A1 (en) * | 2014-10-23 | 2016-04-28 | 上海雅本化学有限公司 | Preparation method for 1-substituted-1h-1,2,3-triazole-4-carboxylic acid |
| CN105585534A (en) * | 2014-10-23 | 2016-05-18 | 上海雅本化学有限公司 | Preparation method of 1-subtituted-1H-1,2,3-triazole-4-carboxylic acid |
| US20180029999A1 (en) * | 2014-10-23 | 2018-02-01 | Aba Chemicals (Shanghai) Limited | Preparation Method for 1-substituted-1H-1,2,3-triazole 4-carboxylic acid |
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