CN102408386B - 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
- CN102408386B CN102408386B CN201110212052.1A CN201110212052A CN102408386B CN 102408386 B CN102408386 B CN 102408386B CN 201110212052 A CN201110212052 A CN 201110212052A CN 102408386 B CN102408386 B CN 102408386B
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- China
- Prior art keywords
- benzyl
- methyl
- triazole
- propyl
- bis
- Prior art date
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- -1 2,4-disubstituted-2H-1, 2, 3-triazole Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical class C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 42
- 239000004327 boric acid Substances 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 239000003960 organic solvent Substances 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 16
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 16
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 16
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 16
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 15
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical compound C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 8
- 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 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 8
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 8
- 229940043232 butyl acetate Drugs 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- 229940093499 ethyl acetate Drugs 0.000 claims description 8
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 8
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 8
- 229940117955 isoamyl acetate Drugs 0.000 claims description 8
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 8
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 8
- 229940017219 methyl propionate Drugs 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 8
- TWSRVQVEYJNFKQ-UHFFFAOYSA-N pentyl propanoate Chemical compound CCCCCOC(=O)CC TWSRVQVEYJNFKQ-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 229940090181 propyl acetate Drugs 0.000 claims description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 8
- 235000011152 sodium sulphate Nutrition 0.000 claims description 8
- 238000000638 solvent extraction Methods 0.000 claims description 8
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 235000011089 carbon dioxide Nutrition 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 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 group OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 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
- 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
- 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
- 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
- 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
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims 9
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 9
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims 9
- 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Chemical group C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 9
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 9
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- PXGCUTZOOVBRHV-UHFFFAOYSA-N 2-benzyl-4-methyltriazole Chemical compound N1=C(C)C=NN1CC1=CC=CC=C1 PXGCUTZOOVBRHV-UHFFFAOYSA-N 0.000 description 3
- GFNZYOVVRMWTOF-UHFFFAOYSA-N 2-methyltriazole-4-carboxylic acid Chemical compound CN1N=CC(C(O)=O)=N1 GFNZYOVVRMWTOF-UHFFFAOYSA-N 0.000 description 3
- KUFNEMCYFOJAGR-UHFFFAOYSA-N 4-benzyl-2h-triazole Chemical compound C=1C=CC=CC=1CC1=CNN=N1 KUFNEMCYFOJAGR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 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
- 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
- IOCJMTUXBWCWIW-UHFFFAOYSA-N Cc1ccc(C[n](nc2)nc2Br)cc1 Chemical compound Cc1ccc(C[n](nc2)nc2Br)cc1 IOCJMTUXBWCWIW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- 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
- 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
- WSYIQYWWTLLKGL-UHFFFAOYSA-N Cc1ccc(C[n](nc2)nc2C(O)=O)cc1 Chemical compound Cc1ccc(C[n](nc2)nc2C(O)=O)cc1 WSYIQYWWTLLKGL-UHFFFAOYSA-N 0.000 description 1
- KWYDRABUDRVWPF-UHFFFAOYSA-N Cc1ccc(C[n]2nc(B(O)O)cn2)cc1 Chemical compound Cc1ccc(C[n]2nc(B(O)O)cn2)cc1 KWYDRABUDRVWPF-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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 organic synthesis intermediate preparing technical field, relate in particular to new compound 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives 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
Replace-2H-1 of 2,4-bis-, 2,3-triazole derivatives is the novel compound with huge exploitation value of a class.Compound take triazole as parent nucleus has potential using value widely, is the important intermediate of current many medicines, weedicide and agrochemical compound, is also 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, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, further, the invention provides 2-replacement-2H-1,2,3-triazole-4-carboxylic acid and 2-replacement-2H-1, the preparation method of 2,3-triazole-4-boric acid.
Technical scheme: in order to realize foregoing invention object, the technical solution used in the present invention is as follows:
Replace-2H-1 of 2,4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that: replace-2H-1 of 2,4-bis-, 2,3-triazole derivatives has following structure:
Formula I
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl; R2 represents carboxyl or boronate.
When R2 is carboxyl, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1,2,3-triazole-4-carboxylic acid (formula II);
Formula II
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
When R2 is boronate, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1,2,3-triazole-4-boric acid (formula III).
Formula III
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound formula II of the present invention can be prepared by compound formula VIII.
Formula VIII
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound formula VIII is described later in detail in applicant's No. 201110166067.9 patent application.
Compound formula VIII of the present invention is dissolved in mass volume ratio 1: 1~100, in preferably 1: 5~20 organic solvent, adds 0.1~50%, the preferably metal catalyst of 0.5~10% weight ratio, pass into hydrogen, maintain pressure 1~100atm, preferably 1~10atm, at 0~200 ℃, preferably 10~50 ℃, react 1~50 hour, at room temperature filter, be evaporated to dryly, enriched material obtains compound formula II through recrystallization;
Described organic solvent is the mixing of one or more arbitrary proportions in alcohols or 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, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, ethyl acetate, methyl alcohol;
Described metal catalyst is that one or more in palladium metal, ruthenium, platinum are carried on to the catalyzer that the charge capacity made on gac, aluminum oxide or Zeolite support is 1~10%, preferably 5~10% palladium charcoal.
Reaction formula is as follows:
Compound formula I of the present invention can also be prepared by compound formula VI.
Formula VI
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
Compound formula VI of the present invention is dissolved in mass volume ratio 1: 2~20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, pass into carbon dioxide approximately 10~30 minutes, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, enriched material obtains compound formula II through recrystallization;
Compound formula VI of the present invention is dissolved in mass volume ratio 1: 2~20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, add compound boric acid ester (formula IX), stir 0.1~2 hour, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, enriched material obtains compound formula III through recrystallization;
Formula IX
Wherein, R3 represents 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 formula VI of the present invention and isopropylmagnesium chloride-lithium chloride mixture is 1: 0.8~2.0, preferably 1: 1.2~1.5; The mol ratio of compound formula VI and boric acid ester (formula IX) or carbonic acid gas is 1: 1~10, preferably 1: 1.2~2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
Compound formula VI reacts with grignard reagent isopropylmagnesium chloride-lithium chloride mixture generation format exchange, generates compound formula VII.
Compound formula VII does not need to separate, and directly formats and reacts with carbonic acid gas or boric acid ester again, generates compound formula II or compound formula III.
Reaction formula is as follows:
Isopropylmagnesium chloride-lithium chloride mixture of the present invention is the tetrahydrofuran solution of its different volumetric molar concentrations, and commercially available concentration is generally 1.0~1.3 mol/L.
Compound formula VI of the present invention is prepared by compound formula IV.
Formula IV
Wherein, R1 represents alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl.
The preparation method of compound formula IV is described later in detail in applicant's No. 201110166067.9 patent application.
Compound formula IV of the present invention is dissolved in mass volume ratio 1: 2~20 ether, tetrahydrofuran (THF) or 1,4-dioxane, be cooled to-78~0 ℃, add isopropylmagnesium chloride, stir 0.1~2 hour, add mass ratio 1: 1~20 water, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dryly, obtain compound formula VI.
The mol ratio of compound formula IV of the present invention and isopropylmagnesium chloride is 1: 0.8~1.2, preferably 1: 1~1.1; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
Compound formula IV reacts with grignard reagent isopropylmagnesium chloride generation format exchange, generates compound formula V.Compound formula V, directly reacts with water, 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/L.
Compound formula I of the present invention also can be prepared by compound formula IV one kettle way, and midbody compound formula VI does not need to separate.Operation steps is as follows: compound formula IV is dissolved in mass volume ratio 1: 2~20 ether, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78~0 ℃, add isopropylmagnesium chloride, stir 0.1~2 hour, slowly add C1~C4 lower alcohol, stir 0.5~1 hour, at-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, pass into carbon dioxide approximately 10~30 minutes or add compound boric acid ester (formula IX), stir 0.1~2 hour, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains compound formula I through recrystallization.
The mol ratio of compound formula IV of the present invention and C1~C4 lower alcohol is 1: 0.8~1.2, preferably 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 formula IV and 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8~2.0, preferably 1: 1.2~1.5; The mol ratio of compound formula IV and boric acid ester (formula IX) or carbonic acid gas is 1: 1~10, preferably 1: 1.2~2; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers, comprise the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, methyl tertiary butyl ether, ethyl acetate, methyl tertiary butyl ether.
One kettle way of the present invention is prepared compound formula I, and compared with the method for fractional steps, total recovery can improve 3~10%.
The method of recrystallization of the present invention comprises the following steps, and by mass volume ratio 1: 1~100, preferably 1: 2~20 add enriched material in organic solvent, and at-20~50 ℃, preferably 0~25 ℃ is stirred 0.5~24 hour, filters, and vacuum-drying, obtains sterling.
Recrystallization of the present invention organic solvent used is fatty acid ester, ketone, the mixing of one or more arbitrary proportions in ethers and hydro carbons, comprise ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, cyclopentanone and pimelinketone, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether and tetrahydrofuran (THF), 1, 4-dioxane, sherwood oil, normal hexane, hexanaphthene, the mixing of one or more arbitrary proportions in methylcyclohexane and normal heptane, the mixed solvent of ethyl acetate or methyl tertiary butyl ether and normal hexane arbitrary proportion.
Of the present invention 2, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives is simple, and the compound yield of acquisition is high.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further explained.
Embodiment 1:
By 10g (41.5mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 100ml tetrahydrofuran (THF), is cooled to-15~-5 ℃, slowly adds 22.4ml (44.8mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue reaction 0.5 hour.Slowly add 10ml water, temperature <-10 ℃,, then extract with 100ml methyl tertiary butyl ether to pH=1~2 with 1.0M hcl acidifying, organic layer is through anhydrous sodium sulfate drying, is evaporated to dryly, obtains the bromo-2-methyl-2H-1 of 4-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 10.6g (41.5mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-ethyl-2H-1 of 4-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 11.16g (41.5mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-n-propyl-2H-1 of 4-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 12.24g (41.5mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-cyclopentyl-2H-1 of 4-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.1g (41.5mmol) 2-phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-phenmethyl-2H-1 of 4-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.7g (41.5mmol) 2-to methylbenzyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.4g (41.5mmol) 2-meta-methoxy phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-meta-methoxy of 4-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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.4g (41.5mmol) 2-to mehtoxybenzyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 13.9g (41.5mmol) 2-to fluorobenzene methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 14.58g (41.5mmol) 2-to chlorophenylmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 16.64g (41.5mmol) 2-to trifluoromethoxy phenmethyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain the bromo-2-of 4-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:
By the bromo-2-methyl-2H-1 of 3.24g (20mmol) 4-, 2,3-triazole is dissolved in 50ml tetrahydrofuran (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 ℃, pass into carbon dioxide approximately 10~30 minutes, 15 ℃ of temperature <.At room temperature, with 1.0M hcl acidifying, to pH=1~2, then extract with 100ml methyl tertiary butyl ether, organic layer, through anhydrous sodium sulfate drying, is evaporated to dry.Residual solid is dissolved in to 5ml ethyl acetate, drips 20ml normal hexane under room temperature, continue to stir 1 hour, filter, room temperature vacuum-drying, obtains 2-methyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-ethyl-2H-1 of 3.52g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-n-propyl-2H-1 of 3.8g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-cyclopentyl-2H-1 of 4.3g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-phenmethyl-2H-1 of 4.76g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.06g (20mmol) 4-to methylbenzyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-meta-methoxy of 5.4g (20mmol) 4-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.4g (20mmol) 4-to mehtoxybenzyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.1g (20mmol) 4-to fluorobenzene methyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.45g (20mmol) 4-to chlorophenylmethyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 6.45g (20mmol) 4-to trifluoromethyl phenmethyl-2H-1,2,3-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:
By the bromo-2-methyl-2H-1 of 3.24g (20mmol) 4-, 2,3-triazole is dissolved in 50ml tetrahydrofuran (THF), at 10~20 ℃, slowly add 18.5ml (24mmol) 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution, finish, continue reaction 2 hours.Be cooled to below-20 ℃, add trimethyl borate 3.5ml (30mmol), continue reaction 0.5~2 hour.At room temperature, with 1.0M hcl acidifying, to pH=1~2, then extract by 100ml ethyl acetate, organic layer, through anhydrous sodium sulfate drying, is evaporated to dry.Resistates is dissolved in 20ml methyl tertiary butyl ether, drips 30ml normal hexane under room temperature, is cooled to 0~5 ℃, stirs 1 hour, and filtration, room temperature vacuum-drying, obtain 2-methyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-ethyl-2H-1 of 3.52g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-n-propyl-2H-1 of 3.8g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-cyclopentyl-2H-1 of 4.3g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-phenmethyl-2H-1 of 4.76g (20mmol) 4-, 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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.06g (20mmol) 4-to methylbenzyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-meta-methoxy of 5.4g (20mmol) 4-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.4g (20mmol) 4-to mehtoxybenzyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.1g (20 mmol) 4-to fluorobenzene methyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 5.45g (20mmol) 4-to chlorophenylmethyl-2H-1,2,3-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, and by bromo-4-2-methyl-2H-1,2,3-triazole replaces with the bromo-2-of 6.45g (20mmol) 4-to trifluoromethyl phenmethyl-2H-1,2,3-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:
By 5g (20.7mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 40ml tetrahydrofuran (THF), is cooled to-15~-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue 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, under room temperature, continue reaction 2 hours.Be cooled to below 0 ℃, pass into carbon dioxide approximately 10~30 minutes, 15 ℃ of temperature <, with 1.0M hcl acidifying, to pH=1~2, then with 100ml methyl tertiary butyl ether extraction, organic layer is through anhydrous sodium sulfate drying, be evaporated to dryly, residual solid is dissolved in to 5ml ethyl acetate, under room temperature, drip 20ml normal hexane, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid 3.3g, yield 88%.
Embodiment 38:
By 5g (20.7mmol) 2-methyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole is dissolved in 40ml tetrahydrofuran (THF), is cooled to-15~-5 ℃, slowly adds 11.2ml (22.4mmol) 2M isopropylmagnesium chloride tetrahydrofuran solution, finish, continue 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, under room temperature, continue reaction 2 hours.Be cooled to below-20 ℃, add trimethyl borate 3.6ml (31mmol), continue reaction 0.5~2 hour, with 1.0M hcl acidifying to pH=1~2,15 ℃ of temperature <, then with 100ml ethyl acetate extraction, organic layer is through anhydrous sodium sulfate drying, be evaporated to dry, resistates is dissolved in 10ml methyl tertiary butyl ether, drips 30ml normal hexane under room temperature, is cooled to 0~5 ℃, stir 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.28g (20.7mmol) 2-ethyl-4, the bromo-2H-1 of 5-bis-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 5.57g (20.7mmol) 2-n-propyl-4, the bromo-2H-1 of 5-bis-, 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, by 2-methyl-4, and the bromo-2H-1 of 5-bis-, 2,3-triazole replaces with 6.11g (20.7mmol) 2-cyclopentyl-4, the bromo-2H-1 of 5-bis-, 2,3-triazole.Obtain 2-cyclopentyl-2H-1,2,3-triazole-4-boric acid 3.37g, yield 90%.
Embodiment 42:
By the bromo-2-methyl-2H-1 of 5g (24.27mmol) 5-, 2,3-triazole-4-carboxylic acid is dissolved in 100ml ethyl acetate, adds 0.25g 5% palladium charcoal, passes into hydrogen, maintains pressure 1~3atm, room temperature reaction 20~24 hours.React complete, filter, filtrate decompression is concentrated into dry.Residual solid is dissolved in to 10ml ethyl acetate, drips 50ml normal hexane under room temperature, continue to stir 1 hour, filter, room temperature vacuum-drying, obtains 2-methyl-2H-1,2,3-triazole-4-carboxylic acid 2.9g, yield 95%.
Claims (15)
- Replace-2H-1 of 1.2,4-bis-, the preparation method of 2,3-triazole derivatives, this 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives has following structure:Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; R2 represents carboxyl or boronate;It is characterized in that, comprise step:Formula IV compound is dissolved in to the ether of mass volume ratio 1:2~20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78~0 ℃, add isopropylmagnesium chloride, stir 0.1~2 hour, slowly add C1~C4 lower alcohol, stir 0.5~1 hour, at-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, pass into carbon dioxide 10~30 minutes or add the compound boric acid ester of formula IX, stir 0.1~2 hour, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains 2 of formula I through recrystallization, replace-2H-1 of 4-bis-, 2, 3-triazole derivatives,Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;Wherein, R3 represents the straight or branched alkyl of C1~C5.
- 2. according to claim 12, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, described formula IV compound and the mol ratio of lower alcohol are 1:0.8~1.2; The lower alcohol of described C1~C4 is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol; The mol ratio of described compound formula 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 ethers.
- Replace-2H-1 of 3.2,4-bis-, the preparation method of 2,3-triazole derivatives, this 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives has following structure:Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; R2 represents carboxyl or boronate;It is characterized in that, comprise step:Formula IV compound is dissolved in to the ether of mass volume ratio 1:2~20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-78~0 ℃, add isopropylmagnesium chloride, stir 0.1~2 hour, add the water of mass ratio 1:1~20, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, obtain formula VI compound, formula VI compound reacts with the compound boric acid ester of carbonic acid gas or formula IX under isopropylmagnesium chloride-lithium chloride exists, further be converted to 2 of formula I, replace-2H-1 of 4-bis-, 2, 3-triazole derivatives,Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl; Wherein, R3 represents the straight or branched alkyl of C1~C5;Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl.
- 4. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the mol ratio of described 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 ethers.
- 5. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, it is characterized in that, when R2 is carboxyl, described 2 in formula I, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1 of formula II, 2,3-triazole-4-carboxylic acid;Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;Described 2-replacement-2H-1, 2, 3-triazole-4-carboxylic acid is prepared by following method: the ether that described formula VI compound formula is dissolved in to mass volume ratio 1:2~20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, pass into carbon dioxide 10~30 minutes, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2, 3-triazole-4-carboxylic acid.
- 6. according to claim 32, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, it is characterized in that: when R2 is boronate, described 2 in formula I, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is the 2-replacement-2H-1 of formula III, 2,3-triazole-4-boric acidWherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;Described 2-replacement-2H-1, 2, 3-triazole-4-boric acid is prepared by following method: the ether that described compound formula VI is dissolved in to mass volume ratio 1:2~20, tetrahydrofuran (THF) or 1, 4-dioxane, be cooled to-20~30 ℃, add isopropylmagnesium chloride-lithium chloride mixture, stir 0.5~5 hour, be cooled to-50~20 ℃, add formula IX compound boric acid ester, stir 0.1~2 hour, be warming up to room temperature, regulate behind pH=1~5 with hydrochloric acid, with organic solvent extraction, through anhydrous sodium sulphate or anhydrous magnesium sulfate drying, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2, 3-triazole-4-boric acid.
- 7. according to claim 62, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the mol ratio of described compound formula 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 is 1:1~10; Described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester or ethers.
- Replace-2H-1 of 8.2,4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, described 2, replace-2H-1 of 4-bis-, 2,3-triazole derivatives is 2-replacement-2H-1 of formula II, 2,3-triazole-4-carboxylic acid;Wherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl;Described 2-replacement-2H-1,2,3-triazole-4-carboxylic acid is prepared by following method: formula VIII compound is dissolved in the organic solvent of mass volume ratio 1:1~100, the metal catalyst that adds 0.1~50% weight ratio, passes into hydrogen, maintains pressure 1~100atm, at 0~200 ℃, react 1~50 hour, at room temperature filter, be evaporated to dry, enriched material obtains described 2-replacement-2H-1 through recrystallization, 2,3-triazole-4-carboxylic acidWherein, R1 represents methyl, ethyl, n-propyl, pentamethylene base, benzyl, 4-methyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 4-luorobenzyl, 4-chlorobenzyl or 4-trifluoro-methoxybenzyl.
- 9. according to claim 82, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in alcohols or fatty acid ester, and described metal catalyst is that one or more in palladium metal, ruthenium, platinum are carried on to the catalyzer that the charge capacity made on gac, aluminum oxide or Zeolite support is 1~10%.
- 10. according to 2 described in any one in claim 1,5,6,8, replace-2H-1 of 4-bis-, the preparation method of 2,3-triazole derivatives, is characterized in that, the method of described recrystallization comprises the following steps, by mass volume ratio 1:1~100, enriched material is added in organic solvent, at-20~50 ℃, stir 0.5~24 hour, filter, vacuum-drying, obtains sterling.
- 11. is according to claim 10 2, replace-2H-1 of 4-bis-, and the preparation method of 2,3-triazole derivatives, is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in fatty acid ester, ketone, ethers and hydro carbons.
- 12. according to 2 described in claim 1 or 3, replace-2H-1 of 4-bis-, and the preparation method of 2,3-triazole derivatives, is characterized in that, R3 represents methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl or isopentyl.
- 13. according to 2 described in any one in claim 2,4,7, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is the mixing of one or more arbitrary proportions in ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, methyl tertiary butyl ether.
- 14. according to claim 92, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, Isoamyl Acetate FCC, methyl propionate, ethyl propionate, propyl propionate, the mixing of one or more arbitrary proportions in butyl propionate and amyl propionate.
- 15. according to claim 11 2, replace-2H-1 of 4-bis-, 2, the preparation method of 3-triazole derivatives, it is characterized in that, described organic solvent is ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl 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, cyclopentanone and pimelinketone, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether and tetrahydrofuran (THF), 1, 4-dioxane, sherwood oil, normal hexane, hexanaphthene, the mixing of one or more arbitrary proportions in methylcyclohexane and normal heptane.
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CN201110212052.1A CN102408386B (en) | 2011-07-27 | 2011-07-27 | Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives |
PCT/CN2011/001279 WO2013013348A1 (en) | 2011-07-27 | 2011-08-03 | Method for preparing 2, 4-di-substituted-2h-1, 2, 3-triazole derivative |
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