WO2013013348A1 - Method for preparing 2, 4-di-substituted-2h-1, 2, 3-triazole derivative - Google Patents
Method for preparing 2, 4-di-substituted-2h-1, 2, 3-triazole derivative Download PDFInfo
- Publication number
- WO2013013348A1 WO2013013348A1 PCT/CN2011/001279 CN2011001279W WO2013013348A1 WO 2013013348 A1 WO2013013348 A1 WO 2013013348A1 CN 2011001279 W CN2011001279 W CN 2011001279W WO 2013013348 A1 WO2013013348 A1 WO 2013013348A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- fluorenyl group
- acetate
- triazole
- formula
- Prior art date
Links
- -1 2, 4-di-substituted-2h-1, 2, 3-triazole Chemical class 0.000 title claims abstract description 116
- 238000000034 method Methods 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 21
- 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 18
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 18
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- 239000001569 carbon dioxide Substances 0.000 claims description 11
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 11
- 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
- 229940072049 amyl acetate Drugs 0.000 claims description 10
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 10
- 229940043232 butyl acetate Drugs 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 10
- 229930195729 fatty acid Natural products 0.000 claims description 10
- 239000000194 fatty acid Substances 0.000 claims description 10
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 10
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 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
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 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
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical compound C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 9
- 229940017219 methyl propionate Drugs 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-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
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 8
- 229940093499 ethyl acetate Drugs 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000005620 boronic acid group Chemical group 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- CGKQZIULZRXRRJ-UHFFFAOYSA-N Butylone Chemical compound CCC(NC)C(=O)C1=CC=C2OCOC2=C1 CGKQZIULZRXRRJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910021536 Zeolite Inorganic materials 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-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
- 125000004494 ethyl ester group Chemical group 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
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [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
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- PSXLCTPHDAEPLK-UHFFFAOYSA-N CC(C)[Mg] Chemical compound CC(C)[Mg] PSXLCTPHDAEPLK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 1
- IUGMFAGXILFTSB-UHFFFAOYSA-M lithium;oxolane;chloride Chemical compound Cl[Li].C1CCOC1 IUGMFAGXILFTSB-UHFFFAOYSA-M 0.000 claims 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims 1
- 235000019341 magnesium sulphate Nutrition 0.000 claims 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 1
- 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 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 abstract description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- BNHACSBPYOBEEC-UHFFFAOYSA-N 4,5-dibromo-2-methyltriazole Chemical compound CN1N=C(Br)C(Br)=N1 BNHACSBPYOBEEC-UHFFFAOYSA-N 0.000 description 14
- OEFNDZLVSBSRMG-UHFFFAOYSA-N 4-bromo-2-methyltriazole Chemical compound CN1N=CC(Br)=N1 OEFNDZLVSBSRMG-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- NLNDFFUTWBPIJM-UHFFFAOYSA-N 4,5-dibromo-2-cyclopentyltriazole Chemical compound N1=C(Br)C(Br)=NN1C1CCCC1 NLNDFFUTWBPIJM-UHFFFAOYSA-N 0.000 description 4
- IKEWONYTNWDSND-UHFFFAOYSA-N Brc1cnn(n1)C1CCCC1 Chemical compound Brc1cnn(n1)C1CCCC1 IKEWONYTNWDSND-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 3
- KTSIELCAQWRVAI-UHFFFAOYSA-N 2-cyclopentyltriazole-4-carboxylic acid Chemical compound OC(=O)c1cnn(n1)C1CCCC1 KTSIELCAQWRVAI-UHFFFAOYSA-N 0.000 description 3
- AXCCFSAPICGOBI-UHFFFAOYSA-N 4,5-dibromo-2-propyltriazole Chemical compound CCCN1N=C(Br)C(Br)=N1 AXCCFSAPICGOBI-UHFFFAOYSA-N 0.000 description 3
- OKCRGENEZFTYKD-UHFFFAOYSA-N 4-bromo-2-[(4-methoxyphenyl)methyl]triazole Chemical compound COc1ccc(Cn2ncc(Br)n2)cc1 OKCRGENEZFTYKD-UHFFFAOYSA-N 0.000 description 3
- PUVQVJPJOFGBFT-UHFFFAOYSA-N 4-bromo-2-ethyltriazole Chemical compound CCN1N=CC(Br)=N1 PUVQVJPJOFGBFT-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
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 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 2
- FEUUHWYUKDPCKU-UHFFFAOYSA-N 2-ethyltriazole-4-carboxylic acid Chemical compound CCN1N=CC(C(O)=O)=N1 FEUUHWYUKDPCKU-UHFFFAOYSA-N 0.000 description 2
- ZAFJCESPRXTGMG-UHFFFAOYSA-N 4-bromo-2-[(3-methoxyphenyl)methyl]triazole Chemical compound COc1cccc(Cn2ncc(Br)n2)c1 ZAFJCESPRXTGMG-UHFFFAOYSA-N 0.000 description 2
- RMSNIWSLKWSSBP-UHFFFAOYSA-N CCCn1ncc(Br)n1 Chemical compound CCCn1ncc(Br)n1 RMSNIWSLKWSSBP-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- QKNZPNNPSSAHAJ-UHFFFAOYSA-N Fc1ccc(C[n](nc2)nc2Br)cc1 Chemical compound Fc1ccc(C[n](nc2)nc2Br)cc1 QKNZPNNPSSAHAJ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VKYBUEJAQKBUFU-UHFFFAOYSA-N hexylhydrazine Chemical compound CCCCCCNN VKYBUEJAQKBUFU-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- NKPPGMSJFBPQAK-UHFFFAOYSA-N (2-methyltriazol-4-yl)boronic acid Chemical compound Cn1ncc(n1)B(O)O NKPPGMSJFBPQAK-UHFFFAOYSA-N 0.000 description 1
- UPVMUAJKHQHWNB-UHFFFAOYSA-N 1,3-oxazol-4-ylboronic acid Chemical compound OB(O)C1=COC=N1 UPVMUAJKHQHWNB-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 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
- IXYMUKHSOHCKHP-UHFFFAOYSA-N 2-benzyl-4,5-dibromotriazole Chemical compound N1=C(Br)C(Br)=NN1CC1=CC=CC=C1 IXYMUKHSOHCKHP-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
- CFKZTQWMLBGDDA-UHFFFAOYSA-N 2-propyltriazole-4-carboxylic acid Chemical compound CCCN1N=CC(C(O)=O)=N1 CFKZTQWMLBGDDA-UHFFFAOYSA-N 0.000 description 1
- GTODOEDLCNTSLG-UHFFFAOYSA-N 2h-triazole-4-carboxylic acid Chemical compound OC(=O)C1=CNN=N1 GTODOEDLCNTSLG-UHFFFAOYSA-N 0.000 description 1
- IZWBTEMIDFFIPC-UHFFFAOYSA-N 4,5-dibromo-2-[(4-methoxyphenyl)methyl]triazole Chemical compound C1=CC(OC)=CC=C1CN1N=C(Br)C(Br)=N1 IZWBTEMIDFFIPC-UHFFFAOYSA-N 0.000 description 1
- HSRUCDVHLCXDBM-UHFFFAOYSA-N 4,5-dibromo-2-ethyltriazole Chemical compound CCN1N=C(Br)C(Br)=N1 HSRUCDVHLCXDBM-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
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 0 CN=C(BO)C=NN* Chemical compound CN=C(BO)C=NN* 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- QQSQBZBJNVZQJE-UHFFFAOYSA-N Fc1ccc(C[n](nc2Br)nc2Br)cc1 Chemical compound Fc1ccc(C[n](nc2Br)nc2Br)cc1 QQSQBZBJNVZQJE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KLJZNMCFTRZSTE-UHFFFAOYSA-N OB(c1n[n](Cc2ccccc2)nc1)O Chemical compound OB(c1n[n](Cc2ccccc2)nc1)O KLJZNMCFTRZSTE-UHFFFAOYSA-N 0.000 description 1
- WQWZJXKFKNVHHQ-UHFFFAOYSA-N OC(c1n[n](Cc(cc2)ccc2F)nc1)=O Chemical compound OC(c1n[n](Cc(cc2)ccc2F)nc1)=O WQWZJXKFKNVHHQ-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical group OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- FWQWBCXBNYKFCJ-UHFFFAOYSA-N methylcyclohexane Chemical compound C[C-]1CCCCC1 FWQWBCXBNYKFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 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
Definitions
- the present invention relates to the field of preparation of organic synthetic intermediates, and in particular to a novel compound 2,4-disubstituted-2H-1 , 2,3-triazole derivatives and preparation methods thereof. Furthermore, the present invention relates to a novel compound 2-substituted-2H-1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid And its preparation method. Background technique
- 2,4-Disubstituted -2H-1,2,3-triazole derivatives are a new class of compounds with great developmental value.
- Triazole-based compounds have a wide range of potential applications and are important intermediates for many drugs, herbicides, and insecticides. They are also the major pharmacophores in many drug molecules.
- 2-Substituted-2H- 1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid are novel active intermediates that can be used very Important active precursors are used in organic synthesis. Disclosure of the Invention Objects of the Invention: An object of the present invention is to provide a process for the preparation of a novel 2,4-disubstituted-2H-1,2,3-triazole derivative. Further, the present invention provides a 2-substitution- Process for the preparation of 2H-1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid.
- Technical Solution In order to achieve the above object, the technical solution adopted by the present invention is as follows:
- a process for producing a 2,4-disubstituted-2H- 1,2,3-triazole derivative characterized in that the 2,4-disubstituted-2H-1,2,3-triazole derivative has the following Structure:
- R1 represents a fluorenyl group, an aryl group, an aryl group, a fluorenyl group
- Heteroaryl fluorenyl, heterocyclic fluorenyl; R2 represents carboxy or boronic acid.
- R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
- the 2,4-disubstituted-2H-1,2,3-triazole derivative is 2-substituted-2H-1,2,3-triazole-4-boronic acid (Formula 111).
- R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
- the compound of the formula II described in the present invention can be prepared from the compound of the formula VIII.
- R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
- the compound of the present invention is dissolved in an organic solvent having a mass to volume ratio of 1: 1-100, preferably 1: 5-20, and a metal catalyst having a weight ratio of 0.1 to 50%, preferably 0.5 to 10%, is introduced.
- Hydrogen maintain pressure 1 ⁇ 100 aim, preferably 1 ⁇ 10 aim, at 0 ⁇ 200°C, preferably 10 ⁇ 50 V, reaction for 1 ⁇ 50 hours, filter at room temperature, concentrate to dryness under reduced pressure, concentrate recrystallize Obtaining a compound formula;
- the organic solvent is one or a mixture of two or more of alcohols or fatty acid esters, including methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and different Pentanol, ethyl formate, propyl formate, butyl formate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate And a mixture of one or more of ethyl propionate, propyl propionate, butyl propionate and amyl propionate in any ratio, preferably ethyl acetate or methanol;
- the metal catalyst is a catalyst having a loading of 1 to 10%, preferably 5 to 10%, prepared by supporting one or more of metal palladium, rhodium and platinum on activated carbon, alumina or a zeolite carrier. Palladium charcoal.
- the compound of the formula I of the present invention can also be prepared by the formula VI.
- R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroarylheteroaryl fluorenyl group, a heterocyclic fluorenyl group.
- the compound of the present invention is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1:2-20, cooled to -20 to 30 ° C, and added with isopropylmagnesium chloride-lithium chloride.
- the compound of the present invention is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1:2-20, cooled to -20 to 30 ° C, and added with isopropylmagnesium chloride-lithium chloride.
- R 3 represents a linear or branched fluorenyl group of C1 to C5, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, N-pentyl, isoamyl.
- the molar ratio of the compound of the formula VI to the isopropylmagnesium chloride-lithium chloride complex of the present invention is 1: 0.8-2.0, preferably 1: 1.2-1.5; the compound of the formula VI and the borate ester (formula IX) or carbon dioxide
- the molar ratio is 1: 1-10, preferably 1: 1.2-2;
- the organic solvent is one or a mixture of two or more of fatty acid esters or ethers, including ethyl formate, propyl formate, Butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, C Mixing one or more of acid propyl ester, butyl propionate and amyl propionate, diethyl ether, prop
- the compound of formula VI undergoes a format exchange reaction with the format reagent isopropylmagnesium chloride-lithium chloride complex to form compound VII.
- the compound of formula VII does not need to be separated, and is directly subjected to a format reaction with carbon dioxide or a boric acid ester.
- the formula of formula II or the compound of formula IIL is generated as follows;
- the isopropylmagnesium chloride-lithium chloride complex of the present invention is a tetrahydrofuran solution of different molar concentrations, and the commercially available concentration is usually 1.0 to 1.3 mol/liter.
- the compound of the formula VI of the present invention is prepared from the compound of the formula IV.
- R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
- the molar ratio of the compound of the formula IV to the isopropylmagnesium chloride of the present invention is 1: 0.8-1.2
- the organic solvent is one or a mixture of two or more of fatty acid esters or ethers, including ethyl formate, propyl formate, butyl formate, methyl acetate, acetic acid.
- One or a mixture of two or more of amyl propionate, diethyl ether, propyl ether, diisopropyl ether and methyl tert-butyl ether is preferably an ethyl acetate or a methyl tert-butyl ether.
- the compound IV is subjected to a format exchange reaction with the format reagent isopropylmagnesium chloride to form a compound of formula V.
- Compound V is directly reacted with water and post-treated to give compound VI.
- the isopropylmagnesium chloride according to the present invention is a tetrahydrofuran solution, a 2-methyltetrahydrofuran solution or a diethyl ether solution of different molar concentrations, and a commercially available concentration is usually 1.0 to 2.0 mol/liter.
- the compound of the formula I of the present invention can also be prepared by the compound IV-pot method, and the intermediate compound formula VI does not need to be separated.
- the molar ratio of the compound of the formula IV to the C1 to C4 lower alcohol of the present invention is 1: 0.8-1.2, preferably 1: 1-1.1; the lower alcohol of C1 to C4 includes methanol, ethanol, n-propanol, and different Propyl alcohol, n-butanol or tert-butanol; the molar ratio of the compound of formula IV to 1.3 M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8-2.0, preferably 1: 1.2-1.5; With boron
- the molar ratio of the acid ester (formula IX) or carbon dioxide is 1:1-10, preferably 1:1.2-2; the organic solvent is one or a mixture of two or more of a fatty acid ester or an ether, Including ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl
- the one-pot method of the present invention prepares compound I, and the total yield can be increased by 3 to 10% compared with the stepwise method.
- the method for recrystallization according to the present invention comprises the steps of adding the concentrate to an organic solvent at a mass to volume ratio of 1: 1-100, preferably 1: 2-20, at -20 to 50 ° C, preferably 0 to 25 °. C is stirred for 0.5 to 24 hours, filtered, and dried under vacuum to obtain a pure product.
- the organic solvent used for the recrystallization according to the present invention is a mixture of one or a mixture of two or more of a fatty acid ester, a ketone, an ether, and a hydrocarbon, and includes ethyl formate, propyl formate, butyl formate, and acetic acid.
- Methyl ester ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, C Butyl acrylate and amyl propionate, acetone, 2-butanone, cyclopentanone and cyclohexanone, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofuran, 1,4-dioxane Mixing one or more of petroleum ether, n-hexyl hydrazine, cyclohexanyl, methylcyclohexanide and n-heptanium in any ratio, preferably in any ratio of ethyl acetate or methyl tert-butyl ether and
- Example 2 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 10.6 g (41.5 mmol) of 2-ethyl-4,5-dibromo -2H-1,2,3-triazole. 4-bromo-2-ethyl-2H-1,2,3-triazole 6.94 g was obtained in a yield of 95%.
- Example 9 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 13.9 g (41.5 mmol) of 2-p-fluorobenzyl-4. 5-Dibromo-2H-1,2,3-triazole. 4-Bromo-2-p-fluorobenzyl-2H-1,2,3-triazole 10.2 g was obtained in a yield of 96%.
- Example 13 The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2 ⁇ -1,2,3-triazole with 3.52 g (20 mmol) 4-bromo-2-ethyl-2H-1,2 , 3-triazole. 2.1 g of 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 74%.
- Example 14 The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 3.8 g (20 mmol) 4-bromo-2-n-propyl-2H-1 , 2,3-triazole. 2.45 g of 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 79%.
- Example 18 The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2 ⁇ -1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-m-methoxybenzyl- 2H-1,2,3-triazole.
- Example 20 The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.1 g (20 mmol) 4-bromo-2-p-fluorobenzyl-2H -1,2,3-triazole.
- Example 29 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2 ⁇ -1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-m-methoxybenzyl. -2H-1,2,3-triazole. There was obtained 3.82 g of 2-m-methoxybenzyl-2H-1,2,3-triazole-4-boronic acid in a yield of 82%.
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
Disclosed is a method for preparing the compound of 2, 4-di-substituted-2H-1, 2, 3-triazole derivative, in particular to a method for preparing the compounds of 2-substituted-2H-1, 2, 3-triazole-4-carboxylic acid and 2-substituted-2H-1, 2, 3-triazole-4-boric acid.
Description
2， 4-二取代 -2H-1， 2， 3-三氮唑衍生物的制备方法 技术领域 本发明涉及有机合成中间体制备技术领域， 尤其涉及新化合物 2,4-二 取代 -2H-1,2,3-三氮唑衍生物及其制备方法。更进一步来说，本发明涉及新 化合物 2-取代 -2H-1,2,3-三氮唑 -4-羧酸和 2-取代 -2H-1,2,3-三氮唑 -4-硼酸及 其制备方法。 背景技术 TECHNICAL FIELD The present invention relates to the field of preparation of organic synthetic intermediates, and in particular to a novel compound 2,4-disubstituted-2H-1 , 2,3-triazole derivatives and preparation methods thereof. Furthermore, the present invention relates to a novel compound 2-substituted-2H-1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid And its preparation method. Background technique
2,4-二取代 -2H-1,2,3-三氮唑衍生物是一类新型的具有巨大开发价值 的化合物。 以三氮唑为母核的化合物具有广泛的潜在应用价值， 是目前许 多药物、 除草剂和杀虫剂等化合物的重要中间体， 也是很多药物分子中主 要的药效基团。 2,4-Disubstituted -2H-1,2,3-triazole derivatives are a new class of compounds with great developmental value. Triazole-based compounds have a wide range of potential applications and are important intermediates for many drugs, herbicides, and insecticides. They are also the major pharmacophores in many drug molecules.
2-取代 -2H- 1,2,3-三氮唑 -4-羧酸和 2-取代 -2H-1,2,3-三氮唑 -4-硼酸是新 型的活性中间体，可以作为非常重要的活性前体，在有机合成中得到应用。 发明内容 发明目的：本发明的目的在于提供一种新型 2,4-二取代 -2H-1,2,3-三氮 唑衍生物的制备方法， 更进一步来说， 本发明提供 2-取代 -2H-1,2,3-三氮 唑 -4-羧酸和 2-取代 -2H-1,2,3-三氮唑 -4-硼酸的制备方法。 技术方案： 为了实现上述发明目的， 本发明采用的技术方案如下： 2-Substituted-2H- 1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid are novel active intermediates that can be used very Important active precursors are used in organic synthesis. Disclosure of the Invention Objects of the Invention: An object of the present invention is to provide a process for the preparation of a novel 2,4-disubstituted-2H-1,2,3-triazole derivative. Further, the present invention provides a 2-substitution- Process for the preparation of 2H-1,2,3-triazole-4-carboxylic acid and 2-substituted-2H-1,2,3-triazole-4-boronic acid. Technical Solution: In order to achieve the above object, the technical solution adopted by the present invention is as follows:
2,4-二取代 -2H- 1,2,3-三氮唑衍生物的制备方法， 其特征在于： 2,4-二 取代 -2H-1,2,3-三氮唑衍生物具有如下结构： A process for producing a 2,4-disubstituted-2H- 1,2,3-triazole derivative, characterized in that the 2,4-disubstituted-2H-1,2,3-triazole derivative has the following Structure:
/Γ /Γ
Ν、 , Ν Ν, , Ν
Ν Ν
I I
Ri
式 I 其中， Rl表示垸基、 芳基、 芳垸基、 环垸基
Ri Wherein R1 represents a fluorenyl group, an aryl group, an aryl group, a fluorenyl group
杂芳基垸基、 杂环垸基； R2表示羧基或硼酸基。 Heteroaryl fluorenyl, heterocyclic fluorenyl; R2 represents carboxy or boronic acid.
当 R2是羧基时， 所述的 2,4-二取代 -2H-1,2,3 When R2 is a carboxyl group, the 2,4-disubstituted -2H-1,2,3
-2H-1,2,3-三氮唑 -4-羧酸 （式 II);
-2H-1,2,3-triazole-4-carboxylic acid (formula II);
式 II 其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。 Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
当 R2是硼酸基时， 所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物为 2-取 代 -2H-1,2,3-三氮唑 -4-硼酸 （式 111)。 When R 2 is a boronic acid group, the 2,4-disubstituted-2H-1,2,3-triazole derivative is 2-substituted-2H-1,2,3-triazole-4-boronic acid (Formula 111).
HO
式 III 其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。 HO Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
本发明所述的化合物式 II可以由化合物式 VIII制备得到。 The compound of the formula II described in the present invention can be prepared from the compound of the formula VIII.
Br^ COOH Br^ COOH
Ν、 Oh,
N N
I I
Ri Ri
式 VIII 其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。
中已经有详细的描述。 Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group. A detailed description has been made.
本发明所述的化合物式 VIII溶于质量体积比 1 : 1-100, 优选 1 : 5-20 的有机溶剂中， 加入 0.1~50%， 优选 0.5~10%的重量比的金属催化剂， 通 入氢气， 维持压力 1~100 aim, 优选 1~10 aim, 在 0~200°C， 优选 10~50 V， 反应 1~50小时， 在室温下过滤， 减压浓缩至干， 浓缩物经重结晶得 到化合物式 Π; The compound of the present invention is dissolved in an organic solvent having a mass to volume ratio of 1: 1-100, preferably 1: 5-20, and a metal catalyst having a weight ratio of 0.1 to 50%, preferably 0.5 to 10%, is introduced. Hydrogen, maintain pressure 1~100 aim, preferably 1~10 aim, at 0~200°C, preferably 10~50 V, reaction for 1~50 hours, filter at room temperature, concentrate to dryness under reduced pressure, concentrate recrystallize Obtaining a compound formula;
所述的有机溶剂为醇类或脂肪酸酯类中的一种或两种以上任意比例 的混合， 包括甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇、 正戊醇、 异 戊醇、 甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯中的一种或两种以上任意比例 的混合， 优选乙酸乙酯、 甲醇； The organic solvent is one or a mixture of two or more of alcohols or fatty acid esters, including methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and different Pentanol, ethyl formate, propyl formate, butyl formate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate And a mixture of one or more of ethyl propionate, propyl propionate, butyl propionate and amyl propionate in any ratio, preferably ethyl acetate or methanol;
所述的金属催化剂是将金属钯、 钌、 铂中的一种或两种以上负载于活 性炭、氧化铝或沸石载体上制成的负载量为 1~10%的催化剂，优选 5~10% 的钯炭。 The metal catalyst is a catalyst having a loading of 1 to 10%, preferably 5 to 10%, prepared by supporting one or more of metal palladium, rhodium and platinum on activated carbon, alumina or a zeolite carrier. Palladium charcoal.
反应式如下所示：
The reaction formula is as follows:
VI II I I VI II I I
本发明所述的化合物式 I还可 合物式 VI制备得到。
The compound of the formula I of the present invention can also be prepared by the formula VI.
式 VI 其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基 杂芳基垸基、 杂环垸基。
本发明所述的化合物式 VI溶于质量体积比 1 : 2~20的乙醚、 四氢呋 喃或 1,4-二氧六环， 冷却至 -20~30°C， 加入异丙基氯化镁-氯化锂复合物， 搅拌 0.5~5小时， 冷却至 -50~20°C， 通入二氧化碳气体约 10~30分钟， 升 温至室温， 用盐酸调节 pH = 1~5后， 用有机溶剂萃取， 经无水硫酸钠或 无水硫酸镁干燥， 减压浓缩至干， 浓缩物经重结晶得到化合物式 Π; Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroarylheteroaryl fluorenyl group, a heterocyclic fluorenyl group. The compound of the present invention is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1:2-20, cooled to -20 to 30 ° C, and added with isopropylmagnesium chloride-lithium chloride. The mixture is stirred for 0.5 to 5 hours, cooled to -50 to 20 ° C, carbon dioxide gas is introduced for about 10 to 30 minutes, warmed to room temperature, adjusted to pH = 1 to 5 with hydrochloric acid, and extracted with an organic solvent. Drying over sodium sulfate or anhydrous magnesium sulfate, concentrating to dryness under reduced pressure, and concentrating the concentrate to give compound hydrazine;
本发明所述的化合物式 VI溶于质量体积比 1 : 2~20的乙醚、 四氢呋 喃或 1,4-二氧六环， 冷却至 -20~30°C， 加入异丙基氯化镁-氯化锂复合物， 搅拌 0.5~5小时，冷却至 -50~20°C，加入化合物硼酸酯（式 IX),搅拌 0.1~2 小时， 升温至室温， 用盐酸调节 pH = 1~5后， 用有机溶剂萃取， 经无水 硫酸钠或无水硫酸镁干燥， 减压浓缩至干， 浓缩物经重结晶得到化合物式 III； The compound of the present invention is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1:2-20, cooled to -20 to 30 ° C, and added with isopropylmagnesium chloride-lithium chloride. The mixture is stirred for 0.5 to 5 hours, cooled to -50 to 20 ° C, and the compound borate (formula IX) is added, stirred for 0.1 to 2 hours, warmed to room temperature, and adjusted to pH = 1 to 5 with hydrochloric acid. Solvent extraction, drying over anhydrous sodium sulfate or anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, the concentrate is recrystallized to give compound III;
R30 OR3 式 IX 其中， R3表示 C1~C5的直链或支链垸基， 包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 正戊基、 异戊基。 R 3 0 OR 3 Formula IX wherein R 3 represents a linear or branched fluorenyl group of C1 to C5, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, N-pentyl, isoamyl.
本发明所述的化合物式 VI与异丙基氯化镁 -氯化锂复合物的摩尔比为 1： 0.8-2.0, 优选 1 : 1.2-1.5； 化合物式 VI与硼酸酯（式 IX)或二氧化碳 的摩尔比为 1 : 1-10, 优选 1 : 1.2-2； 所述的有机溶剂为脂肪酸酯类或醚 类中的一种或两种以上任意比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸 丁酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异 丁酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁 酯和丙酸戊酯、 乙醚、 丙醚、 异丙醚、 甲基叔丁基醚中的一种或两种以上 任意比例的混合， 优选乙酸乙酯、 甲基叔丁基醚。 The molar ratio of the compound of the formula VI to the isopropylmagnesium chloride-lithium chloride complex of the present invention is 1: 0.8-2.0, preferably 1: 1.2-1.5; the compound of the formula VI and the borate ester (formula IX) or carbon dioxide The molar ratio is 1: 1-10, preferably 1: 1.2-2; the organic solvent is one or a mixture of two or more of fatty acid esters or ethers, including ethyl formate, propyl formate, Butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, C Mixing one or more of acid propyl ester, butyl propionate and amyl propionate, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, preferably ethyl acetate, methyl unbranched Butyl ether.
化合物式 VI与格式试剂异丙基氯化镁-氯化锂复合物发生格式交换反 应， 生成化合物式 VII。 化合物式 VII不需分离，直接再与二氧化碳或硼酸酯进行格式化反应，
生成化合物式 II或化合物式 IIL 反应式如下所; The compound of formula VI undergoes a format exchange reaction with the format reagent isopropylmagnesium chloride-lithium chloride complex to form compound VII. The compound of formula VII does not need to be separated, and is directly subjected to a format reaction with carbon dioxide or a boric acid ester. The formula of formula II or the compound of formula IIL is generated as follows;
X X
本发明所述的异丙基氯化镁 -氯化锂复合物是其不同摩尔浓度的四氢 呋喃溶液， 市售的浓度通常为 1.0~1.3摩尔 /升。 The isopropylmagnesium chloride-lithium chloride complex of the present invention is a tetrahydrofuran solution of different molar concentrations, and the commercially available concentration is usually 1.0 to 1.3 mol/liter.
本发明所述的化合物式 VI由化合物式 IV制备得到。 The compound of the formula VI of the present invention is prepared from the compound of the formula IV.
Br N、 .N Br N, .N
N Br N Br
I 式 IV 其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。 Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
化合物式 IV的制备方法在申请人的第 201110166067.9号专利申请中 已经有详细的描述。 The preparation of the compound of the formula IV has been described in detail in the applicant's patent application No. 201110166067.9.
本发明所述的化合物式 IV溶于质量体积比 1 : 2~20的乙醚、 四氢呋 喃或 1,4-二氧六环，冷却至 -78~0°C，加入异丙基氯化镁，搅拌 0.1~2小时， 加入质量比 1 : 1~20的水， 用盐酸调节 pH = 1~5后， 用有机溶剂萃取， 经无水硫酸钠或无水硫酸镁干燥， 减压浓缩至干， 得到化合物式 VI。 本发明所述的化合物式 IV与异丙基氯化镁的摩尔比为 1 : 0.8-1.2,
优选 1 : 1-1.1； 所述的有机溶剂为脂肪酸酯类或醚类中的一种或两种以上 任意比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸 乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸 异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯、 乙醚、 丙醚、 异丙醚、 甲基叔丁基醚中的一种或两种以上任意比例的混合， 优选 乙酸乙酯、 甲基叔丁基醚。 The compound of the present invention is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane having a mass to volume ratio of 1: 2-20, cooled to -78 to 0 ° C, added with isopropyl magnesium chloride, and stirred at 0.1~. 2 hours, adding water with a mass ratio of 1: 1~20, adjusting the pH with hydrochloric acid = 1~5, extracting with an organic solvent, drying over anhydrous sodium sulfate or anhydrous magnesium sulfate, and concentrating to dryness under reduced pressure to give compound VI. The molar ratio of the compound of the formula IV to the isopropylmagnesium chloride of the present invention is 1: 0.8-1.2, Preferably, the organic solvent is one or a mixture of two or more of fatty acid esters or ethers, including ethyl formate, propyl formate, butyl formate, methyl acetate, acetic acid. Ethyl ester, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and One or a mixture of two or more of amyl propionate, diethyl ether, propyl ether, diisopropyl ether and methyl tert-butyl ether is preferably an ethyl acetate or a methyl tert-butyl ether.
化合物式 IV与格式试剂异丙基氯化镁发生格式交换反应， 生成化合 物式 V。 化合物式 V， 直接与水反应， 经后处理， 得到化合物 VI。 The compound IV is subjected to a format exchange reaction with the format reagent isopropylmagnesium chloride to form a compound of formula V. Compound V is directly reacted with water and post-treated to give compound VI.
反应式如下所示：
The reaction formula is as follows:
VI 本发明所述的异丙基氯化镁是其不同摩尔浓度的四氢呋喃溶液、 2-甲 基四氢呋喃溶液或者乙醚溶液， 市售的浓度通常为 1.0~2.0摩尔 /升。 VI The isopropylmagnesium chloride according to the present invention is a tetrahydrofuran solution, a 2-methyltetrahydrofuran solution or a diethyl ether solution of different molar concentrations, and a commercially available concentration is usually 1.0 to 2.0 mol/liter.
本发明所述的化合物式 I也可以由化合物式 IV—锅法制备得到， 中 间体化合物式 VI不需分离。操作步骤如下： 化合物式 IV溶于质量体积比 1： 2~20的乙醚、 四氢呋喃或 1,4-二氧六环， 冷却至 -78~0°C， 加入异丙基 氯化镁， 搅拌 0.1~2小时， 缓慢加入 C1~C4低级醇， 搅拌 0.5~1小时， 在 -20~30°C下， 加入异丙基氯化镁-氯化锂复合物， 搅拌 0.5~5小时， 冷却至 -50~20°C， 通入二氧化碳气体约 10~30分钟或加入化合物硼酸酯（式 IX), 搅拌 0.1~2小时，升温至室温，用盐酸调节 pH = 1~5后，用有机溶剂萃取， 经无水硫酸钠或无水硫酸镁干燥， 减压浓缩至干， 浓缩物经重结晶得到化 合物式 I。 The compound of the formula I of the present invention can also be prepared by the compound IV-pot method, and the intermediate compound formula VI does not need to be separated. The operation steps are as follows: Compound IV is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1:2~20, cooled to -78~0 °C, added with isopropylmagnesium chloride, stirred 0.1~2 Hours, slowly add C1~C4 lower alcohol, stir for 0.5~1 hour, add isopropylmagnesium chloride-lithium chloride complex at -20~30 °C, stir for 0.5~5 hours, cool to -50~20° C, pass carbon dioxide gas for about 10~30 minutes or add compound borate (formula IX), stir for 0.1~2 hours, warm to room temperature, adjust pH with hydrochloric acid = 1~5, extract with organic solvent, pass anhydrous Dry over sodium sulfate or anhydrous magnesium sulfate, and concentrate to dryness under reduced pressure.
本发明所述的化合物式 IV与 C1~C4低级醇的摩尔比为 1 : 0.8-1.2, 优选 1 : 1-1.1； 所述的 C1~C4的低级醇包括甲醇、 乙醇、 正丙醇、 异丙 醇、 正丁醇或叔丁醇； 所述的化合物式 IV与 1.3 M异丙基氯化镁-氯化锂 四氢呋喃溶液的摩尔比为 1 : 0.8-2.0, 优选 1 : 1.2-1.5； 化合物式 IV与硼
酸酯 （式 IX)或二氧化碳的摩尔比为 1 : 1-10, 优选 1 : 1.2-2； 所述的有 机溶剂为脂肪酸酯类或醚类中的一种或两种以上任意比例的混合，包括甲 酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁 酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸 乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯、 乙醚、 丙醚、 异丙醚、 甲基叔丁 基醚中的一种或两种以上任意比例的混合，优选乙酸乙酯、甲基叔丁基醚。 The molar ratio of the compound of the formula IV to the C1 to C4 lower alcohol of the present invention is 1: 0.8-1.2, preferably 1: 1-1.1; the lower alcohol of C1 to C4 includes methanol, ethanol, n-propanol, and different Propyl alcohol, n-butanol or tert-butanol; the molar ratio of the compound of formula IV to 1.3 M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution is 1: 0.8-2.0, preferably 1: 1.2-1.5; With boron The molar ratio of the acid ester (formula IX) or carbon dioxide is 1:1-10, preferably 1:1.2-2; the organic solvent is one or a mixture of two or more of a fatty acid ester or an ether, Including ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, propionic acid a mixture of one or more of methyl ester, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, or any combination of two or more Preferred is ethyl acetate or methyl tert-butyl ether.
本发明所述的一锅法制备化合物式 I， 与分步法相比， 总收率可提高 3~10%。 本发明所述的重结晶的方法包括以下步骤， 按质量体积比 1 : 1-100, 优选 1 : 2-20将浓缩物加入有机溶剂中， 在 -20~50°C， 优选 0~25°C搅拌 0.5~24小时， 过滤， 真空干燥， 得到纯品。 本发明所述的重结晶所用有机溶剂为脂肪酸酯类、 酮类、 醚类及烃类 中的一种或两种以上任意比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁 酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁 酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯 和丙酸戊酯、 丙酮、 2-丁酮、 环戊酮和环己酮、 乙醚、 丙醚、 异丙醚、 甲 基叔丁基醚和四氢呋喃、 1,4-二氧六环、 石油醚、 正己垸、 环己垸、 甲基 环己垸和正庚垸中的一种或两种以上任意比例的混合，优选乙酸乙酯或甲 基叔丁基醚和正己垸任意比例的混合溶剂。 The one-pot method of the present invention prepares compound I, and the total yield can be increased by 3 to 10% compared with the stepwise method. The method for recrystallization according to the present invention comprises the steps of adding the concentrate to an organic solvent at a mass to volume ratio of 1: 1-100, preferably 1: 2-20, at -20 to 50 ° C, preferably 0 to 25 °. C is stirred for 0.5 to 24 hours, filtered, and dried under vacuum to obtain a pure product. The organic solvent used for the recrystallization according to the present invention is a mixture of one or a mixture of two or more of a fatty acid ester, a ketone, an ether, and a hydrocarbon, and includes ethyl formate, propyl formate, butyl formate, and acetic acid. Methyl ester, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, C Butyl acrylate and amyl propionate, acetone, 2-butanone, cyclopentanone and cyclohexanone, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofuran, 1,4-dioxane Mixing one or more of petroleum ether, n-hexyl hydrazine, cyclohexanyl, methylcyclohexanide and n-heptanium in any ratio, preferably in any ratio of ethyl acetate or methyl tert-butyl ether and n-hexyl hydrazine Solvent.
本发明所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备方法简单易 行， 获得的化合物收率高。 具体实施方式 下面结合具体实施例对本发明做进一步的解释。 The preparation method of the 2,4-disubstituted-2H-1,2,3-triazole derivative of the present invention is simple and easy, and the obtained compound has a high yield. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further explained below in conjunction with specific embodiments.
实施例 1： Example 1:
买施例 2:
操作方法同实施例 1，将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 10.6g (41.5 mmol) 2-乙基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-乙基 -2H-1,2,3- 三氮唑 6.94 g，收率 95%。 ¾ NMR (CDC13, 400 MHz): δ 7.52 (s, 1H), 4.44 (t, J =7.2 Hz, 2H), 1.55 (t, J=7.2 Hz, 3H); 13C NMR (CDC13, 400 MHz): δ 135. L 121.4, 50.8, 14.7。 Buying Example 2: The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 10.6 g (41.5 mmol) of 2-ethyl-4,5-dibromo -2H-1,2,3-triazole. 4-bromo-2-ethyl-2H-1,2,3-triazole 6.94 g was obtained in a yield of 95%. 3⁄4 NMR (CDC1 3 , 400 MHz): δ 7.52 (s, 1H), 4.44 (t, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H); 13 C NMR (CDC1 3 , 400 MHz): δ 135. L 121.4, 50.8, 14.7.
买施例 3:
Buying Example 3:
操作方法同买施例 1， 将 2-甲基 -4,5-二溴 -2Η-1,2,3-三氮唑替换为 11.16g (41.5 mmol) 2-正丙基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-正丙 基 -2H-1,2,3-三氮唑 7.57 g，收率 96%。1HNMR (CDC13, 400 MHz): δ 7.52 (s, 1Η), 4.35 (t, / = 7.2 Hz, 2H), 2.01-1.92 (m, 2H), 0.92 (t, / = 7.4 Hz, 3H); 13C NMR (CDC13, 400 MHz): δ 135.0, 121.4, 57.3, 23.0, 11.0。
买施例 4: The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2Η-1,2,3-triazole with 11.16 g (41.5 mmol) 2-n-propyl-4,5- Dibromo-2H-1,2,3-triazole. 4-bromo-2-n-propyl-2H-1,2,3-triazole 7.57 g was obtained in a yield of 96%. 1 H NMR (CDC1 3 , 400 MHz): δ 7.52 (s, 1Η), 4.35 (t, / = 7.2 Hz, 2H), 2.01-1.92 (m, 2H), 0.92 (t, / = 7.4 Hz, 3H) 13 C NMR (CDC1 3 , 400 MHz): δ 135.0, 121.4, 57.3, 23.0, 11.0. Buying Example 4:
买施例 5:
Buying Example 5:
操作方法同实施例 1，将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 13. lg (41.5 mmol) 2-苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-苯甲基 -2H-1,2,3-三氮唑 9.48 g， 收率 96%。 NMR (CDC13, 400 MHz): δ 7.56 (s, IH), 7.26 7.38-7.32 (m, 5H), 5.55 (s, 2H); 13C NMR (CDC13, 400 MHz): δ 135.8, 134.5, 128.9, 128.6, 128.2, 122.2, 59.4。 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 13. lg (41.5 mmol) 2-benzyl-4,5- Dibromo-2H-1,2,3-triazole. 4-bromo-2-benzyl-2H-1,2,3-triazole 9.48 g was obtained in a yield of 96%. NMR (CDC1 3 , 400 MHz): δ 7.56 (s, IH), 7.26 7.38-7.32 (m, 5H), 5.55 (s, 2H); 13 C NMR (CDC1 3 , 400 MHz): δ 135.8, 134.5, 128.9, 128.6, 128.2, 122.2, 59.4.
买施例 6:
Buying Example 6:
操作方法同买施例 1，将 2-甲基 -4,5-二溴 -2Η-1,2,3-三氮唑替换为 13.7g (41.5 mmol) 2-对甲苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-对甲苯 甲基 -2H-1,2,3-三氮唑 10.25 g，收率 98%。 NMR (CDC13, 400 MHz): δ 7.53 (s, IH), 7.23 (ABq, / = 8.0 Hz, 2H), 7.15 (ABq, / = 8.0 Hz, 2H), 5.69 (s, 2H),
2.32 (s, 3H); 13C NMR (CDC13, 400 MHz): δ 138.5, 135.7, 131.5, 129.6, 128.3 122.0, 59.2, 21.2。 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2Η-1,2,3-triazole with 13.7 g (41.5 mmol) 2-p-toluenemethyl-4,5 -Dibromo-2H-1,2,3-triazole. 4-Bromo-2-p-toluenemethyl-2H-1,2,3-triazole 10.25 g was obtained in a yield of 98%. NMR (CDC1 3 , 400 MHz): δ 7.53 (s, IH), 7.23 (ABq, / = 8.0 Hz, 2H), 7.15 (ABq, / = 8.0 Hz, 2H), 5.69 (s, 2H), 2.32 (s, 3H); 13 C NMR (CDC1 3 , 400 MHz): δ 138.5, 135.7, 131.5, 129.6, 128.3 122.0, 59.2, 21.2.
实施例 7:
Example 7
操作方法同买施例 1，将 2-甲基 -4,5-二溴 -2Η-1,2,3-三氮唑替换为 14.4g (41.5 mmol) 2-间甲氧基苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-间 甲氧基苯甲基 -2H- 1,2,3-三氮唑 10.78 g， 收率 97%。 ¾ NMR (CDC13, 400 MHz): δ 7.56 (s, IH), 7.26 (t, / = 8.0 Hz, IH), 6.92-6.87 (m, 2H), 6.85 (s, IH), 5.52 (s, 2H), 3.79 (s, 3H); 13C NMR (CDC13, 400 MHz): δ 159.9, 135.9, 135.8, 130.0, 122.2, 120.4, 114.1, 113.7, 59.3, 55.3 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2Η-1,2,3-triazole with 14.4 g (41.5 mmol) 2-m-methoxybenzyl- 4,5-Dibromo-2H-1,2,3-triazole. 4-bromo-2-m-methoxybenzyl-2H- 1,2,3-triazole 10.78 g was obtained in a yield of 97%. 3⁄4 NMR (CDC1 3 , 400 MHz): δ 7.56 (s, IH), 7.26 (t, / = 8.0 Hz, IH), 6.92-6.87 (m, 2H), 6.85 (s, IH), 5.52 (s, 2H), 3.79 (s, 3H); 13 C NMR (CDC1 3 , 400 MHz): δ 159.9, 135.9, 135.8, 130.0, 122.2, 120.4, 114.1, 113.7, 59.3, 55.3
实施例
Example
操作方法同买施例 1，将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 14.4g (41.5 mmol) 2-对甲氧基苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-对 甲氧基苯甲基 -2H- 1,2,3-三氮唑 10.78 g， 收率 97%。 NMR (CDC13, 500 MHz): δ 7.54 (s, IH), 7.30 (ABq, / = 8.2 Hz, 2H), 6.88 (ABq, / = 8.2 Hz, 2H), 5.48 (s, 2H), 3.79 (s, 3H); 13C NMR (CDC13, 500 MHz): δ 159.9, 135.6, 129.8, 126.6, 122.0, 114.2, 59.0, 55.3。 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 14.4 g (41.5 mmol) of 2-p-methoxybenzyl- 4,5-Dibromo-2H-1,2,3-triazole. 4-bromo-2-p-methoxybenzyl-2H- 1,2,3-triazole 10.78 g was obtained in a yield of 97%. NMR (CDC1 3 , 500 MHz): δ 7.54 (s, IH), 7.30 (ABq, / = 8.2 Hz, 2H), 6.88 (ABq, / = 8.2 Hz, 2H), 5.48 (s, 2H), 3.79 ( s, 3H); 13 C NMR (CDC1 3 , 500 MHz): δ 159.9, 135.6, 129.8, 126.6, 122.0, 114.2, 59.0, 55.3.
实施例 9:
操作方法同买施例 1，将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 13.9g (41.5 mmol) 2-对氟苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2-对氟苯 甲基 -2H-1,2,3-三氮唑 10.2 g，收率 96%。 ^NMR (CDC13, 500 MHz): δ 7.56 (s, 1Η), 7.33 (dd, / = 5.7, 8.2 Hz, 2H), 7.03 (dd, / = 8.2, 9.0 Hz, 2H), 5.51(s, 2H); 13C NMR (CDC13, 500 MHz): δ 162.8 (d, / = 246.0 Hz), 135.9, 130.3 (d, •7=3.3 Hz), 130.2 (d,/=8.3 Hz), 122.3, 115.9 (d, / = 21.6 Hz), 58.6。 Example 9 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 13.9 g (41.5 mmol) of 2-p-fluorobenzyl-4. 5-Dibromo-2H-1,2,3-triazole. 4-Bromo-2-p-fluorobenzyl-2H-1,2,3-triazole 10.2 g was obtained in a yield of 96%. ^NMR (CDC1 3 , 500 MHz): δ 7.56 (s, 1 Η), 7.33 (dd, / = 5.7, 8.2 Hz, 2H), 7.03 (dd, / = 8.2, 9.0 Hz, 2H), 5.51 (s, 2H); 13 C NMR (CDC1 3 , 500 MHz): δ 162.8 (d, / = 246.0 Hz), 135.9, 130.3 (d, •7=3.3 Hz), 130.2 (d, /=8.3 Hz), 122.3, 115.9 (d, / = 21.6 Hz), 58.6.
买施例 10:
Buying Example 10:
操作方法同实施例 1， 将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 14.58g (41.5 mmol) 2-对氯苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 4-溴 -2- 对氯苯甲基 -2H-1,2,3-三氮唑 10.5 g，收率 QSO/O HNMR (CDC13, 400 MHz): δ 7.56 (s, 1Η), 7.32 (ABq, /= 8.8 Hz, 2H), 7.26 (ABq, /= 8.8 Hz, 2H), 5.51 (s 2H); 13C NMR (CDC13, 400 MHz): δ 136.0, 135.2, 132.9, 129.6, 129.1, 122.4, The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 14.58 g (41.5 mmol) of 2-p-chlorobenzyl-4,5. -Dibromo-2H-1,2,3-triazole. 4-Bromo-2-p-chlorobenzyl-2H-1,2,3-triazole 10.5 g, yield QSO/O HNMR (CDC1 3 , 400 MHz): δ 7.56 (s, 1 Η), 7.32 (ABq, /= 8.8 Hz, 2H), 7.26 (ABq, /= 8.8 Hz, 2H), 5.51 (s 2H); 13 C NMR (CDC1 3 , 400 MHz): δ 136.0, 135.2, 132.9, 129.6, 129.1 , 122.4,
买施例 11:
Buying Example 11:
操作方法同实施例 1， 将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 16.64g (41.5 mmol) 2-对三氟甲氧基苯甲基 -4,5-二溴 -2H-1,2,3-三氮唑。得到 4-溴 -2-对三氟甲氧基苯甲基 -2H-1,2,3-三氮唑 12.8 g， 收率 96%。 工！！ NMR (CDC13, 400 MHz): δ 7.58 (s, 1H), 7.36 (ABq, /= 8.6 Hz, 2H), 7.20 (ABq, J = 8.6 Hz, 2H), 5.55 (s, 2H); 13C NMR (CDC13, 400 MHz): δ 149.4, 136.0, 133.1, 129.8, 122.5, 121.3, 120.4 (q,/= 256.0 Hz), 58.5。
将 3.24 g (20 mmol) 4-溴 -2-甲基 -2H-1,2,3-三氮唑溶于 50 ml四氢呋喃 在 10~20°C， 缓慢加入 18.5 ml (24 mmol) 1.3M异丙基氯化镁-氯化锂四 呋喃溶液。 加毕， 继续反应 2小时。 冷却至 0°C以下， 通入二氧化碳气 约 10~30分钟， 温度 < 15°C。 在室温下， 用 1.0M盐酸酸化至 pH = l~2 再用 100 ml甲基叔丁基醚萃取， 有机层经无水硫酸钠干燥， 减压浓缩 ^ 干。将残余固体溶于 5 ml乙酸乙酯， 室温下滴加 20 ml正己垸， 继续搅 1小时，过滤，室温真空干燥，得到 2-甲基 -2H-1,2,3-三氮唑 -4-羧酸 1.7 收率 70% NMR (CD3COCD3, 500 MHz): δ 8.07 (s, 1Η), 4.26 (s, 3H); 13 NMR (CD3COCD3, 500 MHz): δ 161.7, 141.0, 137.4, 42.6。 The procedure was the same as in Example 1, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 16.64 g (41.5 mmol) of 2-p-trifluoromethoxybenzyl. -4,5-Dibromo-2H-1,2,3-triazole. 4-Bromo-2-p-trifluoromethoxybenzyl-2H-1,2,3-triazole 12.8 g was obtained in a yield of 96%. work! ! NMR (CDC1 3 , 400 MHz): δ 7.58 (s, 1H), 7.36 (ABq, /= 8.6 Hz, 2H), 7.20 (ABq, J = 8.6 Hz, 2H), 5.55 (s, 2H); 13 C NMR (CDC1 3 , 400 MHz): δ 149.4, 136.0, 133.1, 129.8, 122.5, 121.3, 120.4 (q, /= 256.0 Hz), 58.5. 3.24 g (20 mmol) of 4-bromo-2-methyl-2H-1,2,3-triazole was dissolved in 50 ml of tetrahydrofuran at 10-20 ° C, and slowly added 18.5 ml (24 mmol) 1.3 M Propyl magnesium chloride - lithium chloride tetrafuran solution. After the addition, continue to react for 2 hours. Cool to below 0 ° C, pass carbon dioxide gas for about 10 to 30 minutes, temperature < 15 ° C. It was acidified to pH = 1~2 with EtOAc (EtOAc m. The residual solid was dissolved in 5 ml of ethyl acetate. 20 ml of hexane was added dropwise at room temperature, stirring was continued for 1 hour, filtered, and dried under vacuum at room temperature to give 2-methyl-2H-1,2,3-triazole-4 -carboxylic acid 1.7 yield 70% NMR (CD 3 COCD 3 , 500 MHz): δ 8.07 (s, 1 Η), 4.26 (s, 3H); 13 NMR (CD 3 COCD 3 , 500 MHz): δ 161.7, 141.0 , 137.4, 42.6.
买施例 13 :
操作方法同实施例 12， 将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 3.52 g (20 mmol) 4-溴 -2-乙基 -2H- 1,2,3-三氮唑。 得到 2-乙基 -2H-1,2,3-三氮唑 -4- 羧酸 2.1 g，收率 74%。 ^ NMR (CDC13, 400 MHz): δ 11.57 (bs, 1Η), 8.17 (s, 1H), 4.62 (t, J = 7.2 Hz, 2H), 1.64 (t, J = 7.2 Hz, 2H); 13C NMR (CDC13, 400 MHz) δ 165.3, 138.9, 137.4, 51.1, 14.6。 Buying Example 13: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 3.52 g (20 mmol) 4-bromo-2-ethyl-2H-1,2 , 3-triazole. 2.1 g of 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 74%. ^ NMR (CDC1 3 , 400 MHz): δ 11.57 (bs, 1Η), 8.17 (s, 1H), 4.62 (t, J = 7.2 Hz, 2H), 1.64 (t, J = 7.2 Hz, 2H); 13 C NMR (CDC1 3 , 400 MHz) δ 165.3, 138.9, 137.4, 51.1, 14.6.
买施例 14:
操作方法同买施例 12，将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 3.8 g (20 mmol) 4-溴 -2-正丙基 -2H-1,2,3-三氮唑。 得到 2-正丙基 -2H-1,2,3-三氮唑 -4- 羧酸 2.45 g，收率 79%。 NMR (CD3COCD3, 400 MHz): δ 8.12 (s, 1H), 4.49
(t, J = 7.0 Hz, 2H), 2.03-1.96 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); "C NMR (CD3COCD3, 400 MHz) δ 161.9, 140.8, 137.6, 57.7, 23.6, 11.2。 Buying Example 14: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 3.8 g (20 mmol) 4-bromo-2-n-propyl-2H-1 , 2,3-triazole. 2.45 g of 2-n-propyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 79%. NMR (CD 3 COCD 3 , 400 MHz): δ 8.12 (s, 1H), 4.49 (t, J = 7.0 Hz, 2H), 2.03-1.96 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); "C NMR (CD 3 COCD 3 , 400 MHz) δ 161.9, 140.8, 137.6 , 57.7, 23.6, 11.2.
买施例 15:
操作方法同买施例 12，将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 4.3 g (20 mmol) 4-溴 -2-环戊基 -2H-1,2,3-三氮唑。 得到 2-环戊基 -2H-1,2,3-三氮唑 -4- 羧酸 3.1 g， 收率 85% ¾ NMR (CD3COCD3, 400 MHz): δ 8.09 (s, IH), 5.15-5.09 (m, IH), 2.24-2.14 (m, 4H), 1.90-1.86 (m, 2H), 1.78-1.74 (m, 2H); 13C NMR (CD3COCD3, 400 MHz): δ 161.9, 140.5, 137.4, 67.5, 33.4, 24.9。 Buy Example 15: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 4.3 g (20 mmol) 4-bromo-2-cyclopentyl-2H-1 , 2,3-triazole. Yield 3.1 g of 2-cyclopentyl-2H-1,2,3-triazole-4-carboxylic acid, yield 85% 3⁄4 NMR (CD 3 COCD 3 , 400 MHz): δ 8.09 (s, IH), 5.15-5.09 (m, IH), 2.24-2.14 (m, 4H), 1.90-1.86 (m, 2H), 1.78-1.74 (m, 2H); 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 161.9, 140.5, 137.4, 67.5, 33.4, 24.9.
买施例 16:
操作方法同实施例 12， 将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 4.76 g (20 mmol) 4-溴 -2-苯甲基 -2H-1,2,3-三氮唑。得到 2-苯甲基 -2H-1,2,3-三氮唑 -4-羧酸 3.7 g， 收率 91%。 NMR (CD3COCD3, 400 MHz): δ 8.14 (s, IH), 7.39-7.33 (m, 5H), 5.67 (s, 2H); 13C NMR (CD3COCD3, 400 MHz): δ 165.3, 139.3, 138.1, 133.9, 129.0, 128.8, 128.4, 59.7。 Buy Example 16: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 4.76 g (20 mmol) 4-bromo-2-phenylmethyl-2H-1. 2,3-triazole. 3.7 g of 2-benzyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 91%. NMR (CD 3 COCD 3 , 400 MHz): δ 8.14 (s, IH), 7.39-7.33 (m, 5H), 5.67 (s, 2H); 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 165.3 , 139.3, 138.1, 133.9, 129.0, 128.8, 128.4, 59.7.
买施例 17:
操作方法同实施例 12， 将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 5.06 g (20 mmol) 4-溴 -2-对甲苯甲基 -2H-1,2,3-三氮唑。 得到 2-对甲苯甲基 -2H-1,2,3-三氮唑 -4-羧酸 3.82 g，收率
NMR (CD3COCD3, 400 MHz):
δ 8.11 (s, 1H), 7.28 (ABq, / = 8.0 Hz, 2H), 7.19 (ABq, J = 8.0 Hz, 2H), 5.66 (s 2H), 2.30 (s, 3H); 13C NMR (CD3COCD3, 400 MHz): δ 161.7, 141.3, 139.0, 138.0, 133.1, 130.2, 129.1, 59.6, 21.1。 Buy Example 17: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 5.06 g (20 mmol) 4-bromo-2-p-toluomethyl-2H-1 , 2,3-triazole. Obtained 3.82 g of 2-p-toluomethyl-2H-1,2,3-triazole-4-carboxylic acid, yield NMR (CD 3 COCD 3 , 400 MHz): δ 8.11 (s, 1H), 7.28 (ABq, / = 8.0 Hz, 2H), 7.19 (ABq, J = 8.0 Hz, 2H), 5.66 (s 2H), 2.30 (s, 3H); 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 161.7, 141.3, 139.0, 138.0, 133.1, 130.2, 129.1, 59.6, 21.1.
实施例 18:
操作方法同实施例 12，将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 5.4 g (20 mmol) 4-溴 -2-间甲氧基苯甲基 -2H-1,2,3-三氮唑。 得到 2-间甲氧基苯甲基 -2H-1,2,3-三氮唑 -4-羧酸 3.82 g，收率 82% H NMR (CD3COCD3, 400 MHz): δ 8.13 (s, 1H), 7.29 (i, J = 8.0 Hz, 1H), 6.95-6.90 (m, 3H), 5.69 (s, 2H), 3.78 (s, 3H); 13C NMR (CD3COCD3, 400 MHz): δ 161.7, 160.9, 141.4, 138.1, 137.5, 130.7, 121.1, 114.8, 114.5, 59.7, 55.6。 Example 18 The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-m-methoxybenzyl- 2H-1,2,3-triazole. 2.82 g of 2-m-methoxybenzyl-2H-1,2,3-triazole-4-carboxylic acid, yield 82% H NMR (CD 3 COCD 3 , 400 MHz): δ 8.13 (s , 1H), 7.29 (i, J = 8.0 Hz, 1H), 6.95-6.90 (m, 3H), 5.69 (s, 2H), 3.78 (s, 3H); 13 C NMR (CD 3 COCD 3 , 400 MHz ): δ 161.7, 160.9, 141.4, 138.1, 137.5, 130.7, 121.1, 114.8, 114.5, 59.7, 55.6.
买施 19:
操作方法同实施例 12，将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.4 g (20 mmol) 4-溴 -2-对甲氧基苯甲基 -2H-1,2,3-三氮唑。 得到 2-对甲氧基苯甲基 -2H-1,2,3-三氮唑 -4-羧酸 4.2 g，收率 90%。 ^ NMR (CD3COCD3, 500 MHz): δ 8.10 (s, 1Η), 7.35 (ABq, / = 8.5 Hz, 2H), 6.92 (ABq, / = 8.5 Hz, 2H), 5.63 (s 2H), 3.78 (s, 3H); 13C NMR (CD3COCD3, 500 MHz): δ 161.7, 160.8, 141.2, 138.0, 130.7, 128.0, 114.9, 59.4, 55.6。 Buy 19: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-p-methoxybenzyl- 2H-1,2,3-triazole. 4.2 g of 2-p-methoxybenzyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 90%. ^ NMR (CD 3 COCD 3 , 500 MHz): δ 8.10 (s, 1Η), 7.35 (ABq, / = 8.5 Hz, 2H), 6.92 (ABq, / = 8.5 Hz, 2H), 5.63 (s 2H), 3.78 (s, 3H); 13 C NMR (CD 3 COCD 3 , 500 MHz): δ 161.7, 160.8, 141.2, 138.0, 130.7, 128.0, 114.9, 59.4, 55.6.
买施例 20:
操作方法同买施例 12，将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.1 g (20 mmol) 4-溴 -2-对氟苯甲基 -2H-1,2,3-三氮唑。 得到 2-对氟苯甲基 -2H-1,2,3- 三氮唑—4-羧酸 3.76 g，收率
NMR (CD3COCD3, 400 MHz): δ 8.13 (s, 1Η), 7.46 (dd, / = 5.7, 8.2 Hz, 2H), 7.16 (dd, / = 8.2, 9.0 Hz, 2H), 5.72(s, 2H); 13C NMR (CD3COCD3, 400 MHz): δ 163.6 (d, J = 244.0 Hz), 141.4, 138.1, 132.3 (d, J = 3.0 Hz), 131.4 (d, J = 8.0 Hz), 122.3, 116.3 (d, J = 21.0 Hz), 59.0 ο Buying Example 20: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.1 g (20 mmol) 4-bromo-2-p-fluorobenzyl-2H -1,2,3-triazole. Obtained 3.76 g of 2-p-fluorobenzyl-2H-1,2,3-triazole-4-carboxylic acid, yield NMR (CD 3 COCD 3 , 400 MHz): δ 8.13 (s, 1 Η), 7.46 (dd, / = 5.7, 8.2 Hz, 2H), 7.16 (dd, / = 8.2, 9.0 Hz, 2H), 5.72 (s , 2H); 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 163.6 (d, J = 244.0 Hz), 141.4, 138.1, 132.3 (d, J = 3.0 Hz), 131.4 (d, J = 8.0 Hz) ), 122.3, 116.3 (d, J = 21.0 Hz), 59.0 ο
买施 21 :
操作方法同实施例 12， 将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.45 g (20 mmol) 4-溴 -2-对氯苯甲基 -2H-1,2,3-三氮唑。 得到 2-对氯苯甲基 -2H-1,2,3-三氮唑 -4-羧酸 2.62 g，收率 55%。 NMR (CD3COCD3, 400 MHz): δ 8.14 (s, 1H), 7.42 (s, 4H), 5.74 (s, 2H); 13C NMR (CD3COCD 400 MHz): δ 165.9, 145.8, 142.6, 142.4, 139.3, 135.2, 134.0, 63.2。 Buy 21: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.45 g (20 mmol) 4-bromo-2-p-chlorobenzyl-2H- 1,2,3-triazole. 2.62 g of 2-p-chlorobenzyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 55%. NMR (CD 3 COCD 3 , 400 MHz): δ 8.14 (s, 1H), 7.42 (s, 4H), 5.74 (s, 2H); 13 C NMR (CD 3 COCD 400 MHz): δ 165.9, 145.8, 142.6 , 142.4, 139.3, 135.2, 134.0, 63.2.
买施 22:
操作方法同实施例 12， 将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 6.45 g (20 mmol) 4-溴 -2-对三氟甲基苯甲基 -2H-1,2,3-三氮唑。 得到 2-对对三氟甲 基苯甲基 -2H- 1,2,3-三氮唑 -4-羧酸 4.65 g，收率 81%。 ^ NMR (CD3COCD3, 400 MHz): δ 8.15 (s, 1Η), 7.54 (ABq, / = 8.4 Hz, 2H), 7.36 (ABq, / = 8.4 Hz, 2H), 5.79 (s, 2H); 13C NMR (CD3COCD3, 400 MHz): δ 161.6, 149.9, 141.6, 138.2, 135.4, 131.1, 122.2, 121.4 (q, /= 254.0 Hz), 58.8。 Buy Shi 22: The procedure was the same as in Example 12, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 6.45 g (20 mmol) 4-bromo-2-p-trifluoromethylbenzyl -2H-1,2,3-triazole. There was obtained 4.65 g of 2-p-p-trifluoromethylbenzyl-2H- 1,2,3-triazole-4-carboxylic acid in a yield of 81%. ^ NMR (CD 3 COCD 3 , 400 MHz): δ 8.15 (s, 1Η), 7.54 (ABq, / = 8.4 Hz, 2H), 7.36 (ABq, / = 8.4 Hz, 2H), 5.79 (s, 2H) 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 161.6, 149.9, 141.6, 138.2, 135.4, 131.1, 122.2, 121.4 (q, /= 254.0 Hz), 58.8.
实施例 23：
Example 23
将 3.24 g (20 mmol) 4-溴 -2-甲基 -2H-1,2,3-三氮唑溶于 50 ml四氢呋喃， 在 10~20°C， 缓慢加入 18.5 ml (24 mmol) 1.3M异丙基氯化镁 -氯化锂四氢 呋喃溶液， 加毕， 继续反应 2 小时。 冷却至 -20°C以下， 加入硼酸三甲酯 3.5 ml (30 mmol) ， 继续反应 0.5~2小时。在室温下， 用 1.0 M盐酸酸化至 pH = l~2， 再用 100 ml乙酸乙酯萃取， 有机层经无水硫酸钠干燥， 减压浓 缩至干。 残余物溶于 20 ml甲基叔丁基醚， 室温下滴加 30 ml正己垸， 冷 却至 0~5°C， 搅拌 1 小时， 过滤、 室温真空干燥， 得到 2-甲基 -2H-1,2,3- 三氮唑—4-硼酸 1.6 g， 收率 63%。 NMR (DMSO-i 6, 400 MHz): δ 7.93 (s, 1H), 4.19 (s, 3H); 13C NMR (DMSO-i 6, 400 MHz): δ 142.0, 41.0。 3.24 g (20 mmol) of 4-bromo-2-methyl-2H-1,2,3-triazole was dissolved in 50 ml of tetrahydrofuran, and at 10-20 ° C, 18.5 ml (24 mmol) of 1.3 M was slowly added. Isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution was added and the reaction was continued for 2 hours. Cool to below -20 ° C, add 3.5 ml of trimethyl borate (30 mmol) and continue the reaction for 0.5 to 2 hours. The mixture was acidified with EtOAc (EtOAc m. The residue was dissolved in 20 ml of methyl tert-butyl ether. 30 ml of hexane was added dropwise at room temperature, cooled to 0 to 5 ° C, stirred for 1 hour, filtered and dried under vacuum at room temperature to give 2-methyl-2H-1. 2,3-triazole- 4-boronic acid 1.6 g, yield 63%. NMR (DMSO-i 6, 400 MHz): δ 7.93 (s, 1H), 4.19 (s, 3H); 13 C NMR (DMSO-i 6, 400 MHz): δ 142.0, 41.0.
买施例 24:
Buy example 24:
操作方法同实施例 23， 将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 3.52 g (20 mmol) 4-溴 -2-乙基 -2H- 1,2,3-三氮唑。 得到 2-乙基 -2H-1,2,3-三氮唑 -4- 硼酸 1.0 g，收率 72%。 NMR (DMSO-i 6, 400 MHz): δ 7.92 (s, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-i 6, 400 MHz) δ 140.6, 49.0, 14.7。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 3.52 g (20 mmol) 4-bromo-2-ethyl-2H-1,2 , 3-triazole. 1.0 g of 2-ethyl-2H-1,2,3-triazole-4-boronic acid was obtained in a yield of 72%. NMR (DMSO-i 6, 400 MHz): δ 7.92 (s, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13 C NMR (DMSO-i 6, 400 MHz) δ 140.6, 49.0, 14.7.
买施例 25:
Buy example 25:
操作方法同实施例 23，将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 3.8 g (20 mmol) 4-溴 -2-正丙基 -2H-1,2,3-三氮唑。 得到 2-正丙基 -2H-1,2,3-三氮唑 -4- 硼酸 2.66 g， 收率 86% o ¾ NMR (DMSO-i 6, 400 MHz): δ 7.94 (s, 1H), 4.40 (t, / = 6.8 Hz, 2H), 1.92-1.86 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H); 13C NMR
(DMSO-i 6, 400 MHz) δ 141.6, 140.6, 55.4, 22.7, 10.9。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 3.8 g (20 mmol) 4-bromo-2-n-propyl-2H-1. 2,3-triazole. 2.66 g of 2-n-propyl-2H-1,2,3-triazole-4-boronic acid, yield 86% o 3⁄4 NMR (DMSO-i 6, 400 MHz): δ 7.94 (s, 1H), 4.40 (t, / = 6.8 Hz, 2H), 1.92-1.86 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H); 13 C NMR (DMSO-i 6, 400 MHz) δ 141.6, 140.6, 55.4, 22.7, 10.9.
实施例 2
Example 2
操作方法同买施例 23，将 4-溴 -2-甲基 -2Η- 1 ,2,3-三氮唑替换为 4.3 g (20 mmol) 4-溴 -2-环戊基 -2H-1,2,3-三氮唑。 得到 2-环戊基 -2H-1,2,3-三氮唑 -4- 硼酸 3.08 g， 收率 85%。 NMR (DMSO-i 6, 400 MHz): δ 7.92 (s, IH), 5.09-5.02 (m, IH), 2.14-2.03 (m, 4H), 1.984-1.78 (m, 2H), 1.69-1.66 (m, 2H); 13C NMR (DMSO-i 6, 400 MHz): δ 141.5 (bs), 140.4, 64.9, 32.4, 23.9。 买施例 27:
The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 4.3 g (20 mmol) 4-bromo-2-cyclopentyl-2H-1 , 2,3-triazole. There was obtained 3.08 g of 2-cyclopentyl-2H-1,2,3-triazole-4-boronic acid in a yield of 85%. NMR (DMSO-i 6, 400 MHz): δ 7.92 (s, IH), 5.09-5.02 (m, IH), 2.14-2.03 (m, 4H), 1.984-1.78 (m, 2H), 1.69-1.66 ( m, 2H); 13 C NMR (DMSO-i 6, 400 MHz): δ 141.5 (bs), 140.4, 64.9, 32.4, 23.9. Buy Example 27:
操作方法同实施例 23， 将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 4.76 g (20 mmol) 4-溴 -2-苯甲基 -2H-1,2,3-三氮唑。得到 2-苯甲基 -2H-1,2,3-三氮唑 —4-硼酸 3.53 g， 收率 87%。 NMR (DMSO-i 6, 400 MHz): δ 7.99 (s, IH), 7.37-7.24 (m, 5H), 5.68 (s, 2H); 13C NMR (DMSO-i 6, 400 MHz): δ 142.1, 141.1, 137.1, 133.0, 129.0, 127.6, 57.2, 20.6。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 4.76 g (20 mmol) of 4-bromo-2-phenylmethyl-2H-1. 2,3-triazole. There was obtained 3.53 g of 2-benzyl-2H-1,2,3-triazole-4-boronic acid in a yield of 87%. NMR (DMSO-i 6, 400 MHz): δ 7.99 (s, IH), 7.37-7.24 (m, 5H), 5.68 (s, 2H); 13 C NMR (DMSO-i 6, 400 MHz): δ 142.1 , 141.1, 137.1, 133.0, 129.0, 127.6, 57.2, 20.6.
买施例 28:
Buy Example 28:
操作方法同实施例 23， 将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.06 g (20 mmol) 4-溴 -2-对甲苯甲基 -2H-1,2,3-三氮唑。 得到 2-对甲苯甲基 -2H-1,2,3-三氮唑 -4-硼酸 3.81 g，收率 88%。 ^ NMR (DMSO-i 6, 400 MHz): δ 7.96 (s, IH), 7.15 (s, 4H), 5.62 (s, 2H), 2.27 (s, 3H); 13C NMR (DMSO-i 6,
400 MHz): δ 142.0, 141.1 136.0, 128.5, 127.8, 127.6, The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.06 g (20 mmol) 4-bromo-2-p-toluomethyl-2H-1 , 2,3-triazole. There was obtained 3.81 g of 2-p-toluomethyl-2H-1,2,3-triazole-4-boronic acid in a yield of 88%. ^ NMR (DMSO-i 6, 400 MHz): δ 7.96 (s, IH), 7.15 (s, 4H), 5.62 (s, 2H), 2.27 (s, 3H); 13 C NMR (DMSO-i 6, 400 MHz): δ 142.0, 141.1 136.0, 128.5, 127.8, 127.6,
实施例 29:
操作方法同买施例 23，将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 5.4 g (20 mmol) 4-溴 -2-间甲氧基苯甲基 -2H-1,2,3-三氮唑。 得到 2-间甲氧基苯甲基 -2H-1,2,3-三氮唑 -4-硼酸 3.82 g，收率 82%。 ¾ NMR (DMSO-i 6, 400 MHz): δ 8.37 (bs, 2H), 7.96 (s, 1H), 7.26 (t, / = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.63 (s, 2H), 3.72 (s, 3H); 13C NMR (DMSO-i 6, 400 MHz): δ 159.2, 141.1, 138.1, 137.5, 129.6, 119.6, 113.3, 113.1, 57.2, 55 Example 29 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-m-methoxybenzyl. -2H-1,2,3-triazole. There was obtained 3.82 g of 2-m-methoxybenzyl-2H-1,2,3-triazole-4-boronic acid in a yield of 82%. 3⁄4 NMR (DMSO-i 6, 400 MHz): δ 8.37 (bs, 2H), 7.96 (s, 1H), 7.26 (t, / = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H) , 6.80 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.63 (s, 2H), 3.72 (s, 3H); 13 C NMR (DMSO-i 6, 400 MHz): δ 159.2, 141.1, 138.1, 137.5, 129.6, 119.6, 113.3, 113.1, 57.2, 55
买施例 30:
Buy Example 30:
操作方法同实施例 23，将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.4 g (20 mmol) 4-溴 -2-对甲氧基苯甲基 -2H-1,2,3-三氮唑。 得到 2-对甲氧基苯甲基 -2H-1,2,3-三氮唑 -4-硼酸 3.77 g，收率 S /c^H NMR (CD3COCD3, 400 MHz): δ 7.90 (s, 1Η), 7.27 (ABq, / = 8.6 Hz, 2H), 6.89 (ABq, / = 8.6 Hz, 2H), 5.58 (s, 2H), 3.77 (s, 3H); 13C NMR (CD3COCD3, 400 MHz): δ 160.5, 141.7, 130.3, 129.0, 114.8, 58.4, 55.6。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.4 g (20 mmol) 4-bromo-2-p-methoxybenzyl- 2H-1,2,3-triazole. 2.77 g of 2-p-methoxybenzyl-2H-1,2,3-triazole-4-boronic acid was obtained in a yield S/c^H NMR (CD 3 COCD 3 , 400 MHz): δ 7.90 ( s, 1Η), 7.27 (ABq, / = 8.6 Hz, 2H), 6.89 (ABq, / = 8.6 Hz, 2H), 5.58 (s, 2H), 3.77 (s, 3H); 13 C NMR (CD 3 COCD 3 , 400 MHz): δ 160.5, 141.7, 130.3, 129.0, 114.8, 58.4, 55.6.
买施例 31
Buying example 31
操作方法同实施例 23，将 4-溴 -2-甲基 -2H- 1 ,2
mmol) 4-溴 -2-对氟苯甲基 -2H-1,2,3-三氮唑。 得到 2-对氟苯甲基 -2H-1,2,3- 三氮唑—4-硼酸 3.1 g， 收率 70%。 NMR (DMSO-i 6, 400 MHz): δ 7.97 (s, 1H), 7.46 (dd, J = 5.7, 8.6 Hz, 2H), 7.19 (dd, J = 8.6, 9.0 Hz, 2H), 5.67 (s, 2H); 13C NMR (DMSO-i 6, 400 MHz): δ 161.7 (d, / = 243.0 Hz), 141.1, 132.2 (d, J = 3.0 Hz), 129.9 (d, /= 9.0 Hz), 115.4 (d, /= 22.0 Hz), 56.5。 The same operation method as in Example 23, 4-bromo-2-methyl-2H-1, 2 Methyl) 4-bromo-2-p-fluorobenzyl-2H-1,2,3-triazole. There was obtained 3.1 g of 2-p-fluorobenzyl-2H-1,2,3-triazole-4-boronic acid in a yield of 70%. NMR (DMSO-i 6, 400 MHz): δ 7.97 (s, 1H), 7.46 (dd, J = 5.7, 8.6 Hz, 2H), 7.19 (dd, J = 8.6, 9.0 Hz, 2H), 5.67 (s , 2H); 13 C NMR (DMSO-i 6, 400 MHz): δ 161.7 (d, / = 243.0 Hz), 141.1, 132.2 (d, J = 3.0 Hz), 129.9 (d, /= 9.0 Hz), 115.4 (d, /= 22.0 Hz), 56.5.
买施例 32:
Buy example 32:
操作方法同实施例 23， 将 4-溴 -2-甲基 -2H-1,2,3-三氮唑替换为 5.45 g (20 mmol) 4-溴 -2-对氯苯甲基 -2H-1,2,3-三氮唑。 得到 2-对氯苯甲基 -2H-1,2,3-三氮唑 -4-硼酸 2.45 g，收率 52%。 ¾ NMR (DMSO-i 6, 400 MHz): δ 7.99 (s, 1H), 7.42 (ABq, / = 8.4 Hz, 2H), 7.27 (ABq, / = 8.4 Hz, 2H), 5.69 (s: 2H); 13C NMR (DMSO-i 6, 400 MHz) δ 141.2, 135.0, 132.5, 129.5, 128.5, 128.4, 56.6。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2H-1,2,3-triazole with 5.45 g (20 mmol) 4-bromo-2-p-chlorobenzyl-2H- 1,2,3-triazole. 2.45 g of 2-p-chlorobenzyl-2H-1,2,3-triazole-4-boronic acid was obtained in a yield of 52%. 3⁄4 NMR (DMSO-i 6, 400 MHz): δ 7.99 (s, 1H), 7.42 (ABq, / = 8.4 Hz, 2H), 7.27 (ABq, / = 8.4 Hz, 2H), 5.69 (s : 2H) 13 C NMR (DMSO-i 6, 400 MHz) δ 141.2, 135.0, 132.5, 129.5, 128.5, 128.4, 56.6.
买施例 33 :
Buy Example 33:
操作方法同实施例 23， 将 4-溴 -2-甲基 -2Η-1,2,3-三氮唑替换为 6.45 g (20 mmol) 4-溴 -2-对三氟甲基苯甲基 -2H-1,2,3-三氮唑。 得到 2-对对三氟甲 基苯甲基 -2H- 1,2,3-三氮唑 -4-硼酸 3.79 g， 收率 66%。 NMR (DMSO-i 6, 400 MHz): δ 8.00 (s, 1H), 7.39 (ABq, / = 9.2 Hz, 2H), 7.36 (ABq, / = 9.2 Hz, 2H), 5.74 (s, 2H); 13C NMR (DMSO-i 6, 400 MHz): δ 147.9 (d, J = 2.0 Hz), 141.3, 135.5, 129.7,121.3, 119.9 (q, / = 245.0 Hz), 56.5。 The procedure was the same as in Example 23, replacing 4-bromo-2-methyl-2Η-1,2,3-triazole with 6.45 g (20 mmol) 4-bromo-2-p-trifluoromethylbenzyl -2H-1,2,3-triazole. There was obtained 3.79 g of 2-p-p-trifluoromethylbenzyl-2H- 1,2,3-triazole-4-boronic acid in a yield of 66%. NMR (DMSO-i 6, 400 MHz): δ 8.00 (s, 1H), 7.39 (ABq, / = 9.2 Hz, 2H), 7.36 (ABq, / = 9.2 Hz, 2H), 5.74 (s, 2H); 13 C NMR (DMSO-i 6, 400 MHz): δ 147.9 (d, J = 2.0 Hz), 141.3, 135.5, 129.7, 121.3, 119.9 (q, / = 245.0 Hz), 56.5.
买施例 34:
将 5 g (20.7 mmol) 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑溶于 40 ml四氢呋 喃， 冷却至 -15〜- 5°C， 缓慢加入 11.2 ml (22.4 mmol) 2 M异丙基氯化镁四 氢呋喃溶液， 加毕， 继续反应 0.5小时。缓慢加入 0.88 ml (21.74 mmol) 甲 醇， 升温至 5~15°C， 加入 17.3 ml (22.4 mmol) 1.3 M异丙基氯化镁-氯化锂 四氢呋喃溶液， 加毕， 室温下继续反应 2小时。 冷却至 0°C以下， 通入二 氧化碳气体约 10~30分钟， 温度 < 15 °C， 用 1.0 M盐酸酸化至 pH = l~2， 再用 100 ml甲基叔丁基醚萃取， 有机层经无水硫酸钠干燥， 减压浓缩至 干， 将残余固体溶于 5 ml乙酸乙酯， 室温下滴加 20 ml正己垸， 继续搅拌 1小时，过滤，室温真空干燥，得到 2-甲基 -2H-1,2,3-三氮唑 -4-羧酸 1.74 g， 收率 66%。 Buy Example 34: Dissolve 5 g (20.7 mmol) of 2-methyl-4,5-dibromo-2H-1,2,3-triazole in 40 ml of tetrahydrofuran, cool to -15~- 5 °C, slowly add 11.2 ml (22.4 mmol) 2 M isopropylmagnesium chloride tetrahydrofuran solution, after completion, the reaction was continued for 0.5 hours. 0.88 ml (21.74 mmol) of methanol was slowly added, and the temperature was raised to 5 to 15 ° C. 17.3 ml (22.4 mmol) of a 1.3 M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution was added thereto, and the reaction was continued at room temperature for 2 hours. Cool to below 0 °C, pass carbon dioxide gas for about 10~30 minutes, temperature < 15 °C, acidify to pH = l~2 with 1.0 M hydrochloric acid, extract with 100 ml of methyl tert-butyl ether, organic layer The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. EtOAcjjjjjjjjjjjjjj -1,2,3-triazole-4-carboxylic acid 1.74 g, yield 66%.
买施例 35 :
Buy example 35:
操作方法同实施例 34， 将 2-甲基 -4, .溴-211-1,2,3-三氮唑替换为 5.28g (20.7 mmol) 2-乙基 -4,5-二溴 -2H-1,2,3 It唑。得到 2-乙基 -2H-1,2,3- 三氮唑 -4-羧酸 2.34 g， 收率 80%。 The procedure was the same as in Example 34, replacing 2-methyl-4, .bromo-211-1,2,3-triazole with 5.28 g (20.7 mmol) of 2-ethyl-4,5-dibromo-2H. -1,2,3 Itazole. 2.34 g of 2-ethyl-2H-1,2,3-triazole-4-carboxylic acid was obtained in a yield of 80%.
买施例 36:
操作方法同实施例 34， 将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 .57g (20.7 mmol) 2-正丙基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 2-正丙基
-2H- 1,2,3- 买施例 37: Buy Example 36: The procedure was the same as in Example 34, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with .57 g (20.7 mmol) 2-n-propyl-4,5-di Bromo-2H-1,2,3-triazole. 2-n-propyl -2H- 1,2,3- Buying Example 37:
买施例 38:
将 5 g (20.7 mmol) 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑溶于 0 ml四氢呋 喃， 冷却至 -15〜- 5°C， 缓慢加入 11.2 ml (22.4 mmol) 2 M异丙基氯化镁四 氢呋喃溶液， 加毕， 继续反应 0.5小时。缓慢加入 0.88 ml (21.74 mmol) 甲 醇， 升温至 5~15°C， 加入 17.3 ml (22.4 mmol) 1.3 M异丙基氯化镁-氯化锂 四氢呋喃溶液， 加毕， 室温下继续反应 2 小时。 冷却至 -20°C以下， 加入 硼酸三甲酯 3.6 ml (31 mmol) ， 继续反应 0.5~2小时， 用 1.0 M盐酸酸化 至 pH = l~2， 温度 < 15°C， 再用 100 ml乙酸乙酯萃取， 有机层经无水硫 酸钠干燥， 减压浓缩至干， 残余物溶于 10 ml甲基叔丁基醚， 室温下滴加 30 ml正己垸， 冷却至 0~5 °C， 搅拌 1小时， 过滤、 室温真空干燥， 得到 2-甲基 -2H-1,2,3-三氮唑 -4-硼酸 1.97 g， 收率 75%。 买施 39:
操作方法同买施例 38，将 2-甲基 -4 Buy Example 38: Dissolve 5 g (20.7 mmol) of 2-methyl-4,5-dibromo-2H-1,2,3-triazole in 0 ml of tetrahydrofuran, cool to -15~-5 °C, slowly add 11.2 ml (22.4 mmol) 2 M isopropylmagnesium chloride tetrahydrofuran solution, after completion, the reaction was continued for 0.5 hours. 0.88 ml (21.74 mmol) of methanol was slowly added, and the temperature was raised to 5 to 15 ° C. 17.3 ml (22.4 mmol) of a 1.3 M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution was added thereto, and the reaction was continued for 2 hours at room temperature. Cool to below -20 °C, add 3.6 ml (31 mmol) of trimethyl borate, continue the reaction for 0.5 to 2 hours, acidify to pH = l~2 with 1.0 M hydrochloric acid, temperature < 15 ° C, then use 100 ml of acetic acid The organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness. After 1 hour, filtration and vacuum drying at room temperature gave 1.97 g of 2-methyl-2H-1,2,3-triazole-4-boronic acid in a yield of 75%. Buy 39: The method of operation is the same as the purchase of Example 38, 2-methyl-4
g (20.7 mmol) 2-乙基 -4,5-二溴 -2H-1,2,3 g (20.7 mmol) 2-ethyl -4,5-dibromo -2H-1,2,3
唑 -4-硼酸 2.54 g， 收率 87%。 Oxazole-4-boronic acid 2.54 g, yield 87%.
买施例 40:
Buying Example 40:
操作方法同实施例 38， 将 2-甲基 -4,5-二溴 -2H-1,2,3-三氮唑替换为 5.57g (20.7 mmol) 2-正丙基 -4,5-二溴 -2H-1,2,3-三氮唑。 得到 2-正丙基 -2H-1,2,3-三氮唑 -4-硼酸 2.95 g， 收率 92%。 The procedure was the same as in Example 38, replacing 2-methyl-4,5-dibromo-2H-1,2,3-triazole with 5.57 g (20.7 mmol) 2-n-propyl-4,5-di Bromo-2H-1,2,3-triazole. 2.95 g of 2-n-propyl-2H-1,2,3-triazole-4-boronic acid was obtained in a yield of 92%.
买施例 41 Buying example 41
买施例 42:
将 5 g (24.27 mmol) 5-溴 -2-甲基 -2H-1,2,3-三氮唑 -4-羧酸溶于 100 ml 乙酸乙酯， 加入 0.25 g 5%钯炭， 通入氢气， 维持压力 l~3 atm， 室温反应 20-24 小时。反应完毕， 过滤， 滤液减压浓缩至干。将残余固体溶于 10 ml 乙酸乙酯， 室温下滴加 50 ml正己垸， 继续搅拌 1小时， 过滤， 室温真空 干燥， 得到 2-甲基 -2H-1,2,3-三氮唑 -4-羧酸 2.9 g， 收率 95%。
Buy example 42: 5 g (24.27 mmol) of 5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylic acid was dissolved in 100 ml of ethyl acetate, and 0.25 g of 5% palladium on carbon was added. Hydrogen, maintain pressure l~3 atm, react at room temperature for 20-24 hours. The reaction was completed, filtered, and the filtrate was concentrated to dryness. The residual solid was dissolved in 10 ml of ethyl acetate. 50 ml of hexanes were added dropwise at room temperature, stirring was continued for 1 hour, filtered, and dried under vacuum at room temperature to give 2-methyl-2H-1,2,3-triazole-4 - 2.9 g of a carboxylic acid, yield 95%.
Claims
1. 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备方法， 该 2,4-二取代 -2H-1,2,3-三氮唑衍生物具有如下结构： A process for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative, the 2,4-disubstituted-2H-1,2,3-triazole derivative having the following structure :
/Γ /Γ
Ν、 ,Ν Ν, ,Ν
Ν I Ν I
Ri Ri
式 I Formula I
其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； R2表示羧基或硼酸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group; and R2 represents a carboxyl group or a boronic acid group;
其特征在于， 包含步骤： It is characterized by the steps of:
将式 IV化合物溶于质量体积比 1 : 2-20的乙醚、 四氢呋喃或 1,4-二 氧六环， 冷却至 -78~0°C， 加入异丙基氯化镁， 搅拌 0.1~2小时， 缓慢加入 C1~C4低级醇， 搅拌 0.5~1小时， 在 -20~30°C下， 加入异丙基氯化镁 -氯化 锂复合物，搅拌 0.5~5小时，冷却至 -50~20°C，通入二氧化碳气体约 10~30 分钟或加入式 IX的化合物硼酸酯， 搅拌 0.1~2小时， 升温至室温， 用盐酸 调节 pH = 1~5后， 用有机溶剂萃取， 经无水硫酸钠或无水硫酸镁干燥， 减压浓缩至干， 浓缩物经重结晶得到式 I的 2,4-二取代 -2H-1,2,3-三氮唑衍 The compound of the formula IV is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1: 2-20, cooled to -78 to 0 ° C, added with isopropyl magnesium chloride, stirred for 0.1 to 2 hours, slowly Add C1~C4 lower alcohol, stir for 0.5~1 hour, add isopropylmagnesium chloride-lithium chloride complex at -20~30°C, stir for 0.5~5 hours, cool to -50~20°C, pass Add carbon dioxide gas for about 10~30 minutes or add the compound borate of formula IX, stir for 0.1~2 hours, warm to room temperature, adjust pH to 1~5 with hydrochloric acid, extract with organic solvent, anhydrous sodium sulfate or no The water is dried over magnesium sulfate, concentrated to dryness under reduced pressure, and the concentrate is recrystallized to give 2,4-disubstituted-2H-1,2,3-triazole of formula I.
生物， Br Ν、 ,Ν Creature, Br Ν, ,Ν
Ν Br Ν Br
I I
Ri Ri
式 IV Formula IV
其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group;
R30 OR3 式 IX
其中， R3表示 C1~C5的直链或支链垸基， 包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 正戊基、 异戊基。 R 3 0 OR 3 formula IX Wherein R3 represents a linear or branched fluorenyl group of C1 to C5, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl .
2. 根据权利要求 1 所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备 方法， 其特征在于， 所述的式 IV化合物与低级醇的摩尔比为 1 : 0.8-1.2； 所述的 C1~C4 的低级醇包括甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇或叔 丁醇； 所述的化合物式 IV与 1.3M异丙基氯化镁-氯化锂四氢呋喃溶液的 摩尔比为 1 : 0.8-2.0； 式 IV化合物与式 IX硼酸酯或二氧化碳的摩尔比为 1： 1-10； 所述的有机溶剂为脂肪酸酯类或醚类中的一种或两种以上任意 比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯、 乙醚、 丙醚、 异 丙醚、 甲基叔丁基醚中的一种或两种以上任意比例的混合。 The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 1, wherein the molar ratio of the compound of the formula IV to the lower alcohol is 1 : 0.8-1.2; the C1-C4 lower alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; the compound of formula IV and 1.3 M isopropylmagnesium chloride- The molar ratio of the lithium chloride tetrahydrofuran solution is 1: 0.8-2.0; the molar ratio of the compound of the formula IV to the boronic acid ester of the formula IX or carbon dioxide is 1: 1-10; the organic solvent is in a fatty acid ester or ether. Mixing one or more of any ratio, including ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, Amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether One or a mixture of two or more of any ratio.
3. 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备方法， 该 2,4-二取代 -2H-1,2,3-三氮唑衍生物具有如下结构： 3. A process for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative, the 2,4-disubstituted-2H-1,2,3-triazole derivative having the following structure :
/Γ /Γ
Ν、 , Ν Ν, , Ν
Ν Ν
I I
Ri Ri
式 I Formula I
其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； R2表示羧基或硼酸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group; and R2 represents a carboxyl group or a boronic acid group;
其特征在于， 包含步骤： It is characterized by the steps of:
将式 IV化合物溶于质量体积比 1 : 2-20的乙醚、 四氢呋喃或 1,4-二 氧六环， 冷却至 -78~0°C， 加入异丙基氯化镁， 搅拌 0.1~2小时， 加入质量 比 1 : 1~20的水， 用盐酸调节 pH=l~5后， 用有机溶剂萃取， 经无水硫酸 钠或无水硫酸镁干燥， 减压浓缩至干， 得到式 VI化合物， 式 VI化合物进 一步转换为式 I 的 2,4-二取代 -2H-1,2,3-三氮唑衍生物， The compound of the formula IV is dissolved in diethyl ether, tetrahydrofuran or 1,4-dioxane in a mass ratio of 1: 2-20, cooled to -78 to 0 ° C, added with isopropyl magnesium chloride, stirred for 0.1 to 2 hours, added The water having a mass ratio of 1:1 to 20 is adjusted with a hydrochloric acid to adjust the pH to 1-5, and then extracted with an organic solvent, dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give a compound of formula VI. The compound is further converted to a 2,4-disubstituted-2H-1,2,3-triazole derivative of formula I,
Br Ν、 ,Ν Br Ν, ,Ν
Ν Br Ν Br
I I
Ri
式 IV Ri Formula IV
其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基 杂芳基垸基、 杂环垸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroarylheteroaryl fluorenyl group, a heterocyclic fluorenyl group;
ΝΝ
I I
Ri Ri
式 VI Formula VI
其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。 Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, or a heterocyclic fluorenyl group.
4. 根据权利要求 3所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备 方法， 其特征在于， 所述式 IV 化合物与异丙基氯化镁的摩尔比为 1 : 0.8-1.2；所述的有机溶剂为脂肪酸酯类或醚类中的一种或两种以上任意比 例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯、 乙醚、 丙醚、 异 丙醚、 甲基叔丁基醚中的一种或两种以上任意比例的混合。 The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 3, wherein the molar ratio of the compound of the formula IV to isopropylmagnesium chloride Is 1: 0.8-1.2; the organic solvent is one or a mixture of two or more of fatty acid esters or ethers, including ethyl formate, propyl formate, butyl formate, methyl acetate, acetic acid. Ethyl ester, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and One or a mixture of two or more of amyl propionate, diethyl ether, dipropyl ether, diisopropyl ether, and methyl tert-butyl ether.
5. 根据权利要求 1或 3所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的 制备方法，其特征在于，式 I中当 R2是羧基时，所述的 2,4-二取代 -2H-1,2,3- 三氮唑衍生物为式 II的 2-取代 -2H-1,2,3-三氮唑 -4-羧酸； The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 1 or 3, wherein when R2 is a carboxyl group, The 2,4-disubstituted-2H-1,2,3-triazole derivative is a 2-substituted-2H-1,2,3-triazole-4-carboxylic acid of formula II;
COOH COOH
Ν ir、 i ,Ν Ν ir, i , Ν
Ri Ri
式 II 其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group;
所述 2-取代 -2H-1,2,3-三氮唑 -4-羧酸通过下述方法制备： 将所述式 VI
却至 -20~30°C， 加入异丙基氯化镁-氯化锂复合物， 搅拌 0.5~5小时， 冷却 至 -50~20°C， 通入二氧化碳气体约 10~30分钟， 升温至室温， 用盐酸调节 pH = l~5后， 用有机溶剂萃取， 经无水硫酸钠或无水硫酸镁干燥， 减压浓 缩至干， 浓缩物经重结晶得到所述 2-取代 -2H-1,2,3-三氮唑 -4-羧酸。 The 2-substituted-2H-1,2,3-triazole-4-carboxylic acid is prepared by the following method: But to -20~30 °C, add isopropylmagnesium chloride-lithium chloride complex, stir for 0.5~5 hours, cool to -50~20 °C, pass carbon dioxide gas for about 10~30 minutes, warm up to room temperature. After adjusting pH = 1~5 with hydrochloric acid, it is extracted with an organic solvent, dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The concentrate is recrystallized to give the 2-substituted-2H-1,2 , 3-triazole-4-carboxylic acid.
6. 根据权利要求 1或 3所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的 制备方法，其特征在于，式 I中当 R2是羧基时，所述的 2,4-二取代 -2H-1,2,3- 三氮唑衍生物为式 II的 2-取代 -2H-1,2,3-三氮唑 -4-羧酸； The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 1 or 3, wherein when R2 is a carboxyl group, The 2,4-disubstituted-2H-1,2,3-triazole derivative is a 2-substituted-2H-1,2,3-triazole-4-carboxylic acid of formula II;
COOH COOH
Ν m、 ,iΝ Ν m, ,iΝ
Ν Ν
I I
Ri Ri
式 II Formula II
其中， R1表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group;
所述 2-取代 -2H-1,2,3-三氮唑 -4-羧酸通过下述方法制备： 式 VIII化合 物溶于质量体积比 1 : 1~100的有机溶剂中， 加入 0.1~50%重量比的金属 催化剂， 通入氢气， 维持压力 l~100atm， 在 0~200°C， 反应 1~50小时， 在室温下过滤，减压浓缩至干，浓缩物经重结晶得到所述 2-取代 -2H-1,2,3- 三氮唑 -4-羧酸， The 2-substituted-2H-1,2,3-triazole-4-carboxylic acid is prepared by the following method: The compound of the formula VIII is dissolved in an organic solvent having a mass to volume ratio of 1:1 to 100, and 0.1 to 50 is added. % by weight of metal catalyst, hydrogen gas is introduced, maintaining pressure l~100atm, reacting at 0~200°C for 1~50 hours, filtering at room temperature, concentration to dryness under reduced pressure, and recrystallizing the concentrate to obtain the 2 -Substituting -2H-1,2,3-triazole-4-carboxylic acid,
Br^ COOH Br^ COOH
Ν、 Oh,
N N
I I
Ri Ri
式 VIII Formula VIII
其中， RI表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基。 Wherein RI represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group.
7. 根据权利要求 6所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制备 方法， 其特征在于， 所述的有机溶剂为醇类或脂肪酸酯类中的一种或两种 以上任意比例的混合， 包括甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇、 正戊醇、 异戊醇、 甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸异戊酯、
丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯中的一种或两种以 上任意比例的混合； 所述的金属催化剂是将金属钯、 钌、 铂中的一种或两 种以上负载于活性炭、氧化铝或沸石载体上制成的负载量为 1~10%的催化 剂。 The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 6, wherein the organic solvent is an alcohol or a fatty acid ester. Mixing one or more of any ratio, including methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, isoamyl alcohol, ethyl formate, propyl formate, butyrate Ester, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, Mixing one or more of any ones or more of methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate; the metal catalyst is a metal palladium, rhodium, platinum One or more of the catalysts loaded on activated carbon, alumina or zeolite supports are loaded with a catalyst content of 1 to 10%.
8. 根据权利要求 1或 3所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的 制备方法， 其特征在于： 式 I 中当 R2 是硼酸基时， 所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物为式 III的 2-取代 -2H-1,2,3-三氮唑 -4-硼酸， The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 1 or 3, wherein: when R2 is a boronic acid group in the formula I, The 2,4-disubstituted-2H-1,2,3-triazole derivative is 2-substituted-2H-1,2,3-triazole-4-boronic acid of formula III,
HO HO
B-OH B-OH
Ν m、 ,iΝ Ν m, ,iΝ
Ν I Ν I
Ri Ri
式 III Formula III
其中， Rl表示垸基、 芳基、 芳垸基、 环垸基、 环垸基垸基、 杂芳基、 杂芳基垸基、 杂环垸基； Wherein R1 represents a fluorenyl group, an aryl group, an aryl fluorenyl group, a cyclodecyl group, a cyclodecyl fluorenyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heterocyclic fluorenyl group;
所述 2-取代 -2H-1,2,3-三氮唑 -4-硼酸通过下述方法制备： 将所述化合 物式 VI溶于质量体积比 1 : 2~20的乙醚、 四氢呋喃或 1,4-二氧六环， 冷 却至 -20~30°C， 加入异丙基氯化镁-氯化锂复合物， 搅拌 0.5~5小时， 冷却 至 -50~20°C， 加入式 IX化合物硼酸酯， 搅拌 0.1~2小时， 升温至室温， 用 盐酸调节 pH = 1~5后， 用有机溶剂萃取， 经无水硫酸钠或无水硫酸镁干 燥， 减压浓缩至干， 浓缩物经重结晶得到所述 2-取代 -2H-1,2,3-三氮唑 -4- 硼酸。 The 2-substituted-2H-1,2,3-triazole-4-boronic acid is prepared by the following method: the compound of the formula VI is dissolved in diethyl ether, tetrahydrofuran or 1, in a mass ratio of 1:2-20. 4-dioxane, cooled to -20~30 ° C, add isopropylmagnesium chloride-lithium chloride complex, stir for 0.5~5 hours, cool to -50~20 °C, add borate of compound of formula IX After stirring for 0.1 to 2 hours, the temperature is raised to room temperature, and the pH is adjusted to 1 to 5 with hydrochloric acid, and then extracted with an organic solvent, dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The 2-substituted-2H-1,2,3-triazole-4-boronic acid.
9. 根据权利要求 6或 8所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的 制备方法， 其特征在于， 所述的化合物式 VI与异丙基氯化镁 -氯化锂复合 物的摩尔比为 1 : 0.8-2.0； 式 VI化合物与式 IX硼酸酯或二氧化碳的摩尔 比为 1 : 1-10； 所述的有机溶剂为脂肪酸酯类或醚类中的一种或两种以上 任意比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁酯、 乙酸甲酯、 乙酸 乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁酯、 乙酸戊酯、 乙酸 异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯和丙酸戊酯、 乙醚、 丙醚、 异丙醚、 甲基叔丁基醚中的一种或两种以上任意比例的混合。
The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 6 or 8, wherein the compound of the formula VI and isopropylmagnesium chloride The molar ratio of the lithium chloride complex is 1: 0.8-2.0; the molar ratio of the compound of the formula VI to the boronic acid ester of the formula IX or carbon dioxide is 1: 1-10; the organic solvent is a fatty acid ester or ether. Mixing one or more of any ratio, including ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate , amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether One or a mixture of two or more of any ratio.
10. 根据权利要求 1、 5、 6、 8 中任一项所述的 2,4-二取代 -2H-1,2,3- 三氮唑衍生物的制备方法， 其特征在于， 所述的重结晶的方法包括以下步 骤， 按质量体积比 1 : 1~100将浓缩物加入有机溶剂中， 在 -20~50°C搅拌 0.5~24小时， 过滤， 真空干燥， 得到纯品。 The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to any one of claims 1, 5, 6, and 8, characterized in that The method for recrystallization includes the following steps: adding the concentrate to an organic solvent at a mass to volume ratio of 1:1 to 100, stirring at -20 to 50 ° C for 0.5 to 24 hours, filtering, and drying under vacuum to obtain a pure product.
11. 根据权利要求 10所述的 2,4-二取代 -2H-1,2,3-三氮唑衍生物的制 备方法， 其特征在于， 所述的有机溶剂为脂肪酸酯类、 酮类、 醚类及烃类 中的一种或两种以上任意比例的混合， 包括甲酸乙酯、 甲酸丙酯、 甲酸丁 酯、 乙酸甲酯、 乙酸乙酯、 乙酸丙酯、 乙酸丁酯、 乙酸异丙酯、 乙酸异丁 酯、 乙酸戊酯、 乙酸异戊酯、 丙酸甲酯、 丙酸乙酯、 丙酸丙酯、 丙酸丁酯 和丙酸戊酯、 丙酮、 2-丁酮、 环戊酮和环己酮、 乙醚、 丙醚、 异丙醚、 甲 基叔丁基醚和四氢呋喃、 1,4-二氧六环、 石油醚、 正己垸、 环己垸、 甲基 环己垸和正庚垸中的一种或两种以上任意比例的混合。
The method for producing a 2,4-disubstituted-2H-1,2,3-triazole derivative according to claim 10, wherein the organic solvent is a fatty acid ester or a ketone. Mixing one or more of ethers and hydrocarbons in any ratio, including ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate Ester, isobutyl acetate, amyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate and amyl propionate, acetone, 2-butanone, cyclopentane Ketones and cyclohexanone, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofuran, 1,4-dioxane, petroleum ether, n-hexyl, cyclohexanyl, methylcyclohexane and n-glycol One or a mixture of two or more of any ratio.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110212052.1 | 2011-07-27 | ||
| CN201110212052.1A CN102408386B (en) | 2011-07-27 | 2011-07-27 | Preparation method of 2,4-disubstituted-2H-1, 2, 3-triazole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013013348A1 true WO2013013348A1 (en) | 2013-01-31 |
Family
ID=45910776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2011/001279 WO2013013348A1 (en) | 2011-07-27 | 2011-08-03 | Method for preparing 2, 4-di-substituted-2h-1, 2, 3-triazole derivative |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102408386B (en) |
| WO (1) | WO2013013348A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105585534B (en) * | 2014-10-23 | 2018-05-18 | 上海雅本化学有限公司 | A kind of preparation method of 1- substitutions -1H-1,2,3- triazole -4- carboxylic acids |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1289326A (en) * | 1998-02-27 | 2001-03-28 | 辉瑞产品公司 | N-[(substituted five-membered di-or thiaza diunsaturated ring) carbonyl] guanidine derivatives for the treatment of ischemia |
| CN101389625A (en) * | 2006-02-27 | 2009-03-18 | 先正达有限公司 | Herbicidal isoxazoline compounds |
| CN101687860A (en) * | 2007-04-23 | 2010-03-31 | 阿斯利康(瑞典)有限公司 | Novel n- (8-heteroaryltetrahydronaphtalene-2yl) or n- (5- heteroarylchromane-3-yl) carboxamide derivatives for the treatment of pain |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013511562A (en) * | 2009-11-24 | 2013-04-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Hepatitis C inhibitor compound |
-
2011
- 2011-07-27 CN CN201110212052.1A patent/CN102408386B/en active Active
- 2011-08-03 WO PCT/CN2011/001279 patent/WO2013013348A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1289326A (en) * | 1998-02-27 | 2001-03-28 | 辉瑞产品公司 | N-[(substituted five-membered di-or thiaza diunsaturated ring) carbonyl] guanidine derivatives for the treatment of ischemia |
| CN101389625A (en) * | 2006-02-27 | 2009-03-18 | 先正达有限公司 | Herbicidal isoxazoline compounds |
| CN101687860A (en) * | 2007-04-23 | 2010-03-31 | 阿斯利康(瑞典)有限公司 | Novel n- (8-heteroaryltetrahydronaphtalene-2yl) or n- (5- heteroarylchromane-3-yl) carboxamide derivatives for the treatment of pain |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102408386B (en) | 2014-05-07 |
| CN102408386A (en) | 2012-04-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2015044844A (en) | Polymorph of eltrombopag and eltrombopag salt and manufacturing method thereof | |
| US20100048915A1 (en) | Method for preparing medetomidine and its salts. | |
| EA019682B1 (en) | New salt of bazedoxifene | |
| BR112012019648B1 (en) | Process of producing a compost and compost | |
| WO2013013348A1 (en) | Method for preparing 2, 4-di-substituted-2h-1, 2, 3-triazole derivative | |
| WO2014163932A1 (en) | Preparation of haloalkoxyarylhydrazines and intermediates therefrom | |
| JP2009062360A (en) | Method for producing cinacalcet | |
| WO2007094225A9 (en) | Process for production of 5-alkoxy-4-hydroxymethylpyrazole compound | |
| JPS6046104B2 (en) | Method for producing butene derivatives | |
| JP2022531576A (en) | Intermediates used in the process of preparing XPO1 inhibitors and in the preparation of XPO1 inhibitors | |
| TW200404798A (en) | Process for preparing a pharmaceutically active compound | |
| US5183891A (en) | Method for the preparation of substituted 1,4-dihydro-4-oxo-cinnoline-3-carboxylic acid, esters and salts thereof, and intermediates used in their preparation | |
| JP2020528437A (en) | A novel intermediate useful for the synthesis of aminopyrimidine derivatives, the process for preparing it, and the process for preparing aminopyrimidine derivatives using it. | |
| CN109180564B (en) | Preparation method of piperidine and derivatives thereof | |
| CN112521375A (en) | Preparation method of rosuvastatin calcium intermediate | |
| JP4422609B2 (en) | Method for producing a specific crystalline structure form of polymorphic material | |
| JP4714921B2 (en) | Production method of pimobendan and its intermediate | |
| WO2014029042A1 (en) | 2-substituted-2h-1, 2, 3-triazole derivative and preparation method thereof | |
| JP7492997B2 (en) | Manufacturing process for olaparib | |
| JP2013517235A (en) | Process for the preparation of indazole-3-carboxylic acid and N- (S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-3-carboxamide hydrochloride | |
| CN107629014A (en) | The synthetic method of the acetic acid of 5 methyl 4H, 1,2,4 triazoles 3 | |
| US11780824B2 (en) | Process for preparing osimertinib or a salt thereof | |
| CN111587245B (en) | Method for large-scale preparation of tolimidone | |
| JP2010189293A (en) | Method for producing 1,4-dihydropyridine derivative | |
| WO2014089728A1 (en) | 1-substituted-5-chloro-2h-1,2,3-triazole-4-carboxylate derivative and preparation method therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11870103 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 11870103 Country of ref document: EP Kind code of ref document: A1 |