CN103910694B - A kind of preparation method of 2-aryl nitrile thiazole - Google Patents
A kind of preparation method of 2-aryl nitrile thiazole Download PDFInfo
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- CN103910694B CN103910694B CN201310743947.7A CN201310743947A CN103910694B CN 103910694 B CN103910694 B CN 103910694B CN 201310743947 A CN201310743947 A CN 201310743947A CN 103910694 B CN103910694 B CN 103910694B
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- Prior art keywords
- palladium
- group
- alkyl
- formula
- aryl
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims description 8
- 150000002825 nitriles Chemical class 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000005859 coupling reaction Methods 0.000 claims abstract description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 36
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 7
- 150000003624 transition metals Chemical class 0.000 claims description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims 1
- -1 aryl nitrile thiazoles Chemical class 0.000 abstract description 27
- 239000000463 material Substances 0.000 abstract description 4
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 208000035126 Facies Diseases 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 229960005101 febuxostat Drugs 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 201000005569 Gout Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000006713 insertion reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HMSQZHBSTZZNGI-UHFFFAOYSA-N 2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=C(Br)SC=1C(O)=O HMSQZHBSTZZNGI-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 3
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003556 thioamides Chemical class 0.000 description 3
- 229940116269 uric acid Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- NCPICGMTBCNSGK-UHFFFAOYSA-N 1,1,1-trimethoxy-2-(2-methoxyethoxy)ethane Chemical compound COC(COCCOC)(OC)OC NCPICGMTBCNSGK-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
- QTYUSOHYEPOHLV-FNORWQNLSA-N 1,3-Octadiene Chemical compound CCCC\C=C\C=C QTYUSOHYEPOHLV-FNORWQNLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- JQXJBXVWVPVTOO-UHFFFAOYSA-L 4-diphenylphosphanylbutyl(diphenyl)phosphane;palladium(2+);dichloride Chemical compound Cl[Pd]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 JQXJBXVWVPVTOO-UHFFFAOYSA-L 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- RSBNUWAVVQOBHL-UHFFFAOYSA-N C(CC)O.CC1=C(C(=O)O)C=CC=C1C(=O)O Chemical compound C(CC)O.CC1=C(C(=O)O)C=CC=C1C(=O)O RSBNUWAVVQOBHL-UHFFFAOYSA-N 0.000 description 1
- 0 C*(C)COC1C#CC=C(C2SCC([N+](C)([O-])O*)=C(C)N2)C=*1C#N Chemical compound C*(C)COC1C#CC=C(C2SCC([N+](C)([O-])O*)=C(C)N2)C=*1C#N 0.000 description 1
- CHICHTSMDAKOJU-UHFFFAOYSA-N CC1=C(C(O)=O)SC=N1.Br Chemical compound CC1=C(C(O)=O)SC=N1.Br CHICHTSMDAKOJU-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical group [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- QKLWAMMQKBOTCD-UHFFFAOYSA-N butane;diphenylphosphane Chemical compound CCCC.C=1C=CC=CC=1PC1=CC=CC=C1 QKLWAMMQKBOTCD-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- GDEBSAWXIHEMNF-UHFFFAOYSA-O cupferron Chemical compound [NH4+].O=NN([O-])C1=CC=CC=C1 GDEBSAWXIHEMNF-UHFFFAOYSA-O 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- PBTHJVDBCFJQGG-UHFFFAOYSA-N methyl azide Chemical compound CN=[N+]=[N-] PBTHJVDBCFJQGG-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of new intermediate (II), and use itself and compound shown in formula (III) to carry out the method that coupling reaction prepares 2 aryl nitrile thiazoles (I):Wherein, X is Cl, Br or I；Y is F, Cl, Br, I, N2、‑OSO2Ra、‑OCORaOr OSi (Ra)3；R1For C1‑6Alkyl or C6‑10Aryl；RaFor C1‑6Alkyl or C6‑10Aryl；Described each C1‑6Alkyl and C6‑10Aryl is replaced individually optionally.These process conditions are gentle, and impurity is less, simple to operate, safely controllable, and energy consumption is relatively low, is particularly suitable for industrialized production.The present invention also discloses the method for new intermediate shown in preparation formula (II).The method material is cheap, and is not required to isolated and purified, greatly reduces reaction cost.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of 2-that can be used as xanthine oxidase inhibitor intermediate
The preparation method of aryl nitrile thiazole.
Background technology
Gout (Gout) is a group of heterogeneity, metabolism caused by long-term purine metabolic disturbance and (or) underexcretion
Property disease.Hyperuricemia is the main cause causing gout.The medicine for the treatment of hyperuricemia is roughly divided into two classes: urate excretion promotees
Enter agent and uric acid synthetic inhibitor (xanthine oxidase inhibitor).
Febuxostat is first non-Huang fast alcohols a new generation xanthine oxidase inhibitor, and it is by suppression xanthine oxidase
Change enzyme activity, stop and reduce hypoxanthine, xanthine synthesize uric acid thus reduce the purpose of blood uric acid；Clinical experiment
Show, its better tolerance, can effectively control hematuria levels, be used for clinically treating gout.This medicine is first by Di Ren company of Japan
At the beginning of 2004 Japanese publication list, IPSEN company European application list, FDA in February, 2009 approved in the U.S.
Listing.
Compound (I) is important febuxostat intermediate:
Wherein, R1For C1-6Alkyl or C6-10Aryl.
Traditional intermediate synthetic route is in series carried out continuously, and can be divided into two kinds: one is first to draw on phenyl ring
Enter thioamides base so that it is have the ethyl acetoacetate of leaving group to react with 2 bit strips, cyclization, form basic framework, the most again
Introducing cyano group on phenyl ring, similar technique is found in WO1992009279, JP6293746, JP6329647, JP10045733,
JP10139770, WO2010142653, WO2012014117, WO2012032528, CN101665471, CN101759657,
CN102002016, CN102070559, CN102079731, CN102229581；Another kind is the most contrary, is initially formed double cyanogen
Based compound, after one of them cyano group is converted into thioamides, continues and 2 bit strips has the ethyl acetoacetate of leaving group anti-
Should, cyclization, form important febuxostat intermediate.Similar technique is found in CN101863854, WO2011141933,
CN101497589, JP6345724, Heterocycles, 1998,47 (2);857-964, WO2011082623,
CN101386604, CN102276550.Additionally, the optimization to traditional handicraft also includes following patent: WO2011031409,
WO2011139886, WO2012066561, WO2012073259, WO2012131590, CN102234253, CN102002017,
CN101723915。
Traditional linear synthetic method, common itinerary is long, and wherein involved functional group's conversion is the most frequent.At molecule
Middle structure when introducing cyano group, if by the approach such as diazotising or replacement, often can use the examinations such as the potassium cyanide of severe toxicity, Cupricin.
Agent, according to introduce aldehyde radical, reconvert becomes the way of cyano group, though can avoid use cyanide, can use polyphosphoric acids, three
Fluoroethanoic acid or other mixed acid does reaction dissolvent, corrosivity is strong, and safety is low, and easily causes pollution.And building cyclization
When reaction generates thiazole ring, then need to be firstly introduced into thioamides group, usually can use thioacetamide, phosphorus pentasulfide, very
To gas cure hydrogen, reagent toxicity is relatively big, and with foul odour, pollution increases the weight of.
In recent years, part company begins with convergence synthetic method, i.e. utilizes the aromatic ring coupling reaction of metal catalytic, by phenyl ring
Fragment combines with thiazole ring fragment, forms intermediate (I).Such as, WO2007097403, WO201107367 and
CN102285937 records and has utilized Suzuki coupling, realized basic framework and build, but, owing to the method employs boron
Reagent, and intermediate needs separating-purifying, therefore high expensive.It is true that most of coupling reactions are in addition to catalyst, it is often necessary to
Separately adding reagent (such as organic acid, cupferron etc.), add the pollution of the requirement to equipment and environment, meanwhile, conventional coupling is anti-
Should be substantially all and need to carry out under conditions of backflow or high temperature, and the time of partial reaction is up to a couple of days, power consumption is relatively big, uncomfortable
Amplify in industry.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides the Febuxostat bone of a kind of applicable industrialized production
The new method that framework is built.First phenyl ring fragment is reacted by the method with cheap zinc powder, obtains organic zinc compound, and compound is not
Need separating-purifying, direct and thiazole ring fragment coupling, i.e. can get febuxostat intermediate, the reaction condition of this coupling is gentle,
Especially the highest with the reaction yield under room temperature, impurity is minimum, simple to operate, safely controllable, and energy consumption is relatively low, is particularly suitable for industrialization
Produce.
This method step is brief, and raw material is cheap, mild condition, and total recovery is high, and on the impact of operator and environment relatively
Little.
The present invention provides the method that one prepares 2-aryl nitrile thiazole (I), including: in appropriate solvent, make formula
(II) compound shown in compound shown in and formula (III) carries out coupling reaction, obtains target compound (I):
Wherein, X is Cl, Br or I；
Y is Cl, Br, I, N2、-OSO2Ra、-OCORaOr-OSi (Ra)3；
R1For C1-6Alkyl or C6-10Aryl；
RaFor C1-6Alkyl or C6-10Aryl；
Described each C1-6Alkyl and C6-10Aryl is independently selected from D, F, Cl, Br, I, N by 1,2,3 or 4 individually optionally3、
CN、OH、NH2、SH、(C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkylamino, (C1-C6) alkylthio group, (C3-C6) cycloalkyl
(C3-C6) group of heterocyclic radical replaced.
In one embodiment, X is Br or I.
In another embodiment, Y is Br, I ,-OMs ,-OTf ,-OSO2C6H5Or-OTs.
In another embodiment, R1For methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group or phenyl.
In another embodiment, coupling reaction of the present invention is carried out under certain reaction temperature, implements at some
In example, described reaction temperature is-20 DEG C to 100 DEG C；In other embodiment, reaction temperature is 0 DEG C to 80 DEG C；At other
In some embodiments, reaction temperature is 10 DEG C to 50 DEG C.
In another embodiment, coupling reaction of the present invention is carried out in the presence of transition metal catalysts,
In some embodiments, described transition-metal catalyst is 0 valency palladium or the salt of II valency palladium；In other embodiment, transition
Metallic catalyst is tetrakis triphenylphosphine palladium (0) (Pd (PPh3)4), three (dibenzalacetone) two palladium (0) (Pd2(dba)3), vinegar
Acid palladium (II) (Pd (OAc)2), palladium dydroxide (II) (Pd (OH)2), Palladous chloride. (II) (PdCl2), double (benzonitrile) palladium chloride
(II)(Pd(PhCN)2Cl2), double (acetonitrile) palladium chloride (II) (Pd (CH3CN)2Cl2), (1,1'-double (diphenylphosphine) two cyclopentadienyl
Ferrum) palladium chloride (II) (Pd (dppf) Cl2), 1,2-bis-(diphenylphosphino) ethane palladium chloride (II) (Pd (dppe) Cl2)、
1,3-bis-(diphenylphosphine) propane palladium chloride (II) (Pd (dppp) Cl2), double (diphenylphosphine butane) palladium chloride of 1,4-
(II)(Pd(dppb)Cl2), double (tricyclohexyl phosphine) palladium chloride (II) (Pd (PCy3)2Cl2), two (triphenylphosphine) diacetyl
Epoxide palladium (II) (Pd (PPh3)2(CH3COO)2), double (triphenylphosphine) palladium chloride (II) (Pd (PPh3)2Cl2), (1,5-ring
Octadiene) palladium chloride (II) (Pd (cod) Cl2), two (acetylacetone,2,4-pentanedione) palladium (II) (Pd (acac)2) or their combination in any.
In another embodiment, described transition-metal catalyst and the molar percentage of the compound shown in formula (III)
It is 0.01%-20% in certain embodiments；Other embodiment is 0.1%-10%；Some other embodiment is
0.5%-5%。
The present invention provides a kind of compound as shown in formula (II)
Wherein, X is Cl, Br or I.
The present invention also provides one to prepare the method for compound as shown in (II), comprising: in appropriate solvent, by formula
(IV) compound shown in and metal Zn carry out insertion reaction, obtain compound shown in formula (II):
Wherein, X is Cl, Br or I.
In one embodiment, insertion reaction of the present invention can be optionally at LiCl or SnCl2In the presence of react.
In some embodiments, it is also possible to be optionally added into activator trim,ethylchlorosilane and halogenated alkane simultaneously.
In another embodiment, described halogenated alkane be glycol dibromide, 1,2-dichloroethanes, 1,2-ethylidene periodide
Or methylene bromide.
In another embodiment, insertion reaction of the present invention is carried out under certain reaction temperature.Implement at some
In example, described reaction temperature is room temperature to 150 DEG C；In other embodiment, described reaction temperature is 40 DEG C to 100 DEG C.
It is molten that appropriate solvent in insertion reaction of the present invention and coupling reaction is each independently alcohols solvent, ethers
Agent, esters solvent, aromatic solvent, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, N-crassitude
Ketone, water or their combination in any.
In one embodiment, described alcohols solvent is ethylene glycol, methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol
Or its their combination in any.
In another embodiment, described ether solvent be oxolane, ether, dioxane, methyl tertiary butyl ether(MTBE),
Dimethoxy, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether. or their combination in any.
In another embodiment, described esters solvent is ethyl acetate, isopropyl acetate or their combination in any.
In another embodiment, described aromatic solvent is benzene,toluene,xylene or their combination in any.
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This
Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition
In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality
Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one
Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described
Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments
Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity,
Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference
Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with
Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined
Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999,
With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John
Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) "
" described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or
The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one
Component be taken into account in the embodiment of described embodiment and use or use.
Term " optionally " or " optionally " refer to the event described subsequently or situation can but not necessarily occur, and this is retouched
State and include situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to
This key can exist or can not exist, and this description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as
General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
Term " replaces " or " substituted ", represents that the one or more hydrogen atoms in described structure are taken by concrete substituent group
Generation.Unless other aspects show, a substituted group can have a substituent group to carry out in each commutable position of group
Replace.When in given structural formula, more than one position can be selected from one or more substituent groups of concrete group and replaced,
So substituent group can replace in each position identical or differently.
Term " unsubstituted ", represents and specifies group without substituent group.
Term " optionally by .... replaced ", can with term " unsubstituted or quilt ... .. is replaced " exchange use, i.e.
Described structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group bag of the present invention
Include, but be not limited to D, F, Cl, Br, I, N3、CN、OH、NH2、SH、(C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkylamino,
(C1-C6) alkyl sulfenyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention
" each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used
To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase
In same group, do not affect mutually between concrete option expressed between same-sign.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special
Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term
“C1-C6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this
Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this
The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively
The alkylidene group connected or arylene group.
Term " D " or "2H " represent single D-atom.One such atomic group and a methyl are connected, and form list-deuterium
Acute pyogenic infection of nails base (-CDH2), two D-atoms and a methyl are connected, and form double-deuterated methyl (-CD2H), and three D-atoms with
One methyl is connected, and forms three-deuterated methyl (-CD3).
Term " N3" represent a nitrine structure.This group can be connected with other groups, such as, with methyl group
It is connected, triazonmethane (methyl azide, MeN can be formed3)；And be connected with phenyl group, then form aziminobenzene
(PhN3)。
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1-20 carbon atom, saturated straight chain or
Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention
Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-
12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group
Containing 1-4 carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-
Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-
CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (-
CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C
(CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-first
Base-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)
CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-first
Base-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-penta
Base (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C
(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double
Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprises 3-7
Molecular ring, and have one or more attachment point to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance
Ring " exchange use.The example of aromatic yl group can include phenyl, naphthyl and anthracene.Described aromatic yl group can individually optional ground quilt
One or more substituent groups described in the invention are replaced.
Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies
System.In one embodiment, cycloalkyl comprises 3-12 carbon atom；In another embodiment, to comprise 3-8 carbon former for cycloalkyl
Son；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can the most unsubstituted or
Replaced by one or more substituent groups described in the invention.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " is used interchangeably herein, all referring to monocycle, dicyclo or three rings
System, on its medium ring, one or more atoms are replaced by hetero atom individually optionally, and ring can be fully saturated or comprise
One or more degrees of unsaturation, but it is definitely not the fragrance same clan, only one of which junction point is connected to other molecules up.One or many
Individual ring hydrogen atom is replaced by one or more substituent groups described in the invention individually optionally.Some of them embodiment
It is, " heterocycle " that " heterocyclic radical " or " heterocycle " group is monocycle (2-6 the carbon atom and selected from N, the 1-3 of O, P, S of 3-7 ring
Individual hetero atom, is optionally replaced by one or more oxygen atoms at this S or P and obtains as SO, SO2, PO, PO2Group, work as institute
When the ring stated is three-membered ring, only one of which hetero atom), or the former molecular dicyclo of 7-10 (4-9 carbon atom and selected from N,
1-3 the hetero atom of O, P, S, is optionally replaced by one or more oxygen atoms at this S or P and obtains as SO, SO2, PO, PO2's
Group), in bicyclic system, at least a ring is non-aromatic ring.
Heterocyclic radical can be carbon back or hetero atom base.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrochysene furan
Mutter base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur
For morpholinyl, thiophene alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl,
Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2-
Pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranose, 4H-pyranose, dioxacyclohexyl, 1,3-dioxy amyl group,
Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetra-
Hydrogen isoquinoline base.The example of heterocyclic group also includes, on ring, two carbon atoms are by oxygen (=O) substituted hybar X base and 1,1-
Dioxidothiomorpholinyl.
Term " alkoxyl " used in the present invention, relates to alkyl, as defined in the present invention, passes through oxygen atom
(" alkoxyl ") is connected in main carbochain, and such example includes, but is not limited to methoxyl group, ethyoxyl, propoxyl group, fourth
Epoxide etc..
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of bivalence, and some of them are implemented
Example is, alkylthio group is the C of lower level1-6Alkylthio group, such example includes, but is not limited to methyl mercapto (CH3S-)。
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base
Group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two
C1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other embodiment is, alkyl amino is C1-3's
The alkylamino group of lower level.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality
Example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
In the present invention, " room temperature " refers to temperature by about 10 DEG C to about 40 DEG C.In certain embodiments, " room temperature " refers to
Be that temperature is by about 20 DEG C to about 30 DEG C；In other embodiment, " room temperature " refers to 20 DEG C, 22.5 DEG C, 25 DEG C,
27.5 DEG C etc..
In the context of the present invention, all numerals being disclosed that are approximation.The numerical value of each numeral has
It is possible that the difference such as 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%.Whenever disclosing one and there is N value digital, any
There is N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-15% or the number of N+/-20% value
Word can be specifically disclosed, and wherein " +/-" refers to add deduct.Whenever the lower limit disclosed in a numerical range, DL, and one
The individual upper limit, DU, time, any numerical value being within the scope of the disclosed can be specifically disclosed.Particularly, this model is contained
Enclose interior values below: D=DL+K* (DU-DL), wherein K be one by the increment of 1% increase from 1% to 100% variable.As:
1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%, 95%, 96%, 97%, 98%, 99% or 100%.It addition, contain public at this most especially
The above-mentioned numerical range with two D definition opened.
The use of brief word below runs through the present invention:
CDC13Deuterochloroform
1,4-dioxane 1,4-dioxane
DMF N,N-dimethylformamide
DMAc DMAC N,N' dimethyl acetamide
G gram
H hour
Mg milligram
ML, ml milliliter
Mmol mM
Mol mole
OMs mesyl
OTf trifyl
OTs p-toluenesulfonyl
THF oxolane
TLC thin layer chromatography
Specific implementation method
Reference example 1 5-iodo-2-isobutoxy cyanophenyl
2-methyl isophthalic acid-propanol (1.11g, 15.1mmol) is dissolved in DMF (20mL), is cooled to 0
DEG C, it is added thereto to sodium hydride (0.6g, 15.1mmol, 60% are scattered in mineral oil).After mixed liquor stirs 30 minutes at 0 DEG C,
It is added thereto to 2-fluoro-5-ioxynil (2.5g, 10.1mmol), and recovers to room temperature, be stirred overnight.Reaction is finished, and add water cancellation
, and be extracted with ethyl acetate (100mL x3) (30mL).The organic facies merged is dried through anhydrous sodium sulfate, filters, and concentrates, post layer
Analysis (petroleum ether: ethyl acetate (v/v)=40:1) purification, obtaining title compound is yellow liquid (2.7g, 90%).
1H NMR(400MHz,CDCl3)δ(ppm):1.05(d,6H,J=6.7Hz),2.12-2.19(m,1H),3.80(d,
2H,J=6.5Hz),6.72(d,1H,J=8.9Hz),7.77(dd,1H,J=2.2,8.9Hz),7.80(d,1H,J=2.2Hz)。
Embodiment 1 2-zinc bromide-4-methylthiazole-5-carboxylate
Under the conditions of anhydrous and oxygen-free, zinc powder (325mg, 5mmol) and glycol dibromide (94mg, 0.5mmol) are mixed mutually
Close, and be added thereto to DMF (10mL).After mixed-liquor return stirs 0.5 hour, it is cooled to room temperature, Xiang Qi
In be sequentially added into trim,ethylchlorosilane (65mg, 0.6mmol) and 5-iodo-2-isobutoxy cyanophenyl (602mg, 2mmol).Will reaction
Liquid is warming up to 85 DEG C, after stirring 7 hours, and cooling, it is directly used in next step reaction.
Embodiment 2 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate
Under the conditions of anhydrous and oxygen-free, the mixed liquor of above-mentioned preparation is joined 2-bromo-4-methylthiazole-5-carboxylate
(249mg, 1mmol) and Pd (PPh3)4In the mixture of (116mg, 0.1mmol).Being stirred at room temperature, TLC monitors reaction.Reaction knot
Shu Hou, adds saline solution (20mL), and is extracted with ethyl acetate (100mL x3).The organic facies merged is done through anhydrous sodium sulfate
Dry, filter, concentrate, column chromatography (petroleum ether: ethyl acetate (v/v)=10:1) purification, obtaining title compound is white solid
(0.21g, 61%).
1H NMR(400MHz,CDCl3)δ(ppm):1.09(d,6H,J=6.7Hz),1.39(t,3H,J=7.2Hz),2.17-
2.24(m,1H),2.76(s,3H),3.90(d,2H,J=6.5Hz),4.35(q,2H,J=7.2Hz),7.00(d,1H,J=
8.9Hz),8.09(dd,1H,J=2.2,8.9Hz),8,17(d,1H,J=2.2Hz)。
Embodiment 3 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate
Under the conditions of anhydrous and oxygen-free, the mixed liquor of above-mentioned preparation is joined 2-bromo-4-methylthiazole-5-carboxylate
(249mg, 1mmol) and Pd (dppf) Cl2In the mixture of (73mg, 0.1mmol).Being stirred at room temperature, TLC monitors reaction.Reaction
After end, add saline solution (20mL), and be extracted with ethyl acetate (100mL x3).The organic facies merged is done through anhydrous sodium sulfate
Dry, filter, concentrate, column chromatography (petroleum ether: ethyl acetate (v/v)=10:1) purification, obtaining title compound is white solid
(189mg, 55%).
Embodiment 4 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate
Under the conditions of anhydrous and oxygen-free, the mixed liquor of above-mentioned preparation is joined 2-bromo-4-methylthiazole-5-carboxylate
(249mg, 1mmol) and Pd (dppf) Cl2In the mixture of (7.3mg, 0.01mmol).Being stirred at room temperature, TLC monitors reaction.Instead
After should terminating, add saline solution (20mL), and be extracted with ethyl acetate (100mL x3).The organic facies merged is through anhydrous sodium sulfate
Being dried, filter, concentrate, column chromatography (petroleum ether: ethyl acetate (v/v)=10:1) purification, obtaining title compound is white solid
(52mg, 15%).
Embodiment 5 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate
Experiment condition
Reference example 2 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid
2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylate (0.1g, 0.29mmol) is dissolved in
In methanol (5mL), and it is added thereto to 1M sodium hydroxide solution (1mL).Reactant liquor, after 80 DEG C of heated and stirred 3 hours, reduces pressure
Concentrate.Gained residue is scattered in water (10ml) and dichloromethane (20mL), the aqueous phase of separation, and regulates to pH with 1M hydrochloric acid
Value is 1～2.Mixture dichloromethane is extracted (20mL x3), and the organic facies of merging is dried through anhydrous sodium sulfate, filters, dense
Contracting, obtaining title compound is white solid (82mg, 90%).
1H NMR(400MHz,CDCl3)δ(ppm):1.09(d,6H,J=6.7Hz),2.17-2.24(m,1H),2.76(s,
3H),3.90(d,2H,J=6.5Hz),7.00(d,1H,J=8.9Hz),8.09(dd,1H,J=2.2,8.9Hz),8,17(d,1H,J
=2.2Hz)。
Claims (6)
1. the method preparing 2-aryl nitrile thiazole (I), including: in solvent DMF, and
Under conditions of transition-metal catalyst is the salt of 0 valency palladium or II valency palladium, make compound shown in formula (II) and formula (III) shownization
Compound carries out coupling reaction, obtains target compound (I):
Wherein, X is Cl, Br or I；
Y is Cl, Br or I；
R1For methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group.
Method the most according to claim 1, wherein, described reaction temperature is 0 DEG C to 80 DEG C.
Method the most according to claim 1, wherein, described reaction temperature is 10 DEG C to 50 DEG C.
Method the most according to claim 1, wherein, described transition-metal catalyst is tetrakis triphenylphosphine palladium (0) (Pd
(PPh3)4), three (dibenzalacetone) two palladium (0) (Pd2(dba)3), palladium (II) (Pd (OAc)2), palladium dydroxide (II)
(Pd(OH)2), Palladous chloride. (II) (PdCl2), double (benzonitrile) palladium chloride (II) (Pd (PhCN)2Cl2), double (acetonitrile) dichloro
Change palladium (II) (Pd (CH3CN)2Cl2), (1,1'-double (diphenylphosphine) ferrocene) palladium chloride (II) (Pd (dppf) Cl2)、1,
2-bis-(diphenylphosphino) ethane palladium chloride (II) (Pd (dppe) Cl2), 1,3-bis-(diphenylphosphine) propane palladium chloride
(II)(Pd(dppp)Cl2) or their combination in any.
Method the most according to claim 1, wherein, described transition-metal catalyst and the compound shown in formula (III)
Molar percentage is 0.1%-10%.
Method the most according to claim 1, wherein, described transition-metal catalyst and the compound shown in formula (III)
Molar percentage is 0.5%-5%.
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