WO2015174377A1 - 2-ピリドン化合物の製造方法 - Google Patents
2-ピリドン化合物の製造方法 Download PDFInfo
- Publication number
- WO2015174377A1 WO2015174377A1 PCT/JP2015/063509 JP2015063509W WO2015174377A1 WO 2015174377 A1 WO2015174377 A1 WO 2015174377A1 JP 2015063509 W JP2015063509 W JP 2015063509W WO 2015174377 A1 WO2015174377 A1 WO 2015174377A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- added
- organic layer
- mixture
- difluoroethyl
- Prior art date
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- -1 2-pyridone compound Chemical class 0.000 title claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 148
- 238000006243 chemical reaction Methods 0.000 claims description 23
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical group CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 7
- 150000003672 ureas Chemical class 0.000 claims description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- 239000012044 organic layer Substances 0.000 description 76
- 239000000203 mixture Substances 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 239000010410 layer Substances 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 239000002904 solvent Substances 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- 238000002156 mixing Methods 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 229910052708 sodium Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 15
- 238000005859 coupling reaction Methods 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- GSBCSNHSFIDZPP-YAJBTMAUSA-N 3-cyclopropyl-6-[(E)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl]-1H-pyridin-2-one Chemical compound C1(CC1)C=1C(NC(=CC=1)\C(=C\[C@@H]1NC(CC1)=O)\C1=CC=C(C=C1)C(C)(F)F)=O GSBCSNHSFIDZPP-YAJBTMAUSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000007259 addition reaction Methods 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- GSBCSNHSFIDZPP-UWCCDQBKSA-N 3-cyclopropyl-6-[(Z)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl]-1H-pyridin-2-one Chemical compound C1(CC1)C=1C(NC(=CC=1)\C(=C/[C@@H]1NC(CC1)=O)\C1=CC=C(C=C1)C(C)(F)F)=O GSBCSNHSFIDZPP-UWCCDQBKSA-N 0.000 description 6
- NZBVYNUSGCUAJH-UHFFFAOYSA-N 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]-1H-pyridin-2-one Chemical compound C1(CC1)C=1C(NC(=CC=1)C(C1=CC=C(C=C1)C(C)(F)F)=O)=O NZBVYNUSGCUAJH-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- WXFUCIUQPOVNPU-HNMKQIAWSA-N (5r)-5-[(e)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-difluoroethyl)phenyl]ethenyl]pyrrolidin-2-one Chemical compound COC1=NC(C(=C\[C@@H]2NC(=O)CC2)\C=2C=CC(=CC=2)C(C)(F)F)=CC=C1C1CC1 WXFUCIUQPOVNPU-HNMKQIAWSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- OWCOWYGJWMOVKV-UHFFFAOYSA-N (5-cyclopropyl-6-methoxypyridin-2-yl)-[4-(1,1-difluoroethyl)phenyl]methanone Chemical compound COC1=NC(C(=O)C=2C=CC(=CC=2)C(C)(F)F)=CC=C1C1CC1 OWCOWYGJWMOVKV-UHFFFAOYSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- IRBLURCMEFXYRQ-UHFFFAOYSA-N 5-cyclopropyl-6-methoxypyridine-2-carbonitrile Chemical compound COC1=NC(C#N)=CC=C1C1CC1 IRBLURCMEFXYRQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000132 electrospray ionisation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AYIQHLMAWLYTPO-UHFFFAOYSA-N (5-cyclopropylpyridin-2-yl)-[4-(1,1-difluoroethyl)phenyl]methanone Chemical compound C1(CC1)C=1C=CC(=NC=1)C(=O)C1=CC=C(C=C1)C(C)(F)F AYIQHLMAWLYTPO-UHFFFAOYSA-N 0.000 description 2
- WXFUCIUQPOVNPU-MCRQTXEHSA-N (5R)-5-[(Z)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-difluoroethyl)phenyl]ethenyl]pyrrolidin-2-one Chemical compound C1(CC1)C=1C=CC(=NC=1OC)\C(=C/[C@H]1CCC(N1)=O)\C1=CC=C(C=C1)C(C)(F)F WXFUCIUQPOVNPU-MCRQTXEHSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
- QXIBKCFAFRHORF-UHFFFAOYSA-N 1-bromo-4-(1,1-difluoroethyl)benzene Chemical compound CC(F)(F)C1=CC=C(Br)C=C1 QXIBKCFAFRHORF-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- XSJWSPWUYANILV-GRCQKCIOSA-N C(C)(C)(C)OC(=O)N1C(C(=CC=C1\C(=C/[C@@H]1N(C(CC1)=O)C(=O)OC(C)(C)C)\C1=CC=C(C=C1)C(C)(F)F)C1CC1)=O Chemical compound C(C)(C)(C)OC(=O)N1C(C(=CC=C1\C(=C/[C@@H]1N(C(CC1)=O)C(=O)OC(C)(C)C)\C1=CC=C(C=C1)C(C)(F)F)C1CC1)=O XSJWSPWUYANILV-GRCQKCIOSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- MYRUIMMRTFRSLX-UHFFFAOYSA-N N1C(=O)CCC1CS(=O)(=O)C1=NC2=CC=CC=C2S1 Chemical compound N1C(=O)CCC1CS(=O)(=O)C1=NC2=CC=CC=C2S1 MYRUIMMRTFRSLX-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000752 ionisation method Methods 0.000 description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N isobutyl acetate Chemical compound CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 1
- SHSXOQUBBZYVJW-UHFFFAOYSA-N (5-cyclopropyl-1-oxidopyridin-1-ium-2-yl)-[4-(1,1-difluoroethyl)phenyl]methanone Chemical compound C1(CC1)C=1C=CC(=[N+](C=1)[O-])C(C1=CC=C(C=C1)C(C)(F)F)=O SHSXOQUBBZYVJW-UHFFFAOYSA-N 0.000 description 1
- MYRUIMMRTFRSLX-MRVPVSSYSA-N (5r)-5-(1,3-benzothiazol-2-ylsulfonylmethyl)pyrrolidin-2-one Chemical compound N1C(=O)CC[C@@H]1CS(=O)(=O)C1=NC2=CC=CC=C2S1 MYRUIMMRTFRSLX-MRVPVSSYSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ABERLDAQFUZISG-SJLPKXTDSA-N 3-cyclopropyl-6-[(1r)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2r)-5-oxopyrrolidin-2-yl]ethyl]-1h-pyridin-2-one Chemical compound C1=CC(C(F)(F)C)=CC=C1[C@H](C=1NC(=O)C(C2CC2)=CC=1)C[C@@H]1NC(=O)CC1 ABERLDAQFUZISG-SJLPKXTDSA-N 0.000 description 1
- UNMRXWBCQGIBQE-UHFFFAOYSA-N 4-(1,1-difluoroethyl)benzonitrile Chemical compound CC(F)(F)C1=CC=C(C#N)C=C1 UNMRXWBCQGIBQE-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- UKYCFKUHTQPGIX-UHFFFAOYSA-N 5-chloro-6-methoxypyridine-2-carbonitrile Chemical compound COC1=NC(C#N)=CC=C1Cl UKYCFKUHTQPGIX-UHFFFAOYSA-N 0.000 description 1
- IQYPERFVXHAWMQ-UHFFFAOYSA-N 5-cyclopropylpyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC=C1C1CC1 IQYPERFVXHAWMQ-UHFFFAOYSA-N 0.000 description 1
- UXLOHYNDRWUVBM-UHFFFAOYSA-N 6-[1-[4-(1,1-difluoroethyl)phenyl]-2-(5-oxopyrrolidin-2-yl)ethenyl]-1H-pyridin-2-one Chemical compound FC(C)(F)C1=CC=C(C=C1)C(=CC1NC(CC1)=O)C1=CC=CC(N1)=O UXLOHYNDRWUVBM-UHFFFAOYSA-N 0.000 description 1
- SKIPAAMIIFRNNL-UHFFFAOYSA-N 6-benzoyl-1H-pyridin-2-one Chemical class C(C1=CC=CC=C1)(=O)C1=CC=CC(N1)=O SKIPAAMIIFRNNL-UHFFFAOYSA-N 0.000 description 1
- ZYOCLLKGLHOQTP-UHFFFAOYSA-N 6-bromo-3-cyclopropyl-2-methoxypyridine Chemical compound COC1=NC(Br)=CC=C1C1CC1 ZYOCLLKGLHOQTP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 CCCC([*-2]C[C@](c1ccc(C(C)(F)F)cc1)C(N1)=CC=C(C2CC2)C1=O)=O Chemical compound CCCC([*-2]C[C@](c1ccc(C(C)(F)F)cc1)C(N1)=CC=C(C2CC2)C1=O)=O 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001356 alkyl thiols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 235000021384 green leafy vegetables Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- AQBLLJNPHDIAPN-MUCWUPSWSA-K iron(3+);(e)-4-oxopent-2-en-2-olate Chemical compound [Fe+3].C\C([O-])=C/C(C)=O.C\C([O-])=C/C(C)=O.C\C([O-])=C/C(C)=O AQBLLJNPHDIAPN-MUCWUPSWSA-K 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].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 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- VSCLJRSWEGZJNY-UHFFFAOYSA-N sodium;butan-2-olate Chemical compound [Na+].CCC(C)[O-] VSCLJRSWEGZJNY-UHFFFAOYSA-N 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- WFKMQPYZMPDJGD-ISKFKSNPSA-N tert-butyl 3-cyclopropyl-6-[(1R)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2R)-1-[(2-methylpropan-2-yl)oxycarbonyl]-5-oxopyrrolidin-2-yl]ethyl]-2-oxopyridine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(C(=CC=C1[C@H](C[C@@H]1N(C(CC1)=O)C(=O)OC(C)(C)C)C1=CC=C(C=C1)C(C)(F)F)C1CC1)=O WFKMQPYZMPDJGD-ISKFKSNPSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Definitions
- the present invention relates to a method for producing a 2-pyridone compound.
- the 2-pyridone compound (compound (2)) represented by the formula (2) is a compound included in the claims of a compound patent (Patent Document 1) for treating diabetes that claims a series of 2-pyridone compounds.
- Patent Document 1 for treating diabetes that claims a series of 2-pyridone compounds.
- the present invention provides a method for producing a 2-pyridone compound.
- the present inventors constructed a synthetic route for the 6-benzoyl-2-pyridone compound, which is a key intermediate, and obtained the compound (1) using the intermediate as a raw material.
- the present inventors tried to apply a general synthesis method described in Patent Document 1, and found that it was a Z-form as a target product.
- a compound which is an E form is by-produced. Due to the by-product of the E-form compound, the yield of the target compound (1) was lowered, and it was necessary to use column chromatography for purification. .
- the present inventors diligently studied in the production of the compound (1), and found a selective production method of the compound (1) in the Z form.
- the present inventors found for the first time that the compound (1) obtained by the above method is crystallized by using a sodium salt, and established a purification method that does not require column chromatography.
- the present inventors have found an industrially applicable production method for deriving the compound (1) of the following scheme into the compound (2), and completed the present invention.
- the present invention is characterized by the following.
- (I) 2-pyridone compound represented by formula (1) characterized by reacting a 6-benzoyl-2-pyridone compound represented by formula (3) with a sulfone compound represented by formula (4) Manufacturing method.
- IV The compound represented by Formula (1).
- (V) The compound represented by Formula (3).
- (VII) The compound represented by Formula (6).
- n is normal, “i” is iso, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” “Represents ortho,” m “represents meta,” p “represents para,” Boc "represents t-butoxycarbonyl, and” Me “represents methyl.
- (E)” means E body, and “(Z)” means Z body.
- Halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
- C 1-4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, and includes a methyl group, an ethyl group, an n-propyl group, an i-propyl group, and an n-butyl group. I-butyl group, s-butyl group or t-butyl group.
- Scheme 1 Method for producing compound (3) from compound (1-a).
- G 1 represents a protecting group for a hydroxy group in the hydroxypyridyl group.
- Compound (1-a) and compound (1-b) can be obtained by the method described in International Publication No. 2008/103185 or a method analogous thereto.
- Compound (1-c) can be produced.
- Examples of the “addition reaction” include n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropyl using compound (1-b) as a substrate in an inert solvent at a temperature of ⁇ 78 ° C. to 100 ° C.
- An anion generated by using an organic metal reagent such as magnesium bromide, a metal reagent such as magnesium, or a base such as lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide is reacted with a nitrile compound of compound (1-a).
- An organic metal reagent such as magnesium bromide, a metal reagent such as magnesium, or a base such as lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide is reacted with a nitrile compound of compound (1-a).
- a method is mentioned.
- Examples of the “deprotection reaction” include (i) when the protecting group G 1 is an alkyl group or an allyl group, hydrolysis at a temperature of 0 ° C. to 200 ° C. in an inert solvent in the presence of an acid or a strong acid.
- Examples of the deprotection reaction include a method of removing by reaction, a method using trimethylsilyl iodide, a method using aluminum chloride and alkylthiol, and (ii) a protecting group G 1 is a benzyl group, 4- In the case of a methoxybenzyl group, 2,4-dimethoxybenzyl group, benzyloxycarbonyl group, benzhydryl (diphenylmethyl) group, etc., at a temperature of 0 ° C.
- G 1 is an alkyl group
- G 1 represents a C 1-4 alkyl group, preferably a methyl group or an ethyl group, and more preferably a methyl group.
- Compound (6) can be produced.
- addition reaction examples include the same reactions as the “addition reaction” in the steps (1-1) and (1-2) described above.
- Step (2-3) Compound (7) can be produced by subjecting compound (6) to an “oxidation reaction” using an oxidizing agent.
- oxidation reaction for example, a method of giving a compound (7) by reacting an “oxidant” with a compound (6) at ⁇ 20 ° C. to 60 ° C. in an inert solvent such as chloroform and water. Can be mentioned.
- oxidant examples include peracids such as metachloroperbenzoic acid.
- the peracid can also be generated and used in the system by a combination of hydrogen peroxide and an acid or acid anhydride.
- Scheme 3 Method for producing compound (3) from compound (3-a) (In Scheme 3, X represents a halogen atom, and G 1 is the same as above.)
- Compound (3-a) can be obtained by the method described in International Publication No. 2008/103185 or a method analogous thereto.
- Step (3-1) Compound (3-b) can be produced by performing a “coupling reaction” with a cyclopropylmagnesium compound, cyclopropylzinc compound or cyclopropylboronic acid using compound (3-a) as a substrate.
- the “coupling reaction” means, for example, at ⁇ 20 ° C. to 40 ° C., 1,2-dimethoxyethane, methylene chloride, acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone or 1,4-dioxane. And a method of reacting with a cyclopropylmagnesium compound, a cyclopropylzinc compound or a cyclopropylboronic acid in the presence of a palladium, nickel or iron catalyst in an inert solvent.
- a palladium (0) catalyst in the system using palladium acetate (II) or palladium-activated carbon and triphenylphosphine and use it in the reaction.
- nickel catalyst used for the “coupling reaction” include nickel catalysts known to those skilled in the art, such as bis (triphenylphosphine) nickel (II) dichloride.
- a nickel catalyst can be generated in the system using nickel chloride (II) and triphenylphosphine and used for the reaction.
- the iron catalyst used in the “coupling reaction” include iron catalysts known to those skilled in the art, such as tris (2,4-pentanedionato) iron (III). It is also possible to generate an iron catalyst in the system and use it in the reaction.
- Compound (1-c) can be produced.
- addition reaction examples include the addition reactions described in the step (1-1) and the step (1-2) in the above scheme 1.
- Step (3-4) The compound (3) can be produced by carrying out the reaction of the step (1-3) in the above scheme 1.
- Step (4-1) Compound (1) can be produced by performing a “coupling reaction” with compound (4) using compound (3) as a substrate and a base.
- the compound (4) used in the “coupling reaction” can be obtained by the method described in International Publication No. 2008/103185.
- the compound (1) obtained by the “coupling reaction” is obtained as a mixture with the E form.
- the base used in the “coupling reaction” is not particularly limited, and may be used alone or in combination with a plurality of other bases.
- the base is preferably an organic base or an organic metal base, more preferably an alkali metal base of an amine substituted with a silyl group substituted with alkyl, allyl, or both, and more preferably lithium bis (trimethylsilyl) amide.
- the base is preferably used in an amount of 1.0 to 20.0 molar equivalents relative to compound (3), more preferably 3.0 to 10.0 molar equivalents.
- Compound (4) is preferably used in an amount of 1.0 to 10.0 molar equivalents relative to compound (3), more preferably 1.0 to 3.0 molar equivalents.
- the “coupling reaction” is preferably performed in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction.
- solvents include aliphatic hydrocarbons (hexane, heptane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether), halogenated aliphatic hydrocarbons (methylene chloride, chloroform, dichloroethane, etc.), nitriles (acetonitrile, propionitrile, etc.), amides (N, N-dimethylformamide, N, N—) Dimethylacetamide) and the like, more preferably aliphatic hydrocarbons and ethers, still more preferably hexane and tetrahydrofuran, and particularly
- the solvent may be used alone or as a mixture of a plurality of solvents.
- the amount of solvent used is generally affected by whether the substrate is crystalline or not, and can be arbitrarily set according to the type of substrate. Although it does not matter as long as it is within the range, the substrate concentration of the compound (3) is usually 1 to 50% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight.
- the “coupling reaction” can be carried out at any temperature from ⁇ 78 ° C. to the boiling point of the reaction medium, but is usually ⁇ 40 ° C. or higher and 60 ° C. or lower, preferably ⁇ 30 ° C. or higher and 50 ° C., from the viewpoint of reaction operation and industrial viewpoint. In the following, it is more preferably performed at ⁇ 20 ° C. or more and 40 ° C. or less.
- the “coupling reaction” may be performed in the presence of an additive.
- an additive urea derivatives (1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, tetramethylurea, etc.) are preferable. 1,3-dimethyl-2-imidazolidinone is more preferred.
- an additive When an additive is used, it may be used alone or a plurality of additives may be mixed and used.
- the amount of the additive used when used can be arbitrarily set according to the type of the substrate, and is 0.1 to 100 times by weight, preferably 1 to 20 times by weight with respect to the compound (3) as the substrate. More preferably, it is 2 to 6 times by weight.
- an acidic aqueous solution such as sulfuric acid is added to the reaction solution and stirred to decompose the organometallic compound, and the base-derived components are mainly removed by liquid separation, followed by sodium carbonate.
- An alkaline solution such as an aqueous solution is added, and the mixture is separated to extract the target product.
- the desired product can be obtained by performing purification operations such as column chromatography and crystallization on the obtained organic layer.
- Step (5-1) The compound (5) can be produced by using the compound (1) as a substrate to form a sodium salt using sodium alkoxide.
- Compound (5) can be crystallized to obtain high-purity compound (5).
- a solvent for salt formation or crystallization an alcohol solvent or an ester solvent is preferable.
- Sodium alkoxide is preferably used dissolved in an alcohol solvent, and compound (1) is preferably used dissolved in an ester solvent.
- the sodium alkoxide used is an alkoxide having 1 to 4 carbon atoms, such as sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium n-butoxide, sodium s-butoxide, sodium t-butoxide.
- sodium methoxide As the sodium alkoxide, it is more preferable to use a solution of an alcohol corresponding to the alkoxide.
- sodium alkoxides can be used by mixing with other sodium alkoxides in an arbitrary ratio.
- sodium alkoxides are preferably used in an amount of 1.0 to 10.0 molar equivalents, more preferably 1.0 to 3.0 molar equivalents, relative to compound (1).
- the alcohol solvent used is an alcohol having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, and preferably methanol. Alcohol may be added as a sodium alkoxide solution.
- solvents can be used by mixing with other solvents at an arbitrary ratio.
- the alcohol solvent may be used alone or in combination with a plurality of solvents. Further, the amount of the solvent used is affected by the solubility when dissolving the sodium alkoxide, and can be arbitrarily set according to the type of the sodium alkoxide, so long as it can be partially dissolved. Usually, the concentration of sodium alkoxide is 1 to 90% by weight, preferably 5 to 60% by weight, more preferably 10 to 40% by weight.
- the ester solvent used is formate ester (methyl formate, ethyl formate, n-propyl formate), or acetate ester (methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butyl acetate). , T-butyl acetate), and preferably ethyl acetate.
- solvents can be used by mixing with other solvents at an arbitrary ratio.
- the ester solvent may be used alone or as a mixture of a plurality of solvents.
- the amount of solvent used is generally affected by whether the substrate is crystalline or not, and can be arbitrarily set according to the type of substrate. Although it does not matter as long as it is within the range, the substrate concentration of compound (1) is usually 1 to 50% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight.
- Compound (1) is crystallized by either mixing with sodium alkoxide, mixing with sodium alkoxide, heating, cooling, concentrating, dissolving and then adding a poorly soluble solvent (poor solvent), or a combination of these. To do.
- the crystallization temperature is carried out in the range of ⁇ 20 ° C. to 80 ° C. unless otherwise specified, but is preferably ⁇ 10 ° C. to 50 ° C.
- seed crystals can be used.
- the seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing the target solution with a spatula.
- Compound (5) which is a sodium salt of compound (1), is a salt produced from compound (1) and sodium alkoxide, and is a salt composed of an anion of compound (1) and a sodium cation. Further, regarding the ratio of the composition of the salt, the ratio of the anion: sodium cation of the compound (1) is 1: 1.
- the structure of the compound (5) may be a compound represented by the formula (5A), the formula (5B), or the formula (5C).
- the compound (5) is represented by the formula (5A).
- the characteristics of the crystal can be analyzed by powder X-ray diffraction measurement.
- the peak position (peak value) obtained by powder X-ray diffraction measurement is represented by 2 ⁇ .
- the peak value may change depending on the measurement conditions.
- the difference in crystal form should be determined by comprehensively analyzing measurement conditions, peak values, diffraction patterns, and the like.
- Scheme 6 Method for producing compound (2) from compound (5).
- G 2 represents a protecting group for the nitrogen atom in the 2-pyridone group.
- G 3 represents a protecting group for the nitrogen atom in the pyrrolidinyl group substituted with an oxo group.
- Step (6-1) Compound (1) can be obtained by performing a liquid separation operation with an aqueous solution such as an acid or a salt in an organic solvent capable of separating Compound (5) from water.
- the compound (6-b) can be produced by reduction with In this production, an acid or a base can be added as necessary.
- Examples of the “deprotection reaction” include a method using an acid such as hydrochloric acid or trifluoroacetic acid.
- silica gel column chromatography Kanto Chemical “silica gel 60” or Fuji Silysia “PSQ60B” or packed column (YAMAZEN Hi-Flash TM Column or MORITE Purif Pack or Biotage® SNAP KP-Sil Catridge) was used.
- MS mass spectrum
- LCMS-2010EV Shiadzu
- LCMS-IT-TOF Shiadzu
- Agilent 6150 Alignment
- LCQ Deca XP Thermo Fisher Scientific
- an ionization method an ESI (Electrospray Ionization) method or a dual ionization method of ESI and APCI (Atmospheric Pressure Chemical Ionization) method was used.
- Powder X-ray diffraction measurement was carried out using Rigaku MiniFlex600 (line source: Cu, wavelength: 1.54 (10 ⁇ 10 m)), Panaritical X′PertPRO (line source: Cu, wavelength: 1.54 (10 ⁇ 10) m).
- Compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.
- reaction solution was raised to 0 ° C., and 1M hydrochloric acid (437 mL), tetrahydrofuran (365 mL), and 1M hydrochloric acid (146 mL) were added dropwise in this order.
- the reaction solution was separated into an organic layer and an aqueous layer, and then the aqueous layer was extracted with ethyl acetate (1000 mL).
- ethyl acetate 1000 mL
- anhydrous magnesium sulfate was added and dried. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- a 10% aqueous sodium thiosulfate solution (349.82 g) was added to the organic layer and mixed, and the mixture was separated into an organic layer and an aqueous layer.
- a 10% aqueous sodium thiosulfate solution (350.40 g) was added to the organic layer and mixed, and the mixture was separated into an organic layer and an aqueous layer.
- a 10% aqueous sodium thiosulfate solution (353.05 g) and saturated brine (107.24 g) were added and mixed, and the mixture was separated into an organic layer and an aqueous layer.
- the weight of the organic layer was 79.79 g, ethyl acetate (383.57 g) was added, the temperature was raised to 40 ° C., and then normal heptane (38 to 41 ° C.) 385.13 g) was added dropwise over 11 minutes, cooled to 5 ° C. over 42 minutes, and stirred for 15 minutes to form a suspension.
- the obtained organic layer was mixed, an aqueous solution in which potassium hydrogen carbonate (1.35 g) and water (8.43 g) were mixed was added, stirred for 6 minutes, and then separated into an organic layer and an aqueous layer.
- An aqueous solution in which sodium chloride (0.55 g) and water (8.43 g) were mixed was added to the obtained organic layer, stirred for 5 minutes, and then separated into an organic layer and an aqueous layer.
- the solvent was distilled off from the obtained organic layer under reduced pressure.
- metachloroperbenzoic acid (30%) was added to a solution of (5-cyclopropylpyridin-2-yl) [4- (1,1-difluoroethyl) phenyl] methanone (20.00 g) in chloroform (100.00 g). Water-containing product, 34.32 g) was added, and the mixture was washed with chloroform (10.02 g) and stirred at 25 ° C. for 4 hours.
- An aqueous solution obtained by mixing chloroform (150.01 g), sodium thiosulfate (14.31 g) and water (60.01 g) and a 5% aqueous sodium hydrogen carbonate solution (60.01 g) were added to the reaction solution, and after mixing, the organic layer and The aqueous layer was separated.
- a 5% aqueous sodium hydrogen carbonate solution (60.00 g) was added to the organic layer, and after mixing, the organic layer and the aqueous layer were separated.
- a 5% aqueous sodium hydrogen carbonate solution (120.01 g) was added to the organic layer, and after mixing, the organic layer and the aqueous layer were separated.
- a 5% aqueous sodium hydrogen carbonate solution (120.00 g) was added to the organic layer, and after mixing, the organic layer and the aqueous layer were separated.
- Water (60.02 g) was added to the organic layer, and after mixing, the organic layer and the aqueous layer were separated.
- the solvent was distilled off from the obtained organic layer under reduced pressure to obtain a pale yellow solid (25.33 g).
- Ethyl acetate (5.02 g) was added to the obtained aqueous layer and mixed, and then the mixture was separated into an organic layer and an aqueous layer.
- Ethyl acetate (5.01 g) was added to the obtained aqueous layer and mixed, and then the mixture was separated into an organic layer and an aqueous layer.
- saturated brine (5.00 g) was added and mixed, and then the mixture was separated into an organic layer and an aqueous layer.
- Anhydrous magnesium sulfate was added to the obtained organic layer for drying, and after removing the desiccant by filtration, the solvent was distilled off under reduced pressure.
- a 5% aqueous hydrochloric acid solution (0.93 g) was added and stirred, then water and ethyl acetate were added and mixed, and the mixture was separated into an organic layer and an aqueous layer.
- Ethyl acetate (4 mL) was added to the obtained aqueous layer and mixed, and then the mixture was separated into an organic layer and an aqueous layer. Both organic layers were mixed, 5% aqueous sodium hydrogen carbonate solution was added and mixed, and then separated into an organic layer and an aqueous layer.
- Ethyl acetate (2 mL) was added to the obtained aqueous layer and mixed, and then the mixture was separated into an organic layer and an aqueous layer.
- the solvent was distilled off from the obtained organic layer under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain the title compound mixture (1.10 g) as a brown amorphous substance. It was.
- Example 4 (R, Z) -3-cyclopropyl-6- ⁇ 1- [4- (1,1-difluoroethyl) phenyl] -2- [purified by silica gel column chromatography or the like was used.
- Phenyl] -2- [5-oxopyrrolidin-2-yl] vinyl ⁇ pyridin-2 (1H) -one is a by-product (R, E) -3-cyclopropyl in quantitative yield 77.7% -6- ⁇ 1- [4- (1,1-difluoroethyl) phenyl] -2- [5-oxopyrrolidin-2-yl] vinyl ⁇ pyridin-2 (1H) -one has a quantitative yield of 9.2%. Met.
- the reaction solution was quantified after warming to room temperature, and was the main product (target compound) (R, Z) -3-cyclopropyl-6- ⁇ 1- [4- (1,1-difluoroethyl).
- Phenyl] -2- [5-oxopyrrolidin-2-yl] vinyl ⁇ pyridin-2 (1H) -one is a by-product of (R, E) -3-cyclopropyl-quantitative yield 66.2% 6- ⁇ 1- [4- (1,1-difluoroethyl) phenyl] -2- [5-oxopyrrolidin-2-yl] vinyl ⁇ pyridin-2 (1H) -one was obtained in a quantitative yield of 11.5%.
- Table 1 shows the results of Reference Example 1, Example 4, and Example 5.
- the additive represents 1,3-dimethyl-2-imidazolidinone.
- Example 4 When comparing Reference Example 1 and Example 4, in Example 4, the selectivity and yield of the compound that was Z-form were improved. Further, when Example 4 and Example 5 were compared, the selectivity and yield of the compound in the Z form was improved more when 1,3-dimethyl-2-imidazolidinone was added.
- the solvent was distilled off under reduced pressure with respect to the obtained organic layer, ethyl acetate (50 g) was added to the obtained residue, and the solvent was distilled off under reduced pressure.
- Acetonitrile (50 g) was added to the obtained residue, and the solvent was distilled off under reduced pressure.
- Acetonitrile (70 g), triethylamine (8.73 g), and N, N-dimethyl-4-aminopyridine (0.609 g) were mixed with the obtained residue, and then di-tert-butyl dicarbonate (16 .12 g) and acetonitrile (30 g) were added dropwise over 6 minutes. After heating up to 40 degreeC and stirring for 1 hour and 35 minutes, the solvent was distilled off under pressure reduction.
- a 10% aqueous ammonium chloride solution (100 g) and ethyl acetate (100 g) were added to the resulting residue, and after mixing, the organic layer and the aqueous layer were separated.
- Water (50 g) was added to the organic layer, and after mixing, the organic layer and the aqueous layer were separated.
- Ethyl acetate (50 g) was added to the obtained aqueous layer and mixed, and the mixture was separated into an organic layer and an aqueous layer.
- the solvent was distilled off under reduced pressure.
- Toluene (30 g) was added to the obtained residue, and the solvent was distilled off under reduced pressure.
- An aqueous solution in which sodium hydroxide (38.40 g) and water (150.10 g) were mixed was added dropwise thereto, and the mixture was stirred at 33 to 35 ° C. for 30 minutes, and then separated into an organic layer and an aqueous layer.
- An aqueous solution obtained by mixing potassium hydrogen carbonate (29.88 g) and water (150.00 g) was added to the obtained organic layer, and after mixing, the organic layer and the aqueous layer were separated. Water (150.00 g) was added to the obtained organic layer, mixed, and then separated into an organic layer and an aqueous layer.
- the present invention is useful in that 2-pyridone compounds useful as pharmaceuticals or pharmaceutical intermediates can be produced in a high yield from 6-benzoyl-2-pyridone compounds. It should be noted that the entire contents of the specification, claims, abstract and drawings of Japanese Patent Application No. 2014-099755 filed on May 13, 2014 are cited herein as disclosure of the specification of the present invention. Incorporated.
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Abstract
Description
さらに、本発明者らは、下記のスキームの化合物(1)を、化合物(2)へと誘導する工業的に応用可能な製造方法を見出し、本発明を完成させた。
(I)
式(3)で表される6-ベンゾイル-2-ピリドン化合物と、式(4)で表されるスルホン化合物を反応させることを特徴とする、式(1)で表される、2-ピリドン化合物の製造方法。
尿素誘導体存在下で反応させる、(I)に記載の製造方法。
(III)
尿素誘導体が、1,3-ジメチル-2-イミダゾリジノンである、(II)に記載の製造方法。
(IV)
式(1)で表される化合物。
式(3)で表される化合物。
式(1)で表される化合物のナトリウム塩。
式(6)で表される化合物。
式(7)で表される化合物。
式(8)で表される化合物。
式(9)で表される化合物。
式(10)で表される化合物。
化合物(3)の一般的な製造法をスキーム1~3に示すが、一般的製造法例を示すものであり、製造法を限定するものではない。工程を実施する順番を変更する、ヒドロキシ基等に保護基を施して反応を実施し後の工程で脱保護を実施する、それぞれの工程途中において新たな工程を追加する等の当業者において周知の方法を用いる事でも化合物(3)は製造出来る。
化合物(1-a)とヘテロアリールリチウム等のリチウム試薬、ヘテロアリールマグネシウムブロミド等のグリニャール試薬などのアニオンを用いた「付加反応」を行い、得られた化合物を塩酸等の酸で処理することにより化合物(1-c)を製造することができる。
化合物(1-c)が有する保護基G1の「脱保護反応」を行うことにより化合物(3)を製造することができる。
化合物(2-a)とフェニルアリールリチウム等のリチウム試薬、フェニルアリールマグネシウムブロミド等のグリニヤール試薬などのアニオンを用いた「付加反応」を行い、得られた化合物を塩酸等の酸で処理することにより化合物(6)を製造する事ができる。
化合物(6)に対し、酸化剤を用いて「酸化反応」を行うことにより、化合物(7)を製造する事ができる。
化合物(7)に対し、酸無水物を用いて「転移反応」を行うことにより、化合物(3)を製造する事ができる。
化合物(3-a)を基質として、シクロプロピルマグネシウム化合物、シクロプロピル亜鉛化合物又はシクロプロピルボロン酸との「カップリング反応」を行うことにより、化合物(3-b)を製造することができる。
「カップリング反応」に用いるニッケル触媒としては、ビス(トリフェニルホスフィン)ニッケル(II)ジクロリド等の当業者に公知のニッケル触媒が挙げられる。また、塩化ニッケル(II)とトリフェニルホスフィンを用いて系中でニッケル触媒を発生させて反応に用いることもできる。
「カップリング反応」に用いる鉄触媒としては、トリス(2,4-ペンタンジオナト)鉄(III)等の当業者に公知の鉄触媒が挙げられる。また、系中で鉄触媒を発生させて反応に用いることもできる。
化合物(3-b)とフェニルアリールリチウム等のリチウム試薬、フェニルアリールマグネシウムブロミド等のグリニヤール試薬などのアニオンを用いた「付加反応」を行い、得られた化合物を塩酸等の酸で処理することにより、化合物(1-c)を製造する事ができる。
上記スキーム1における工程(1-3)の反応を実施することにより、化合物(3)を製造することができる。
化合物(1)の製造方法をスキーム4に示す。
化合物(3)を基質として、塩基を用いて化合物(4)との「カップリング反応」を行うことにより、化合物(1)を製造することができる。
式(1)で表される化合物のナトリウム塩(以下、化合物(5)ともいう)の製造方法をスキーム5に示す。
スキーム5:化合物(1)から化合物(5)の製造方法。
化合物(1)を基質として、ナトリウムアルコキシドを用いてナトリウム塩とすることにより化合物(5)を製造することができる。化合物(5)は結晶化して高純度の化合物(5)とすることができる。塩形成や結晶化における溶媒としてはアルコール溶媒やエステル溶媒が好ましい。ナトリウムアルコキシドはアルコール溶媒に溶解して使用し、化合物(1)はエステル溶媒に溶解して使用することが好ましい。
ナトリウムアルコキシドはアルコキシドに対応するアルコールの溶液を用いるのがより好ましい。
2θ=6.9±0.2,7.6±0.2,8.8±0.2,11.5±0.2,13.1±0.2,13.6±0.2,16.1±0.2,17.4±0.2,19.6±0.2,20.7±0.2,23.6±0.2である。
化合物(5)及び化合物(1)は、化合物(2)へと誘導する事が出来る。その一般的な製造法をスキーム6に示すが、一般的製造法例を示すものであり、製造法を限定するものではない。工程を実施する順番を変更する、アミド基等に保護基を施して反応を実施し後の工程で脱保護を実施する、それぞれの工程途中において新たな工程を追加する等の当業者において周知の方法を用いる事でも化合物(2)は製造出来る。
化合物(5)を水と分液可能な有機溶媒中、酸や塩等の水溶液との分液操作をする事により化合物(1)を得ることができる。
化合物(1)に二炭酸ジ-tert-ブチル等を作用させることにより、保護基G2及び保護基G3を有する化合物(6-a)を製造することができる。
化合物(6-a)を基質とし、-20℃乃至80℃で、不活性溶媒中、パラジウム-活性炭素、ロジウム-活性炭素、又は白金-活性炭素等を触媒量用いた「接触水素添加反応」により還元することで、化合物(6-b)を製造することができる。この製造には必要に応じて酸又は塩基を添加する事ができる。
化合物(6-b)が有する保護基G2、G3の「脱保護反応」を行うことにより化合物(2)を製造することができる。
s : シングレット(singlet)
d : ダブレット(doublet)
t : トリプレット(triplet)
q : クァルテット(quartet)
dd : ダブルダブレット(double doublet)
m : マルチプレット(multiplet)
br : ブロード(broad)
J : カップリング定数(coupling constant)
Hz : ヘルツ(Hertz)
CDCl3 : 重クロロホルム
V/V : 体積対体積を意味する
300MHz: JNM-ECP300 (JEOL), JNM-ECX300 (JEOL)
600MHz: JNM-ECA600 (JEOL)
解析にはACD/SpecManager ver.12.01(商品名)などを用いた。
micromass ZQ (Waters)
LTQ XL (Thermo Fisher Scientific)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
Agilent 6150 (Agilent)
LCQ Deca XP (Thermo Fisher Scientific)
イオン化法としては、ESI(Electrospray Ionization、エレクトロスプレーイオン化)法または、ESIとAPCI(Atmospheric Pressure Chemical Ionization、大気圧化学イオン化)法とのデュアルイオン化法を用いた。
化合物(3)の製造(その1)
反応液を有機層と水層に分離後、水層を酢酸エチル(1000mL)で抽出した。あわせた有機層に無水硫酸マグネシウムを加え乾燥させ、乾燥剤をろ別後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=100/0→19/1,V/V)で精製し、表題化合物(34.0g,収率74%)を無色油状物質として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.72-0.81(m,2H),1.00-1.10(m,2H),1.96(t,J=18.2Hz,3H),2.10-2.25(m,1H),3.95(s,3H),7.24(d,J=6.9Hz,1H),7.59(d,J=9.0Hz,2H),7.67(d,J=7.8Hz,1H),8.21(d,J=8.6Hz,2H).
MS(+):318[M+H]+.
窒素雰囲気下、23~24℃において(5-シクロプロピル-6-メトキシピリジン-2-イル)[4-(1,1-ジフルオロエチル)フェニル]メタノン(76.31g)とヨウ化カリウム(146.97g)のアセトニトリル(656.07g)溶液にトリメチルシリルクロライド(104.36g)を5分かけて滴下した後、3時間32分かけて64℃まで昇温後、63~64℃で5時間14分攪拌した。室温まで冷却して14時間攪拌後に64℃まで加熱しながら1時間30分攪拌した。冷却後17~30℃において炭酸ナトリウム(50.97g)と水(201.34g)を混合させた水溶液を10分かけて滴下した後、水(102.93g)を加えて減圧下溶媒を留去して669.38gとした。得られた残渣に酢酸エチル(760.66g)を加えた後に混合後有機層と水層に分液した。有機層に10%チオ硫酸ナトリウム水溶液(349.82g)を加えて混合後有機層と水層に分液した。有機層に10%チオ硫酸ナトリウム水溶液(350.40g)を加えて混合後有機層と水層に分液した。有機層に対し減圧下溶媒を留去して116.49gとした後に、酢酸エチル(1496.40g)を加え、33℃まで昇温した。10%チオ硫酸ナトリウム水溶液(353.05g)と飽和食塩水(107.24g)を加えて混合後有機層と水層に分液した。
有機層に対し減圧下溶媒を留去して、有機層の重量を79.79gとした後、酢酸エチル(383.57g)を加え、40℃まで昇温した後に38~41℃においてノルマルヘプタン(385.13g)を11分かけて滴下した後、42分かけて5℃まで冷却して15分攪拌することで懸濁液とした。得られた固体を濾過し、冷却した酢酸エチル(77.09g)とノルマルヘプタン(76.26g)の混合液で洗浄後、50℃で3時間減圧乾燥を行うことで表題化合物(67.95g、収率93.2%)を黄色固体として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.78-0.83(m,2H),1.08-1.14(m,2H),1.96(t,J=18.2Hz,3H),2.25-2.35(m,1H),6.68(d,J=6.8Hz,1H),6.91(d,J=7.2Hz,1H),7.65(d,J=8.2Hz,2H),7.80(d,J=8.2Hz,2H),9.62(s,1H).
MS(+):304[M+H]+.
化合物(3)の製造(その2)
(1)(5-シクロプロピルピリジン-2-イル)[4-(1,1-ジフルオロエチル)フェニル]メタノン
得られた油状物質にヘキサン(10.19g)と酢酸エチル(1.03g)を加え、50℃に昇温後に冷却し、36℃にて酢酸エチル(0.51g)を加えた。その後氷冷して4分撹拌する事で懸濁液とした。得られた固体を濾過し、冷却した酢酸エチル(0.75g)とヘキサン(4.95g)の混合液で洗浄後、40℃で減圧乾燥を行うことで表題化合物(3.98g、収率72.1%)を白色固体として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.80-0.94(m,2H),1.12-1.24(m,2H),1.84-2.07(m,4H),7.46(dd,J=2.4,8.2Hz,1H),7.60(d,J=8.6Hz,2H),8.00(d,J=8.2Hz,1H),8.10(d,J=8.2Hz,2H),8.49(d,J=2.0Hz,1H).
MS(+):288[M+H]+.
1H NMR(300MHz,CDCl3)δ ppm 0.81-0.92(m,2H),1.14-1.28(m,2H),1.91(t,J=18.2Hz,3H),1.87-2.04(m,1H),7.07(dd,J=1.7、8.3Hz,1H),7.34(d,J=8.3Hz,1H),7.59(d,J=8.3Hz,2H),7.86(d,J=8.3Hz,2H),7.99(d,J=1.4Hz,1H).
MS(+):304[M+H]+.
窒素雰囲気下、5-シクロプロピル-2-[4-(1,1-ジフルオロエチル)ベンゾイル]ピリジン1-オキサイド(12.00g)の2-メチルテトラヒドロフラン(120.02g)溶液に無水トリフルオロ酢酸(59.82g)を加えて23~26℃にて7時間攪拌した。この反応液に水酸化ナトリウム(22.15g)と水(36.00g)を混合した水溶液を滴下後に炭酸水素カリウム(11.88g)と水(108.00g)を混合した水溶液を加え、クロロホルム(72.08g)を加えて混合後に有機層と水層に分液した。得られた水層にクロロホルム(60.00g)を加えて撹拌後に有機層と水層に分液した。得られた有機層を混合し、水(60.00g)を加えて撹拌後に有機層と水層に分液した。得られた有機層に対し減圧下溶媒を留去した後に室温で減圧乾燥する事により淡黄色固体(11.77g)を得た。
得られた固体に酢酸エチル(47.08g)を加え、50~51℃にて30分懸濁状態で攪拌した。これを冷却して1℃にて30分攪拌した。得られた固体を濾過し、酢酸エチル(17.67g)で洗浄後、50℃で2時間減圧乾燥を行うことで表題化合物(9.07g、収率75.6%)を淡黄色固体として得た。
MS(+):304[M+H]+.
化合物(3)の製造(その3)
(1)5-シクロプロピル-6-メトキシピコリノニトリル
1H NMR(600MHz,CDCl3)δ ppm 0.69-0.75(m,2H),1.02-1.09(m,2H),2.10-2.16(m,1H),4.00(s,3H),7.10(d,J=7.4Hz,1H),7.20(d,J=7.4Hz,1H).
MS(+):175[M+H]+.
MS(+):318[M+H]+.
実施例1-(2)と同じ方法にて合成した。
(5R)-5-{(Z)-2-(5-シクロプロピル-6-メトキシピリジン-2-イル)-2-[4-(1,1-ジフルオロエチル)フェニル]エテニル}ピロリジン-2-オン(参考例1a)及び
(5R)-5-{(E)-2-(5-シクロプロピル-6-メトキシピリジン-2-イル)-2-[4-(1,1-ジフルオロエチル)フェニル]エテニル}ピロリジン-2-オン(参考例1b)の製造
(5R)-5-{(Z)-2-(5-シクロプロピル-6-メトキシピリジン-2-イル)-2-[4-(1,1-ジフルオロエチル)フェニル]エテニル}ピロリジン-2-オン(参考例1a)
1H NMR(300MHz,CDCl3)δ ppm 0.65-0.71(m,2H),0.96-1.02(m,2H),1.86-2.16(m,5H),2.28-2.49(m,3H),4.00(s,3H),4.65-4.72(m,1H),5.91(d,J=8.9Hz,1H),5.96(br,1H),6.54(d,J=7.7Hz,1H),7.05(d,J=7.0Hz,1H),7.30(d,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H).
MS(+):399[M+H]+.
(5R)-5-{(E)-2-(5-シクロプロピル-6-メトキシピリジン-2-イル)-2-[4-(1,1-ジフルオロエチル)フェニル]エテニル}ピロリジン-2-オン(参考例1b)
1H NMR(600MHz,CDCl3)δ ppm 0.56-0.64(m,2H),0.90-0.97(m,2H),1.93-2.09(m,5H),2.20-2.34(m,2H),2.37-2.45(m,1H),4.04(s,3H),4.07-4.16(m,1H),5.73-5.75(br.s.,1H),6.23(d,J=7.4Hz,1H),6.90(d,J=9.9Hz,1H),6.92(d,J=7.8Hz,1H),7.24(d,J=8.3Hz,2H),7.57(d,J=7.8Hz,2H).
MS(+):399[M+H]+.
カラム:L-ColumnODS(3.0×150mm,3μm)(財団法人化学物質評価研究機構製)
カラムオーブン温度:40℃
溶離液:アセトニトリル-0.01M 酢酸アンモニウム水溶液,22:78(0-15min),22:78-40:60(15-20min),40:60(20-30min),40:60-95:5(30-40min),95:5(40-55min),V/V
溶離液速度:0.4mL/min
検出波長:240nm
(R,Z)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例4a)及び
(R,E)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例4b)の製造
(R,Z)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例4a)
1H NMR(300MHz,CDCl3)δ ppm 0.61-0.71(m,2H),0.90-1.03(m,1H),1.14-1.30(m,1H),1.92(t,J=18.4Hz,3H),1.87-2.00(m,1H),2.09-2.18(m,1H),2.28-2.50(m,3H),4.33-4.41(m,1H),6.05(d,J=7.4Hz,1H),6.16(d,J=10.2Hz,1H),7.03(d,J=7.0Hz,1H),7.35(d,J=8.6Hz,2H),7.46(d,J=8.6Hz,1H),7.81(br,1H),13.17(br,1H).
MS(+):385[M+H]+.
(R,E)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例4b)
1H NMR(300MHz,CDCl3)δ ppm 0.50-0.65(m,2H),0.90-1.03(m,2H),1.91-2.46(m,8H),4.07-4.15(m,1H),5.63(d,J=7.4Hz,1H),6.63(d,J=9.2Hz,1H),6.80(dd,J=0.7,7.4Hz,1H),7.15(s,1H),7.25(d,J=9.2Hz,2H),7.56(d,J=8.5Hz,2H),12.46(br,1H).
MS(+):385[M+H]+.
(R,Z)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例5a)及び
(R,E)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例5b)の製造
(R,Z)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例5a)
MS(+):385[M+H]+.
(R,E)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2(1H)-オン(実施例5b)
MS(+):385[M+H]+.
ナトリウム(R,Z)-3-シクロプロピル-6-{1-[4-(1,1-ジフルオロエチル)フェニル]-2-[5-オキソピロリジン-2-イル]ビニル}ピリジン-2-オラートの製造
(特徴的なピーク)
2θ=6.8,7.5,8.6,11.4,13.1,13.5,16.0,17.3,19.5,20.6,23.5
また同測定で得られた粉末X線回折パターンを、図1に示す。
3-シクロプロピル-6-{(1R)-1-[4-(1,1-ジフルオロエチル)フェニル]-2-[(2R)-5-オキソピロリジン-2-イル]エチル}ピリジン-2(1H)-オンの製造
有機層に水(50g)を加え、攪拌後に有機層と水層に分液した。得られた有機層に対し減圧下溶媒を留去し、得られた残渣に酢酸エチル(50g)を加え、減圧下溶媒を留去した。得られた残渣にアセトニトリル(50g)を加え、減圧下溶媒を留去した。得られた残渣にアセトニトリル(70g)とトリエチルアミン(8.73g)、N,N-ジメチル-4-アミノピリジン(0.609g)を混合した後に、24℃にて二炭酸ジ-tert-ブチル(16.12g)とアセトニトリル(30g)を混合した溶液を6分かけて滴下した。40℃に昇温して1時間35分攪拌した後に減圧下溶媒を留去した。得られた残渣に10%塩化アンモニウム水溶液(100g)及び酢酸エチル(100g)を加え、混合後有機層と水層に分液した。有機層に水(50g)を加え、混合後有機層と水層に分液した。得られた水層に酢酸エチル(50g)を加えて混合後有機層と水層に分液した。得られた有機層を混合後、減圧下溶媒を留去した。得られた残渣にトルエン(30g)を加え、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=77/23→73/27,V/V)で精製し、表題化合物(12.10g,収率84.1%)を淡黄色アモルファス状物質として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.70-0.75(m,2H),1.01-1.07(m,2H),1.40(s,9H),1.58(s,9H),1.93(t,J=18.0Hz,3H),1.96-2.08(m,2H),2.44-2.62(m,3H),5.06-5.14(m,1H),6.04(d,J=9.0Hz,1H),6.91(d,J=7.8Hz,1H),7.26(d,J=7.3Hz,1H),7.28(d,J=7.0Hz,2H),7.46(d,J=8.2Hz,2H).
MS(+):585[M+H]+.
得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=71/29→65/35,V/V)で精製し、表題化合物(5.55g,収率79.1%)を白色アモルファス状物質として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.61-0.66(m,2H),0.91-0.98(m,2H),1.47-1.65(m,1H),1.48(s,9H),1.56(s,9H),1.69-1.77(m,1H),1.86-2.17(m,2H),1.88(t,J=18.2Hz,3H),2.30-2.54(m,2H),2.79-2.87(m,1H),4.07-4.16(m,2H),7.00(d,J=7.8Hz,1H),7.24(d,J=7.0Hz,1H),7.36(d,J=8.6Hz,2H),7.42(d,J=8.6Hz,2H).
MS(+):587[M+H]+.
得られた残渣にエタノールを加えて210.02gとした、18~20℃にて1時間攪拌して懸濁液とした後に3時間かけて56℃まで昇温し、1時間攪拌した。次に-2℃まで冷却した後に103時間攪拌した。得られた固体を濾過し、エタノール(120.00g)で洗浄後、60℃で減圧乾燥を行うことで表題化合物(22.22g、収率84.5%)を白色固体として得た。
1H NMR(300MHz,CDCl3)δ ppm 0.56-0.67(m,2H),0.91-0.98(m,2H),1.66-1.78(m,1H),1.89(t,J=18.1Hz,3H),2.07-2.42(m,6H),3.44-3.53(m,1H),4.08(dd,J=6.0,9.6Hz,1H),5.97(d,J=7.4Hz,1H),6.91(d,J=7.0Hz,1H),7.44(s,4H),7.49(br,1H),12.36(br,1H).
MS(+):387[M+H]+.
なお、2014年5月13日に出願された日本特許出願2014-099755号の明細書、特許請求の範囲、要約書及び図面の全内容をここに引用し、本発明の明細書の開示として、取り入れるものである。
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US15/309,997 US20170267659A1 (en) | 2014-05-13 | 2015-05-11 | Method for producing 2-pyridone compound |
KR1020167025901A KR20170003524A (ko) | 2014-05-13 | 2015-05-11 | 2-피리돈 화합물의 제조 방법 |
JP2016519247A JPWO2015174377A1 (ja) | 2014-05-13 | 2015-05-11 | 2−ピリドン化合物の製造方法 |
CN201580024710.0A CN106573909A (zh) | 2014-05-13 | 2015-05-11 | 2‑吡啶酮化合物的制造方法 |
EP15793046.2A EP3144305A4 (en) | 2014-05-13 | 2015-05-11 | Method for producing 2-pyridone compound |
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US (1) | US20170267659A1 (ja) |
EP (1) | EP3144305A4 (ja) |
JP (1) | JPWO2015174377A1 (ja) |
KR (1) | KR20170003524A (ja) |
CN (1) | CN106573909A (ja) |
TW (1) | TW201605826A (ja) |
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Citations (3)
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WO2011068211A1 (ja) * | 2009-12-04 | 2011-06-09 | 大正製薬株式会社 | 2-ピリドン化合物 |
JP2013010750A (ja) * | 2011-06-02 | 2013-01-17 | Taisho Pharmaceutical Co Ltd | 2−ピリドン化合物を含有する医薬 |
WO2014077235A1 (ja) * | 2012-11-13 | 2014-05-22 | 大正製薬株式会社 | 2-ピリドン化合物 |
-
2015
- 2015-05-11 KR KR1020167025901A patent/KR20170003524A/ko unknown
- 2015-05-11 US US15/309,997 patent/US20170267659A1/en not_active Abandoned
- 2015-05-11 WO PCT/JP2015/063509 patent/WO2015174377A1/ja active Application Filing
- 2015-05-11 CN CN201580024710.0A patent/CN106573909A/zh active Pending
- 2015-05-11 JP JP2016519247A patent/JPWO2015174377A1/ja active Pending
- 2015-05-11 EP EP15793046.2A patent/EP3144305A4/en not_active Withdrawn
- 2015-05-12 TW TW104115031A patent/TW201605826A/zh unknown
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WO2011068211A1 (ja) * | 2009-12-04 | 2011-06-09 | 大正製薬株式会社 | 2-ピリドン化合物 |
JP2013010750A (ja) * | 2011-06-02 | 2013-01-17 | Taisho Pharmaceutical Co Ltd | 2−ピリドン化合物を含有する医薬 |
WO2014077235A1 (ja) * | 2012-11-13 | 2014-05-22 | 大正製薬株式会社 | 2-ピリドン化合物 |
Non-Patent Citations (2)
Title |
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JEAN B. BAUDIN ET AL.: "A direct synthesis of olefins by reaction of carbonyl compounds with lithio derivatives of 2-[alkyl- or (2'- alkenyl)- or benzyl-sulufonyl]-benzothiazoles", TETRAHEDRON LETTERS, vol. 32, no. 9, 1991, pages 1175 - 1178, XP026648765 * |
PAUL R. BLAKEMORE: "The modified Julia olefination: alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS, vol. 1, 2002, pages 2563 - 2585, XP008157314 * |
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JPWO2015174377A1 (ja) | 2017-04-20 |
US20170267659A1 (en) | 2017-09-21 |
CN106573909A (zh) | 2017-04-19 |
KR20170003524A (ko) | 2017-01-09 |
EP3144305A4 (en) | 2017-12-27 |
TW201605826A (zh) | 2016-02-16 |
EP3144305A1 (en) | 2017-03-22 |
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