WO2015137496A1 - 複素環化合物の製造法 - Google Patents
複素環化合物の製造法 Download PDFInfo
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- WO2015137496A1 WO2015137496A1 PCT/JP2015/057541 JP2015057541W WO2015137496A1 WO 2015137496 A1 WO2015137496 A1 WO 2015137496A1 JP 2015057541 W JP2015057541 W JP 2015057541W WO 2015137496 A1 WO2015137496 A1 WO 2015137496A1
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 10
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 207
- 150000003839 salts Chemical class 0.000 claims description 119
- 239000000203 mixture Substances 0.000 claims description 81
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 238000004519 manufacturing process Methods 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 239000003446 ligand Substances 0.000 claims description 29
- 239000013543 active substance Substances 0.000 claims description 26
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 26
- 238000005984 hydrogenation reaction Methods 0.000 claims description 26
- 229910052723 transition metal Inorganic materials 0.000 claims description 26
- 150000003624 transition metals Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 239000012327 Ruthenium complex Substances 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 17
- 125000002524 organometallic group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 7
- 150000008045 alkali metal halides Chemical class 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 9
- QTNLWTQXBGSWMD-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-5-carboxamide Chemical compound NC(=O)C1=CNCCC1 QTNLWTQXBGSWMD-UHFFFAOYSA-N 0.000 abstract description 22
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 abstract description 16
- MMPLRCJXJQDXKX-UHFFFAOYSA-N NC1CN(CCC1)C1=CC(NC(N1)=O)=O Chemical class NC1CN(CCC1)C1=CC(NC(N1)=O)=O MMPLRCJXJQDXKX-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 3
- -1 nipecotic acid ester Chemical class 0.000 description 260
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 190
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 68
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 49
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 150000002430 hydrocarbons Chemical group 0.000 description 47
- 239000002904 solvent Substances 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 45
- 239000000843 powder Substances 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 229910052739 hydrogen Inorganic materials 0.000 description 29
- 239000001257 hydrogen Substances 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 27
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 27
- 229910052786 argon Inorganic materials 0.000 description 26
- 230000003287 optical effect Effects 0.000 description 26
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 25
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 23
- 239000004215 Carbon black (E152) Substances 0.000 description 23
- 229930195733 hydrocarbon Natural products 0.000 description 23
- 239000010948 rhodium Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- BVOCPVIXARZNQN-RXMQYKEDSA-N (R)-nipecotamide Chemical compound NC(=O)[C@@H]1CCCNC1 BVOCPVIXARZNQN-RXMQYKEDSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 125000003710 aryl alkyl group Chemical group 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- 125000003277 amino group Chemical group 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- 229910020366 ClO 4 Inorganic materials 0.000 description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 238000001514 detection method Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000010926 purge Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 239000012453 solvate Substances 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000654 additive Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 235000011181 potassium carbonates Nutrition 0.000 description 11
- 238000006462 rearrangement reaction Methods 0.000 description 11
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical class [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 10
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 description 10
- WDPBPLYUYCRNEA-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)[O-].C(N)(=O)C=1CCC[NH2+]C=1 Chemical compound CC1=CC=C(C=C1)S(=O)(=O)[O-].C(N)(=O)C=1CCC[NH2+]C=1 WDPBPLYUYCRNEA-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000000996 additive effect Effects 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000010949 copper Substances 0.000 description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 150000007529 inorganic bases Chemical class 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- 241000907661 Pieris rapae Species 0.000 description 7
- 235000010233 benzoic acid Nutrition 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
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- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 6
- 150000003303 ruthenium Chemical class 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 6
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 6
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 5
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
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- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical class [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000006337 tetrafluoro ethyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005950 trichloromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003754 zirconium Chemical class 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5027—Polyphosphines
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- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
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- B01J2531/0202—Polynuclearity
- B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
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Definitions
- the present invention relates to a method for producing an optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative useful as a dipeptidyl peptidase inhibitor, Further, the present invention relates to various intermediates useful for the same and methods for producing them.
- Optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative is useful as a dipeptidyl peptidase inhibitor and a therapeutic agent for diabetes It has been known.
- 6- (3-aminopiperidine is obtained by reacting an optically active form of 3-aminopiperidine with a 6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative.
- -1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivatives are disclosed.
- a racemic 3-aminopiperidine is acylated with phthalic anhydride, and the resulting 3-phthalimidopiperidine is optically resolved with optically active tartaric acid and coupled with a xanthine ring.
- Patent Document 3 discloses a method for optical resolution of a racemic isomer of piperidine-3-carboxamide using optically active lactic acid.
- Patent Document 4 a racemic form of piperidine-3-carboxamide is stereoselectively hydrolyzed by an enzyme derived from a microorganism, and after derivatization of optically active piperidine-3-carboxamide, an optically active form of nipecotic acid is obtained from the mixture.
- a method for producing an optically active form of a piperidine-3-carboxamide derivative by separating and removing is disclosed.
- the document also discloses a method for producing an optically active form of 3-aminopiperidine from an optically active form of a piperidine-3-carboxamide derivative by utilizing the Hoffman rearrangement.
- Non-Patent Document 1 discloses a method of obtaining an optically active nipecotic acid ester derivative by asymmetric reduction of a tetrahydropyridinecarboxylic acid ester derivative using a ruthenium complex.
- the object of the present invention is to use an optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative by using a relatively inexpensive raw material. It is to provide a method of manufacturing automatically. Another object of the present invention is useful for producing optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivatives. It is to provide various intermediates and methods for producing them.
- the present invention is as follows.
- R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or a protecting group
- R 2 , R 3 and R 4 independently represent A hydrogen atom or a substituent
- R 5 and R 6 independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group
- R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 may be taken together to form a 5- to 8-membered ring with adjacent atoms.
- the compound represented by the formula or a salt thereof is subjected to a hydrogenation reaction in the presence of an organometallic complex, formula:
- R A , R B , R C and R D independently represent a hydrogen atom or an optionally substituted hydrocarbon group; X represents a halogen atom.
- R 2 ′ , R 3 ′ and R 4 ′ each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R 2 ′ and R 3 ′ or R 3 ′ and R 4 ′ may be taken together to form a 5- to 8-membered ring with adjacent atoms; a carbon atom marked with * represents an asymmetric carbon atom.
- R 7 and R 8 independently represent an optionally substituted hydrocarbon group, a hydrogen atom, or an optionally substituted heterocyclic group; L 1 represents a leaving group.
- R 2 ', R 3' and R 4 ' are independently a hydrogen atom, a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,, R 2' And R 3 ′ or R 3 ′ and R 4 ′ together may form a 5- to 8-membered ring with adjacent atoms; R 7 and R 8 may be independently substituted A good hydrocarbon group, a hydrogen atom, or an optionally substituted heterocyclic group; a carbon atom marked with * represents an asymmetric carbon atom.
- An optically active substance comprising a compound represented by the formula or a mixture thereof, and formula (2):
- an optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative can be efficiently and highly purified with a higher purity. It can be produced in a yield.
- the derivatives are useful as dipeptidyl peptidase inhibitors and diabetes therapeutics.
- the present invention also provides various intermediates useful for producing optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivatives. Bodies and their efficient manufacturing methods can be provided.
- a ruthenium complex useful for a hydrogenation reaction can be provided.
- each substituent has the following definition.
- examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
- examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl.
- Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
- examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
- examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
- examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
- the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
- examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
- examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
- examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
- the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
- Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
- Examples include oxy and hexyloxy.
- examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
- examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
- the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
- examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
- examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
- examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
- a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
- examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
- examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
- examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
- examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
- examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
- examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
- examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
- examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
- the "optionally halogenated C 1-6 alkyl sulfonyl group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
- examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
- examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
- examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
- An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
- examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
- examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
- substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
- the number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
- examples of the “heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
- an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
- the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
- non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, t
- preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
- examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
- examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
- the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
- acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
- the “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
- the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
- the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
- the hydrocarbon-sulfinyl group is a hydrocarbon group.
- a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
- the “acyl group” a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered
- Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
- examples of the “optionally substituted amino group” include, for example, a C 1-6 alkyl group each having 1 to 3 substituents selected from the substituent group A, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7- 16- aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group Mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 7-16 aralkyl-carbamoyl group, C 1-6 alkylsulfonyl group and C 6-1 And an amino group optional
- Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
- examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
- Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
- Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
- mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
- mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
- a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
- pyridylcarbamoyl pyridylcarb
- examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
- thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
- examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
- the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
- examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
- Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
- C 3-10 cycloalkyloxy group eg, cyclohexyloxy
- C 6-14 aryloxy group eg, phenoxy, naphthyloxy
- C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
- C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
- C 6-14 aryl-carbonyloxy group eg, benzoyloxy
- C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
- 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
- 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
- examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
- C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
- the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
- examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
- a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
- Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
- R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or a protecting group.
- hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 1 include a C 1-6 alkyl group, a C 3-10 cycloalkyl group, and a C 6-14 aryl. Group, C 7-16 aralkyl group and the like.
- heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 is preferably selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. And (i) an aromatic heterocyclic group and (ii) a non-aromatic heterocyclic group each containing 4 to 4 heteroatoms.
- the “protecting group” represented by R 1 represents a known protecting group for an amino group, and preferred examples include amide-type protecting groups such as formyl group, acetyl group, and benzoyl group; 9-fluorenylmethoxycarbonyl And carbamate-type protecting groups such as a tert-butoxycarbonyl group and a benzyloxycarbonyl group.
- amide-type protecting groups such as formyl group, acetyl group, and benzoyl group
- carbamate-type protecting groups such as a tert-butoxycarbonyl group and a benzyloxycarbonyl group.
- amino protecting groups described in Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1998, John Wiley & Sons, Inc. can be referred to.
- R 1 is preferably a hydrogen atom.
- R 2 , R 3 and R 4 independently represent a hydrogen atom or a substituent.
- Preferred examples of the “substituent” represented by R 2 , R 3 or R 4 include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, and an optionally substituted heterocyclic ring.
- An optionally substituted hydrocarbon group or an optionally substituted heterocyclic group is more preferable.
- R 2 , R 3 and R 4 are preferably independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl A group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, or an optionally substituted silyl group; more preferably independently hydrogen An atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; particularly preferably a hydrogen atom.
- R 5 and R 6 independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
- hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 5 or R 6 is preferably a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 6 A -14 aryl group, a C 7-16 aralkyl group, and the like.
- heterocyclic group in the “optionally substituted heterocyclic group” represented by R 5 or R 6 include a nitrogen atom, a sulfur atom, and an oxygen atom as a ring atom in addition to a carbon atom.
- R 5 or R 6 a nitrogen atom, a sulfur atom, and an oxygen atom as a ring atom in addition to a carbon atom.
- R 5 and R 6 are preferably a hydrogen atom.
- R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 may be combined to form a 5- to 8-membered ring with adjacent atoms.
- Preferred examples of the “5- to 8-membered ring” formed by R 2 and R 3 , or R 3 and R 4 include a C 5-8 cycloalkane ring, a C 5-8 cycloalkene ring, and a 5- to 8-membered single ring. And cyclic non-aromatic heterocycles.
- Examples of the “C 5-8 cycloalkane ring” exemplified as the “5- to 8-membered ring” include rings such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
- Examples of the “C 5-8 cycloalkene ring” exemplified as the “5- to 8-membered ring” include rings such as cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
- the “5- to 8-membered monocyclic non-aromatic heterocycle” exemplified as the “5- to 8-membered ring” includes a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- Suitable examples of the “5- to 8-membered ring” formed by R 1 and R 2 , or R 5 and R 6 together with adjacent atoms include a 5- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic ring and the like. Can be mentioned.
- the “5- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic ring” exemplified as the “5- to 8-membered ring” contains at least one nitrogen atom in addition to the carbon atom as a ring-constituting atom, And 5- to 8-membered monocyclic non-aromatic heterocycle optionally containing a heteroatom selected from a sulfur atom and an oxygen atom, such as pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, Oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, isoxazoline, isothiazoline, tetrahydroisothiazole (isothiazolidine), tetrahydroisoxazole (isoxazolidine), piperidine, piperazine, tetrahydropyridine, dihydropyridine, tetrahydropyrimidine, dihydr
- a compound of formula (I) is represented by the formula:
- the compound represented by formula (I) is a compound represented by formula (I ′); and the compound represented by formula (II) is a compound represented by formula (II ′).
- the compound represented by the formula (I) is 1,4,5,6-tetrahydropyridine-3-carboxamide; and the compound represented by the formula (II) is piperidine-3-carboxamide.
- the compound represented by the formulas (I) and (II) may be a salt.
- salts of the compounds represented by formulas (I) and (II) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. And the like.
- Suitable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
- the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. And the salt.
- salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, etc. Is mentioned.
- Suitable examples of salts with organic acids include carboxylic acids (ie, organic compounds having one or more carboxy groups; specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, Oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, etc.); sulfonic acid (that is, an organic compound having one or more sulfo groups; specific examples include methanesulfonic acid, trifluoromethanesulfonic acid, benzene) Salts with sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc.).
- carboxylic acids ie, organic compounds having one or more carboxy groups; specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, Oxalic acid, tartaric acid, maleic acid, citric acid,
- salts with basic amino acids include salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
- the salt of the compound represented by formula (I) and (II) is preferably a salt with an organic acid or a salt with an inorganic acid; more preferably a salt with a sulfonate or sulfuric acid; Preferably, it is a sulfonate.
- the sulfonate refers to a salt with an organic compound having one or more sulfo groups, preferably formula: R b SO 3 H (VII) [Wherein, R b represents an optionally substituted hydrocarbon group. ] It is a salt with the compound represented by these.
- the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R b is preferably a C 1-6 alkyl group, a C 3-10 cycloalkyl group.
- R b is preferably an optionally substituted C 6-14 aryl group; more preferably an optionally substituted phenyl group; and still more preferably C 1 A phenyl group optionally substituted by a -6 alkyl group; particularly preferred is a phenyl group optionally substituted by methyl.
- the compound represented by the formula (VII) is preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid. It is.
- the compound represented by the formula (I) or a salt thereof is preferably a salt of 1,4,5,6-tetrahydropyridine-3-carboxamide with sulfonic acid.
- the optically active form of the compound represented by the formula (II) or a salt thereof is preferably a salt of piperidine-3-carboxamide with an optically active form of sulfonic acid.
- the compound represented by the formula (I) or a salt thereof is particularly preferably 1,4,5,6-tetrahydropyridine-3-carboxamide paratoluenesulfonate.
- the optically active form of the compound represented by the formula (II) or a salt thereof is particularly preferably paratoluenesulfonic acid salt of piperidine-3-carboxamide.
- the compounds represented by the formulas (I) and (II) may be solvates (eg, hydrate, ethanol solvate, etc.) or non-solvates (eg, nonhydrate, etc.), respectively. Both are included in compounds (I) and (II).
- R represents an optionally substituted hydrocarbon group.
- the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R is preferably a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, And a C 7-16 aralkyl group. Among them, a C 1-6 alkyl group and a C 6-14 aryl group are preferable, and a C 6-14 aryl group is more preferable.
- R is preferably an optionally substituted C 6-14 aryl group; more preferably an optionally substituted phenyl group; more preferably a C 1-6 alkyl group. It may be a phenyl group. R is particularly preferably a phenyl group optionally substituted by methyl.
- R 2 ′ , R 3 ′ and R 4 ′ each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
- R 2 ′ , R 3 ′ and R 4 ′ are preferably a hydrogen atom.
- R 2 ′ and R 3 ′ , or R 3 ′ and R 4 ′ may be taken together to form a 5- to 8-membered ring with adjacent atoms.
- Preferred examples of the “5- to 8-membered ring” formed by R 2 ′ and R 3 ′ , or R 3 ′ and R 4 ′ include “5” formed by R 2 and R 3 , or R 3 and R 4. The thing similar to the suitable thing of "thru
- R 7 and R 8 independently represent an optionally substituted hydrocarbon group, a hydrogen atom, or an optionally substituted heterocyclic group.
- a preferable “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 7 is a C 6-14 aryl group.
- heterocyclic group in the “optionally substituted heterocyclic group” represented by R 7 is 1 to 3 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom.
- hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 7 and the “heterocyclic group” in the “optionally substituted heterocyclic group” are each in a substitutable position. It may have 1 to 5 (preferably 1 to 3) substituents. Examples of such a substituent include the above substituent group A.
- the substituent is preferably a halogen atom, more preferably a fluorine atom.
- R 7 is preferably an optionally substituted C 6-14 aryl group; more preferably an optionally substituted phenyl group; still more preferably a halogen atom (eg, fluorine atom) and A phenyl group which may be substituted with 1 to 3 substituents selected from a cyano group.
- R 7 include a phenyl group substituted with a cyano group, a cyano group, and a phenyl group substituted with a fluorine atom. Of these, a phenyl group substituted with a cyano group is preferred.
- Suitable examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 8 include a C 1-6 alkyl group.
- R 8 is preferably a hydrogen atom or a C 1-6 alkyl group; more preferably a C 1-6 alkyl group; and still more preferably a methyl group.
- L 1 represents a leaving group
- Examples of the leaving group represented by L 1 include a halogen atom; C 1-6 alkylsulfonyloxy which may be halogenated such as methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy and the like.
- a C 6-10 arylsulfonyloxy group optionally having 1 to 3 substituents selected from a C 1-6 alkoxy group and a nitro group); acyloxy groups such as trichloroacetoxy and trifluoroacetoxy .
- a suitable leaving group represented by L 1 is a halogen atom, and a chlorine atom is particularly preferred.
- the compound of formula (I ′) is 1,4,5,6-tetrahydropyridine-3-carboxamide;
- the compound represented by formula (II ′) is piperidine-3-carboxamide;
- the compound represented by formula (IV) is represented by the formula:
- R E is a hydrogen atom or a fluorine atom; R 8 and L 1 are as defined above.
- the compound represented by formula (IV) is represented by the formula:
- the compound of formula (I ′) is 1,4,5,6-tetrahydropyridine-3-carboxamide;
- the compound represented by formula (II ′) is piperidine-3-carboxamide;
- the compound represented by formula (III) is represented by the formula:
- R E is particularly preferably a hydrogen atom.
- the compounds represented by formulas (I ′) and (II ′) are preferably salts.
- Examples of the salt of the compound represented by the formulas (I ′) and (II ′) include those similar to the salt of the compound represented by the formula (I) and (II). The thing is the same as that suitable as a salt of the compound represented by Formula (I) and (II).
- the compound represented by the formula (I ′) or a salt thereof is preferably a salt of 1,4,5,6-tetrahydropyridine-3-carboxamide with sulfonic acid.
- the optically active form of the compound represented by the formula (II ′) or a salt thereof is preferably a salt of piperidine-3-carboxamide with an optically active form of sulfonic acid.
- the compound represented by the formula (I ′) or a salt thereof is particularly preferably 1,4,5,6-tetrahydropyridine-3-carboxamide paratoluenesulfonate.
- the optically active form of the compound represented by the formula (II ′) or a salt thereof is particularly preferably a paratoluenesulfonic acid salt of piperidine-3-carboxamide.
- Examples of the salt of the compound represented by the formulas (III), (IV) and (V) include the same salts as the salts of the compound represented by the formulas (I) and (II).
- the compounds represented by the formulas (I ′), (II ′), (III), (IV) and (V) may be solvates (eg, hydrates, ethanol solvates, etc.), respectively. , Solvates (eg, non-hydrates, etc.), all of which are represented by the compounds represented by formulas (I ′), (II ′), (III), (IV) and (V). Is included.
- optically active form of the compound represented by the formula (II) or a salt thereof can be produced by the production method (A) shown in the following reaction formula.
- a compound represented by the formula (I) or a salt thereof is subjected to a hydrogenation reaction in the presence of an organometallic complex, thereby producing an optically active form of the compound represented by the formula (II) or a compound thereof.
- a method for producing a salt is described in detail below.
- Organic metal complexes include, in addition to “transition metal complexes (organic transition metal complexes)”, typical metal complexes such as boron complexes, aluminum complexes, and gallium complexes.
- a suitable “organic metal complex” is “transition metal complex (organic transition metal complex)”.
- Examples of the “transition metal complex” include a compound having a catalytic ability of asymmetric hydrogenation reaction in which a “ligand” (preferably an optically active “ligand”) is coordinated to the “transition metal”.
- a “ligand” preferably an optically active “ligand”
- the optically active “ligand” include a phosphine ligand, a diphosphine ligand, an amine ligand, a diamine ligand, and a phosphineamine ligand.
- the “transition metal” is, for example, 0 to 6 valent, preferably 0 to 4 valent, and particularly preferably 0 to 3 valent.
- rhodium complex As the “transition metal complex”, rhodium complex, ruthenium complex, iridium complex, palladium complex, nickel complex, copper complex, osmium complex, platinum complex, iron complex, gold complex, silver complex, zinc complex, titanium complex, cobalt complex , Zirconium complexes, samarium complexes, etc .; more preferably rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes and copper complexes; more preferably rhodium complexes, ruthenium complexes and iridium complexes; A ruthenium complex is preferable.
- transition metal complex formula L is a diphosphine ligand
- Cp * is pentamethylcyclopentadienyl
- Cp is cyclopentadienyl
- cod is 1,5-cyclo octadiene
- Tf is trifluoromethanesulfonyl
- nbd is norbornadiene
- Ph is phenyl
- Ac is acetyl
- Et is ethyl
- dmf N, N- dimethylformamide
- 2-methylallyl is eta 3-2-methylallyl
- en is ethylenediamine
- daipen is 1,1-di 4-anis
- Rhodium complexes [RhCl (L)] 2 , [RhBr (L)] 2 , [RhI (L)] 2 , [RhCp * (L)] 2 , [Rh (cod) (L)] OTf, [Rh ( cod) (L)] BF 4 , [Rh (cod) (L)] ClO 4 , [Rh (cod) (L)] PF 6 , [Rh (cod) (L)] SbF 6 , [Rh (cod) (L)] BPh 4 , [Rh (cod) (L)] B ⁇ 3,5- (CF 3 ) 2 C 6 H 3 ⁇ 4 , [Rh (nbd) (L)] OTf, [Rh (nbd) (L)] BF 4 , [Rh (nbd) (L)] ClO 4 , [Rh (nbd) (L)] PF 6 , [Rh (n
- Iridium complexes [IrCl (L)] 2 , [IrBr (L)] 2 , [IrI (L)] 2 , [IrCp * (L)] 2 , [Ir (cod) (L)] OTf, [Ir ( cod) (L)] BF 4 , [Ir (cod) (L)] ClO 4 , [Ir (cod) (L)] PF 6 , [Ir (cod) (L)] SbF 6 , [Ir (cod) (L)] BPh 4 , [Ir (nbd) (L)] B ⁇ 3,5- (CF 3 ) 2 C 6 H 3 ⁇ 4 , [Ir (nbd) (L)] OTf, [Ir (nbd) (L)] BF 4 , [Ir (nbd) (L)] ClO 4 , [Ir (nbd) (L)] PF 6 ,
- diphosphine ligand represented by L examples include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter sometimes abbreviated as BINAP); BINAP derivatives having a substituent such as a C 1-6 alkyl group or a C 6-14 aryl group on the naphthyl ring of BINAP, such as 2,2′-bis (diphenylphosphino) -6,6′-dimethyl-1, 1′-binaphthyl; BINAP derivatives in which the naphthyl ring of BINAP is partially hydrogenated, such as 2,2′-bis (diphenylphosphino) -5,6,7,8,5 ′, 6 ′, 7 ′, 8′-octahydro -1,1'-binaphthyl (H8BINAP); 1 to 5 substituents such as a C 1-6 alkyl group, a halogen atom,
- the diphosphine ligand represented by L is preferably an optically active substance.
- An optically active ligand is used as the “ligand” used in the “transition metal complex”.
- the “transition metal complex” is obtained from a ligand and another complex serving as a transition metal source by known means (production of a rhodium complex; Journal of the American Chemical Society (J. Am. Chem. Soc. 94, 6429, 1972, Organic Synthesis (Org. Synth.), 67, 33, 1989: Production of ruthenium complexes; Journal of Organic Chemistry (J. Org. Chem). 57), 4053, 1992, Tetrahedron Asym., 2, 43, 1991, Journal of Organic Chemistry (J. Org. Chem.), Volume 59, p. 3064, 1994, Angelevante Hemy International Ed. Chem. Int. Ed., 37, 1703, 1998: Production of Iridium Complex; J. Organomet.
- the “transition metal complex” can also be prepared by adding “ligand” and another complex serving as a transition metal source to the reaction system.
- the “transition metal complex” may itself be added to the reaction vessel, but may be prepared by adding the “transition metal” and the “ligand” to the vessel.
- “transition metal complex” is prepared by adding “transition metal” and “ligand” to the container, 1 to 100 times the theoretical amount necessary to constitute “transition metal complex”
- a rhodium complex of a SKEWPHOS derivative having 1 to 5 substituents such as a C 1-6 alkyl group on one benzene ring on the phosphorus atom of SKEWPHOS is And can be synthesized by the method described in Patent Document WO2013 / 146987.
- the “transition metal complex” is exemplified by [Ru (OAc) 2 (L)] or [Ru (OCOCF 3 ) 2 (L)] among the “ruthenium complexes”.
- the ruthenium complex represented by these is preferable.
- Suitable as "C 1-3 alkyl group" in the "optionally substituted C 1-3 alkyl group” represented by R a include methyl, ethyl, isopropyl, particularly preferably is methyl .
- C 1-3 alkyl group” in the "optionally substituted C 1-3 alkyl group” represented by R a are each 1 to 5 at substitutable positions (preferably 1 to 3) You may have the substituent of. Examples of such a substituent include the above substituent group A.
- the substituent is preferably a halogen atom, more preferably a fluorine atom. When a plurality of substituents are present, each substituent may be the same or different.
- the “optionally substituted C 1-3 alkyl group” represented by R a is preferably methyl or trifluoromethyl, more preferably trifluoromethyl.
- the diphosphine ligand represented by L a include the same ones as exemplified for L; Among them preferably, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (Hereinafter sometimes abbreviated as BINAP); BINAP derivatives having a substituent such as a C 1-6 alkyl group or a C 6-14 aryl group on the naphthyl ring of BINAP, such as 2,2′-bis (diphenylphosphine) Fino) -6,6′-dimethyl-1,1′-binaphthyl; a BINAP derivative in which the naphthyl ring of BINAP is partially hydrogenated, such as 2,2′-bis (diphenylphosphino) -5,6, 7,8,5 ′, 6 ′, 7 ′, 8′-octahydro-1,1′-binaphthyl (H8BINAP); a
- the ruthenium complex represented by the formula (VIII) is preferably formula: [Ru (OCOR a ′) 2 L a ′] (VIII ′) [Wherein R a ′ represents a trifluoromethyl group; L a ′ represents an optically active substance of a diphosphine ligand, (1) Formula:
- An optically active substance comprising a compound represented by the formula or a mixture thereof, and formula (2):
- a bond marked with * indicates an asymmetric axis.
- It is chosen from the optically active substance of the compound represented by these.
- It is a ruthenium complex represented by these.
- the optically active substance composed of the above-mentioned mixture is a compound in which L a ′ is an optically active substance of a compound represented by the formula (IX- a ) and L a ′ is a compound represented by the formula (IX-b).
- the ruthenium complex represented by the formula (VIII) or (VIII ′) is described in, for example, JP-A-62-265293 and Tetrahedron Letters, 39, 4441, 1998. It can be synthesized by referring to the method. These ruthenium complexes are useful as catalysts having high reaction selectivity in various hydrogenation reactions such as the production method (A). Specific examples of suitable ruthenium complexes include the following complexes.
- the amount of the “transition metal complex” used varies depending on the reaction vessel, reaction mode, etc., but is about 1.0 to about 1 to 1 mol of the compound represented by the formula (I) as a substrate or a salt thereof. About 0.00001 mol.
- hydrogen gas in the “hydrogenation reaction” in the production method (A), hydrogen gas, metal hydride, isopropanol, formic acid, benzothiazoline, Hantzsch ester and the like can be used as a hydride donor, and among them, hydrogen gas is used. It is preferable.
- the hydrogen gas In the case of using hydrogen gas, it can be carried out by either batch type or continuous type reaction.
- the hydrogen pressure is, for example, 0.001 to 200 atmospheres, preferably 0.1 to 15 atmospheres.
- an additive such as a base, an acid, or a salt may be added as necessary. Moreover, you may use an additive in mixture of 2 or more types. The additive may be added to the reaction vessel before starting the “hydrogenation reaction”, but may be added during the “hydrogenation reaction”.
- an inorganic base or an organic base can be used as a base that may be added to the “hydrogenation reaction” in the production method (A).
- the inorganic base include alkali metal hydroxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide; lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium Alkali metal alkoxides having 1 to 6 carbon atoms such as ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide; sodium thiomethoxide C1-C6 alkali metal thioalkoxides such as; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate; sodium acetate, Acetates such as potassium, tripotassium phosphat
- organic base examples include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, and ethylenediamine; pyridine, picoline, N, N-dimethylaniline, and the like.
- Aromatic amines and basic amino acids such as arginine, lysine, ornithine and the like can be mentioned.
- the amount of the base used varies depending on the type of solvent and other reaction conditions, but is usually about 0.01 mol or more with respect to 1 mol of the compound represented by the formula (I) as a substrate or a salt thereof, It can also be used as a solvent.
- Examples of the acid that may be added to the “hydrogenation reaction” in the production method (A) include mineral acids (specifically, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, Sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, etc.); carboxylic acid (ie, a compound having one or more carboxy groups; specifically, formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid) Acids, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, etc.); acidic amino acids (specifically, aspartic acid, glutamic acid, etc.); sulfonic acids (ie, one or more sulfo groups) Compounds, such as methane sulfonic acid, trifluoromethane sulfonic acid, benzene s
- the acid that may be used for the “hydrogenation reaction” in the production method (A) is preferably sulfonic acid and sulfuric acid; more preferably, sulfonic acid.
- the sulfonic acid refers to a compound having one or more sulfo groups, preferably a sulfonic acid represented by the above formula (VII); more preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfone. Acid, p-toluenesulfonic acid; particularly preferred is p-toluenesulfonic acid.
- the amount of the acid used varies depending on the type of solvent and other reaction conditions, but is usually about 0.01 mol or more with respect to 1 mol of the compound represented by the formula (I) as a substrate or a salt thereof, It can also be used as a solvent.
- the amount is preferably 0.05 to 1.5 mol.
- the salt that may be added to the “hydrogenation reaction” in the production method (A) include the above-mentioned “acid” that can be used in the “hydrogenation reaction” in addition to the salts exemplified in the “inorganic base” above.
- R A , R B , R C and R D independently represent a hydrogen atom or an optionally substituted hydrocarbon group; X represents a halogen atom.
- the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R A , R B , R C and R D is preferably a C 1-6 alkyl group, C 3-10 Examples thereof include a cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, and the like.
- the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R A , R B , R C and R D is particularly preferably n-butyl.
- the “alkali metal halide” exemplified as the “salt” that may be added to the “hydrogenation reaction” in the production method (A) is an anion of a halogen atom (eg, chlorine, bromine, iodine) and an alkali metal.
- a halogen atom eg, chlorine, bromine, iodine
- alkali metal eg, lithium, sodium, potassium, cesium
- cation salt preferably lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride, potassium chloride, lithium iodide, iodine
- Sodium bromide and potassium iodide more preferably lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride and potassium chloride; particularly preferred is potassium bromide.
- the “alkali metal halide” may be a hydrate.
- Suitable compounds represented by the above formula (VI) are tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, and normal butylammonium chloride.
- the amount of the compound (salt having a halogen anion) to be used varies depending on the type of solvent and other reaction conditions, but is usually 1 to 100 equivalents, preferably 2 to 20 equivalents, relative to the organometallic complex. is there.
- the “salt” that may be added to the “hydrogenation reaction” in the production method (A) is preferably an alkali metal halide; particularly preferably potassium bromide.
- the “hydrogenation reaction” in the production method (A) is usually performed in a solvent.
- a solvent is not particularly limited as long as it can solubilize the raw material compound, the organometallic complex and the additive without inhibiting the reaction.
- methanol ethanol N-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2- Et
- Suitable solvents used in the “hydrogenation reaction” in the production method (A) are alcohols, preferably methanol, ethanol and isopropanol, and particularly preferably isopropanol.
- the amount of the solvent used is appropriately determined depending on the solubility of the compound represented by the formula (I) as a substrate or a salt thereof.
- an alcohol preferably isopropanol
- the reaction is carried out in a solvent at least 100 times the weight of the compound represented by the formula (I) or a salt thereof as a substrate from a state close to no solvent.
- the reaction temperature is usually ⁇ 30 to 160 ° C., preferably 0 to 120 ° C., more preferably 10 to 80 ° C.
- the reaction time is usually 0.1 to 120 hours, preferably 1 to 72 hours.
- optically active form of the compound represented by the formula (II) obtained by the “hydrogenation reaction” or a salt thereof is purified by a known means (eg, fractional recrystallization method, chiral column method, diastereomeric salt method). May be.
- a fractional recrystallization method or a diastereomeric salt method represented by the formula (II).
- the optically active compound or its salt is a paratoluenesulfonic acid salt of piperidine-3-carboxamide, it is particularly preferred to purify it as it is by fractional recrystallization.
- Production method (A) can be used for the production of more complex optically active compounds or salts thereof in combination with another reaction. Below, the manufacturing method of the optically active substance or its salt of the compound represented by Formula (V) using manufacturing method (A) is demonstrated.
- step B-1 the compound represented by formula (II ′) is subjected to an asymmetric hydrogenation reaction by subjecting the compound represented by formula (I ′) or a salt thereof as shown in the following reaction formula.
- This is a process for producing an optically active substance or a salt thereof.
- the asymmetric hydrogenation reaction of Step B-1 was performed by using the compound represented by the formula (I ′) instead of the compound represented by the formula (I), whereby the product represented by the formula (II)
- the production method (A) is the same as the production method (A) except that the optically active form of the compound represented by the formula is changed to the optically active form of the compound represented by the formula (II ′).
- the compound represented by the formula (I ′) is, for example, Journal of Organic Chemistry (J. Org. Chem.), Vol. 31, p. 2487, 1966 and Journal of Organic Chemistry (J. Org). Chem.), 33, 747, 1968.
- Step B-2 In the step B-2, as shown in the following reaction formula, the optically active form of the compound represented by the formula (II ′) obtained in the step B-1 or a salt thereof and the compound represented by the formula (III) or In this step, the salt is subjected to a condensation reaction to produce an optically active compound of the compound represented by formula (IV) or a salt thereof.
- the compound represented by the formula (III) can be synthesized, for example, by the method described in International Publication WO2007-035629.
- the amount of the compound represented by the formula (III) or a salt thereof varies depending on the kind of the solvent and other reaction conditions, but relative to 1 mol of the optically active compound of the compound represented by the formula (II ′) or a salt thereof. In general, the amount is 0.01 to 100 mol, preferably 0.1 to 10 mol, and more preferably 0.9 to 1.1 mol.
- the reaction in step B-2 is usually carried out in a solvent, and a convenient base may be added to promote the reaction.
- the solvent is not particularly limited as long as it can solubilize the raw material compound, the organometallic complex, and the additive without inhibiting the reaction.
- solvents may be mixed and used at an appropriate ratio.
- Suitable solvents for use in step B-2 are alcohols, with isopropanol being particularly preferred.
- the amount of the solvent used is appropriately determined depending on the solubility of the optically active compound of the compound represented by the formula (II ′) or a salt thereof.
- an alcohol preferably isopropanol
- the solvent is used in a solvent at least 100 times by weight of the optically active compound of the compound represented by the formula (II ′) or a salt thereof from a state close to no solvent.
- the reaction can be carried out, it is preferable to use about 2 to about 100 times by weight of the solvent with respect to the optically active form of the compound represented by the formula (II ′) which is usually a substrate or a salt thereof.
- Examples of the base that may be used in Step B-2 include inorganic bases and organic bases.
- Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide; lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium Alkali metal alkoxides having 1 to 6 carbon atoms such as ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide; sodium thiomethoxide C1-C6 alkali metal thioalkoxides such as; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate; sodium acetate, Acetates such as potassium, tripotassium phosphate, phosphate salts such as sodium phosphat
- organic base examples include aliphatics such as trimethylamine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, and 1,8-diazabicyclo [5.4.0] undecene.
- potassium carbonate is particularly preferable.
- the amount of the base used varies depending on the type of solvent and other reaction conditions, but is usually about 0.01 mol or more with respect to 1 mol of the optically active compound of the compound represented by formula (II ′) or a salt thereof. Yes, it can also be used as a solvent.
- the amount of the base used is preferably 0.5 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the optically active compound of the compound represented by formula (II ') or a salt thereof.
- the reaction temperature is usually ⁇ 30 ° C. to 160 ° C., preferably 0 to 120 ° C., more preferably 30 to 90 ° C.
- the reaction time is usually 0.1 to 120 hours, preferably 1 to 72 hours.
- optically active form of the compound represented by the formula (IV) obtained in Step B-2 or a salt thereof is purified by a known means (eg, fractional recrystallization method, chiral column method, diastereomeric salt method). Also good.
- step B-3 the optically active form of the compound represented by compound (IV) or a salt thereof is subjected to a rearrangement reaction, whereby the optical property of the compound represented by compound (V) is determined.
- This is a process for producing an active form or a salt thereof.
- the rearrangement reaction in Step B-3 is preferably performed using an oxidizing agent.
- the “oxidant” include potassium hypochlorite, sodium hypochlorite, tert-butyl hypochlorite, potassium hypobromite, sodium hypobromite, potassium hypoiodite, hypochlorous acid, and the like.
- hypohalites such as sodium iodate; lead tetraacetate; halogens such as bromine and iodine; halogenated imide reagents such as N-bromosuccinimide and N-iodosuccinimide; iodobenzene diacetate, [bis (trifluoro Hypervalent iodine reactants such as acetoxy) iodo] benzene, iodotoluene diacetate, and [bis (trifluoroacetoxy) iodo] toluene are used.
- a suitable oxidizing agent for the rearrangement reaction in Step B-3 is a hypervalent iodine reactant, more preferably iodobenzene diacetate.
- the amount of the oxidizing agent used varies depending on the type of solvent and other reaction conditions, but is usually 0.01 to 100 mol with respect to 1 mol of the optically active compound of the compound represented by formula (IV) or a salt thereof. Yes, preferably 0.1 to 10 mol, and more preferably 0.9 to 2 mol.
- an additive such as a base, an acid, or a salt may be added. You may mix and use 2 or more types of additives as needed.
- the additive may be added to the reaction vessel before starting the rearrangement reaction, or may be added during the rearrangement reaction.
- Examples of the base that may be added to the rearrangement reaction in Step B-3 include inorganic bases and organic bases.
- the inorganic base examples include alkali metal hydroxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide; lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium Alkali metal alkoxides having 1 to 6 carbon atoms such as ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide; sodium thiomethoxide C1-C6 alkali metal thioalkoxides such as; carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; sodium acetate Acetates such as potassium acetate; tripotassium phosphate, phosphate salts such as sodium phosphate; potassium monohydrogen phosphate include phosphoric acid monohydrogen salt such as sodium mono
- organic base examples include aliphatics such as trimethylamine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, and 1,8-diazabicyclo [5.4.0] undecene.
- the amount of the base used varies depending on the type of solvent and other reaction conditions, but is usually about 0.001 mol with respect to 1 mol of the optically active compound of the compound represented by formula (IV) or a salt thereof.
- the amount is preferably 0.001 to 10 mol, more preferably 0.01 to 2 mol, and can also be used as a solvent.
- Examples of the acid that may be added to the rearrangement reaction in Step B-3 include mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and sulfurous acid; phosphoric acid, Phosphoric acid, carbonic acid, bicarbonate; formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid and other carboxylic acids; acidic aspartic acid, glutamic acid, etc.
- mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and sulfurous acid
- phosphoric acid, Phosphoric acid carbonic acid, bicarbonate
- formic acid acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tart
- Amino acids; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like may be used, and two or more kinds may be used as necessary.
- the amount of acid used varies depending on the type of solvent and other reaction conditions, but is usually 0.001 mol or more with respect to 1 mol of the optically active compound of the compound represented by formula (IV) or a salt thereof, The amount is preferably 0.001 to 10 mol, more preferably 0.01 to 2 mol, and can also be used as a solvent.
- Examples of the salt that may be added to the rearrangement reaction in Step B-3 include the above-mentioned “acid” that can be used in the rearrangement reaction in addition to the salt exemplified in the above “inorganic base” as an acid component. Among them, a salt having a halogen anion is preferable. Examples of the salt having a halogen anion include alkali metal halides as described above, ammonium salts represented by the above formula (VI), and the like.
- the amount of salt used varies depending on the type of solvent and other reaction conditions, but is usually about 0.001 mol or more per 1 mol of the optically active compound of the compound represented by formula (IV) or a salt thereof.
- the amount is preferably 0.001 to 10 mol, more preferably 0.01 to 2 mol, and can also be used as a solvent.
- the additive that may be added to the rearrangement reaction in Step B-3 is preferably a base, more preferably sodium hydroxide, pyridine, triethylamine, potassium carbonate, sodium hydrogen carbonate, or ammonium chloride. Pyridine is preferable.
- the reaction in step B-3 is usually performed in a solvent.
- the solvent is not particularly limited as long as it can solubilize the raw material compound, the organometallic complex, and the additive without inhibiting the reaction.
- diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, Ethers such as tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole; methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxy Alcohol
- Suitable solvents for use in Step B-3 are alcohols and nitriles.
- alcohols ethanol and isopropanol are particularly preferable.
- nitriles acetonitrile is particularly preferred.
- the amount of the solvent used is appropriately determined depending on the solubility of the optically active compound of the compound represented by formula (IV) or a salt thereof.
- an alcohol preferably ethanol, isopropanol
- a nitrile preferably acetonitrile
- the reaction can be carried out in a solvent more than double the weight, but the solvent is used in an amount of about 2 to about 100 times by weight with respect to the optically active substance of the compound represented by formula (IV) or a salt thereof, which is usually a substrate. Is preferred.
- the reaction temperature is usually ⁇ 30 ° C. to 160 ° C., preferably 0 to 80 ° C., more preferably 0 to 30 ° C.
- the reaction time is usually 0.1 to 120 hours, preferably 1 to 72 hours.
- optically active form of the compound represented by the formula (V) obtained in Step B-3 or a salt thereof is purified by a known means (eg, fractional recrystallization method, chiral column method, diastereomeric salt method). Also good.
- room temperature usually indicates about 10 ° C. to about 35 ° C.
- the chemical yield is an isolated yield (mol / mol%) or a yield obtained by high performance liquid chromatography.
- the optical purity (asymmetric yield) of the optically active substance was evaluated by enantiomeric excess (% ee). The enantiomer excess was determined by the following equation.
- Enantiomeric excess (% ee) 100 X [(R)-(S)] / [(R) + (S)] or 100 X [(S)-(R)] / [(R) + (S ]] (Wherein (R) and (S) represent the area of each enantiomer in high performance liquid chromatography) Further, the solvent used in the chromatography represents volume%, and the others represent weight%. Proton NMR spectra that cannot be confirmed broadly, such as OH and NH protons, are not described in the data.
- nuclear magnetic resonance spectra were measured under the following conditions.
- 1 H nuclear magnetic resonance spectrum ( 1 H-NMR): Bruker AVANCE 500 (500 MHz) manufactured by Bruker, internal standard substance: tetramethylsilane 13 C nuclear magnetic resonance spectrum ( 13 C-NMR): Bruker AVANCE 500 (125 MHz) manufactured by Bruker, internal standard: CDCl 3
- 19 F nuclear magnetic resonance spectrum ( 19 F-NMR): Bruker AVANCE 500 (202 MHz) manufactured by Bruker, external standard: trifluoroacetic acid
- 31 P nuclear magnetic resonance spectrum ( 31 P-NMR): Bruker AVANCE 500 (471 MHz) manufactured by Bruker, external standard: 85% -H 3 PO 4 aqueous solution
- Nicotinamide 50.00 g [mw.122.12, 0.409 mol], 5% Pd / C 5.00 g and methanol 500 mL were added to a 1 L autoclave. After purging with hydrogen gas, the mixture was stirred at 45 ° C. for 14 hours at a constant hydrogen pressure of 0.1 MPa. After decompression, Pd / C was filtered off with a membrane filter while hot, and the filtrate was concentrated under reduced pressure. 100 mL of methanol was added to the concentrated crystallized product, and the mixture was aged at room temperature for 1 hour and filtered under reduced pressure. The filtrate was washed with 50 mL of methanol. The target compound was obtained by drying under reduced pressure at 50 ° C.
- the filtrate was concentrated under reduced pressure, 100 mL of methanol was added to the concentrated dry solid (powder), and the mixture was suspended and stirred in an ice bath for 1 hour.
- the crystals were collected by vacuum filtration and washed with 30 mL of cold methanol.
- 308 mL of ethanol was added, and 63.75 g [mw, 190.22, 0.335 mol] of paratoluenesulfonic acid monohydrate was added and dissolved.
- the mixture was aged for 3.5 hours at room temperature, and the crystals were collected by vacuum filtration and washed with 100 mL of ethanol.
- the target compound was obtained after vacuum drying at 50 ° C.
- Ethanol 8mL was added to the concentrated dried product (powder), dissolved at 85 ° C, and cooled to 25 ° C. The mixture was aged for 2 hours and filtered under reduced pressure. The filtered product was washed with 6 mL of ethanol. The target compound was obtained by drying at 60 ° C. under reduced pressure. White crystalline powder, 1.813 g, yield 76%, optical purity> 99% ee.
- the target compound was obtained after drying under reduced pressure at 60 ° C.
- White crystalline powder 38.60 g, yield 70%, optical purity 99.7% ee.
- Temperature 40 ° C Holding time: (S) body 11.3min, (R) body 12.2min.
- the mixture was stirred at an internal temperature of 65 ° C. for 23 hours, and 120 mL of water was added. After cooling to 0 ° C. and aging for 2 hours, the mixture was filtered under reduced pressure, and the filtered product was washed with 50 mL of water. The target compound was obtained after drying under reduced pressure at 60 ° C. White crystalline powder, 22.97 g, 95% yield.
- 270 g of potassium carbonate was added at 20 ° C. or lower, and the mixture was stirred for 30 minutes and separated.
- an aqueous sodium chloride solution 24 g of sodium chloride dissolved in 80 mL of water
- 180 mL of ethanol was added to the concentrate, and the mixture was further concentrated under reduced pressure to about 135 mL.
- the concentrated solution was subjected to dust filtration using a membrane filter (0.2 micron) and washed with 32 mL of ethanol.
- a sodium chloride aqueous solution (8 g of sodium chloride dissolved in 30 mL of water) was added to the organic layer, 8 g of sodium chloride was further added, and the mixture was separated after stirring, and 5 g of activated carbon and an appropriate amount of ethanol were added to the organic layer and stirred for 30 minutes. Activated carbon was separated, and the filtrate was concentrated under reduced pressure to about 150 mL. Ethanol 150mL was added to the concentrate, and it concentrated under reduced pressure to about 150mL. Further, 150 mL of ethanol was added to the concentrated solution, and the mixture was concentrated under reduced pressure to about 150 mL.
- the concentrated solution was subjected to dust filtration using a membrane filter (0.2 micron) and washed with 40 mL of ethanol.
- the filtrate was heated to 70 ° C., and an ethanol solution of benzoic acid (16.62 g of benzoic acid [mw.122.21, 136 mmol] dissolved in 100 mL of ethanol) was added dropwise in the range of 70 to 73 ° C. over 30 minutes. After stirring at 70 ° C. for 1.5 hours, 2 hours were required, and the mixture was gradually cooled to 30 ° C. and then cooled to 0 ° C. After stirring at 0 ° C. for 1 hour, the crystals were filtered off. The wet crystal was washed with 100 mL of cooled ethanol and then dried under reduced pressure at 60 ° C. to obtain the target compound. Pale yellowish white crystalline powder, 44.03 g, 70% yield.
- an optically active 6- (3-aminopiperidin-1-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative can be efficiently produced.
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Abstract
Description
光学活性な6-(3-アミノピペリジン-1-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロピリミジン誘導体は、ジペプチジルペプチダーゼ阻害剤および糖尿病の治療薬として有用であることが知られている。
また、当該文献にはピペリジン-3-カルボキサミド誘導体の光学活性体から、ホフマン転位を利用し、3-アミノピペリジンの光学活性体を製造する方法も開示されている。
また、本発明の別の目的は、光学活性な6-(3-アミノピペリジン-1-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロピリミジン誘導体を製造するために有用な各種中間体およびこれらの製造方法を提供することである。
で表される化合物またはその塩を有機金属錯体の存在下で水素化反応に付すことを特徴とする、
式:
で表される化合物の光学活性体またはその塩の製造法。
[2] 有機金属錯体が遷移金属錯体である、上記[1]記載の製造法。
[3] 遷移金属錯体がルテニウム錯体である、上記[2]記載の製造法。
[4] ルテニウム錯体が、
式:
[Ru(OCORa)2La] (VIII)
[式中、Raは、置換されていてもよいC1-3アルキル基を;Laはジホスフィン配位子を示す。]
で表される上記[3]記載の製造法。
[5] 水素化反応が、ハロゲン化アルカリ金属または
式:
の存在下に行われる上記[1]記載の製造法。
[6] 式:
で表される化合物。
[7] 式:
で表される化合物の光学活性体。
[8] 式:
で表される化合物の光学活性体またはその塩と、
式:
で表される化合物またはその塩とを反応させることを特徴とする、
式:
で表される化合物の光学活性体またはその塩の製造法。
[9] 式:
で表される化合物の光学活性体またはその塩を転位反応に付することを特徴とする、
式:
で表される化合物の光学活性体またはその塩の製造法。
[10] (1)式:
で表される化合物またはその塩を有機金属錯体の存在下で水素化反応に付すことにより、
式:
で表される化合物の光学活性体またはその塩を製造する工程;および
(2)式:
で表される化合物の光学活性体またはその塩と、式:
で表される化合物またはその塩とを反応させることにより、
式:
で表される化合物の光学活性体またはその塩を製造する工程を含む、上記[9]記載の製造法。
[11] 式:
[Ru(OCORa’)2La’] (VIII’)
[式中、Ra’は、トリフルオロメチル基を;La’は、ジホスフィン配位子の光学活性体であり、
(1)式:
式:
(2)式:
で表される化合物の光学活性体から選ばれる。]
で表されるルテニウム錯体。
該誘導体は、ジペプチジルペプチダーゼ阻害剤および糖尿病の治療薬として有用である。
また、本発明によれば、光学活性な6-(3-アミノピペリジン-1-イル)-2,4-ジオキソ-1,2,3,4-テトラヒドロピリミジン誘導体を製造するために有用な各種中間体およびこれらの効率的な製造方法を提供することができる。
さらに、本発明によれば、水素化反応に有用なルテニウム錯体を提供することができる。
以下に、本発明を詳細に説明する。
本明細書中、「ハロゲン原子」としては、例えば、フッ素、塩素、臭素、ヨウ素が挙げられる。
本明細書中、「C1-6アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、1-エチルプロピル、ヘキシル、イソヘキシル、1,1-ジメチルブチル、2,2-ジメチルブチル、3,3-ジメチルブチル、2-エチルブチルが挙げられる。
本明細書中、「ハロゲン化されていてもよいC1-6アルキル基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC1-6アルキル基が挙げられる。具体例としては、メチル、クロロメチル、ジフルオロメチル、トリクロロメチル、トリフルオロメチル、エチル、2-ブロモエチル、2,2,2-トリフルオロエチル、テトラフルオロエチル、ペンタフルオロエチル、プロピル、2,2―ジフルオロプロピル、3,3,3-トリフルオロプロピル、イソプロピル、ブチル、4,4,4-トリフルオロブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、5,5,5-トリフルオロペンチル、ヘキシル、6,6,6-トリフルオロヘキシルが挙げられる。
本明細書中、「C2-6アルケニル基」としては、例えば、エテニル、1-プロペニル、2-プロペニル、2-メチル-1-プロペニル、1-ブテニル、2-ブテニル、3-ブテニル、3-メチル-2-ブテニル、1-ペンテニル、2-ペンテニル、3-ペンテニル、4-ペンテニル、4-メチル-3-ペンテニル、1-ヘキセニル、3-ヘキセニル、5-ヘキセニルが挙げられる。
本明細書中、「C2-6アルキニル基」としては、例えば、エチニル、1-プロピニル、2-プロピニル、1-ブチニル、2-ブチニル、3-ブチニル、1-ペンチニル、2-ペンチニル、3-ペンチニル、4-ペンチニル、1-ヘキシニル、2-ヘキシニル、3-ヘキシニル、4-ヘキシニル、5-ヘキシニル、4-メチル-2-ペンチニルが挙げられる。
本明細書中、「C3-10シクロアルキル基」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ[2.2.1]ヘプチル、ビシクロ[2.2.2]オクチル、ビシクロ[3.2.1]オクチル、アダマンチルが挙げられる。
本明細書中、「ハロゲン化されていてもよいC3-10シクロアルキル基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC3-10シクロアルキル基が挙げられる。具体例としては、シクロプロピル、2,2-ジフルオロシクロプロピル、2,3-ジフルオロシクロプロピル、シクロブチル、ジフルオロシクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。
本明細書中、「C3-10シクロアルケニル基」としては、例えば、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロオクテニルが挙げられる。
本明細書中、「C6-14アリール基」としては、例えば、フェニル、1-ナフチル、2-ナフチル、1-アントリル、2-アントリル、9-アントリルが挙げられる。
本明細書中、「C7-16アラルキル基」としては、例えば、ベンジル、フェネチル、ナフチルメチル、フェニルプロピルが挙げられる。
本明細書中、「ハロゲン化されていてもよいC1-6アルコキシ基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC1-6アルコキシ基が挙げられる。具体例としては、メトキシ、ジフルオロメトキシ、トリフルオロメトキシ、エトキシ、2,2,2-トリフルオロエトキシ、プロポキシ、イソプロポキシ、ブトキシ、4,4,4-トリフルオロブトキシ、イソブトキシ、sec-ブトキシ、ペンチルオキシ、ヘキシルオキシが挙げられる。
本明細書中、「C3-10シクロアルキルオキシ基」としては、例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシが挙げられる。
本明細書中、「C1-6アルキルチオ基」としては、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、ヘキシルチオが挙げられる。
本明細書中、「ハロゲン化されていてもよいC1-6アルキルチオ基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC1-6アルキルチオ基が挙げられる。具体例としては、メチルチオ、ジフルオロメチルチオ、トリフルオロメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、4,4,4-トリフルオロブチルチオ、ペンチルチオ、ヘキシルチオが挙げられる。
本明細書中、「C1-6アルキル-カルボニル基」としては、例えば、アセチル、プロパノイル、ブタノイル、2-メチルプロパノイル、ペンタノイル、3-メチルブタノイル、2-メチルブタノイル、2,2-ジメチルプロパノイル、ヘキサノイル、ヘプタノイルが挙げられる。
本明細書中、「ハロゲン化されていてもよいC1-6アルキル-カルボニル基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC1-6アルキル-カルボニル基が挙げられる。具体例としては、アセチル、クロロアセチル、トリフルオロアセチル、トリクロロアセチル、プロパノイル、ブタノイル、ペンタノイル、ヘキサノイルが挙げられる。
本明細書中、「C1-6アルコキシ-カルボニル基」としては、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、sec-ブトキシカルボニル、tert-ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニルが挙げられる。
本明細書中、「C6-14アリール-カルボニル基」としては、例えば、ベンゾイル、1-ナフトイル、2-ナフトイルが挙げられる。
本明細書中、「C7-16アラルキル-カルボニル基」としては、例えば、フェニルアセチル、フェニルプロピオニルが挙げられる。
本明細書中、「5ないし14員芳香族複素環カルボニル基」としては、例えば、ニコチノイル、イソニコチノイル、テノイル、フロイルが挙げられる。
本明細書中、「3ないし14員非芳香族複素環カルボニル基」としては、例えば、モルホリニルカルボニル、ピペリジニルカルボニル、ピロリジニルカルボニルが挙げられる。
本明細書中、「モノ-またはジ-C7-16アラルキル-カルバモイル基」としては、例えば、ベンジルカルバモイル、フェネチルカルバモイルが挙げられる。
本明細書中、「C1-6アルキルスルホニル基」としては、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、sec-ブチルスルホニル、tert-ブチルスルホニルが挙げられる。
本明細書中、「ハロゲン化されていてもよいC1-6アルキルスルホニル基」としては、例えば、1ないし7個、好ましくは1ないし5個のハロゲン原子を有していてもよいC1-6アルキルスルホニル基が挙げられる。具体例としては、メチルスルホニル、ジフルオロメチルスルホニル、トリフルオロメチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、4,4,4-トリフルオロブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニルが挙げられる。
本明細書中、「C6-14アリールスルホニル基」としては、例えば、フェニルスルホニル、1-ナフチルスルホニル、2-ナフチルスルホニルが挙げられる。
本明細書中、「炭化水素基」(「置換されていてもよい炭化水素基」における「炭化水素基」を含む)としては、例えば、C1-6アルキル基、C2-6アルケニル基、C2-6アルキニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14アリール基、C7-16アラルキル基が挙げられる。
[置換基群A]
(1)ハロゲン原子、
(2)ニトロ基、
(3)シアノ基、
(4)オキソ基、
(5)ヒドロキシ基、
(6)ハロゲン化されていてもよいC1-6アルコキシ基、
(7)C6-14アリールオキシ基(例、フェノキシ、ナフトキシ)、
(8)C7-16アラルキルオキシ基(例、ベンジルオキシ)、
(9)5ないし14員芳香族複素環オキシ基(例、ピリジルオキシ)、
(10)3ないし14員非芳香族複素環オキシ基(例、モルホリニルオキシ、ピペリジニルオキシ)、
(11)C1-6アルキル-カルボニルオキシ基(例、アセトキシ、プロパノイルオキシ)、
(12)C6-14アリール-カルボニルオキシ基(例、ベンゾイルオキシ、1-ナフトイルオキシ、2-ナフトイルオキシ)、
(13)C1-6アルコキシ-カルボニルオキシ基(例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ)、
(14)モノ-またはジ-C1-6アルキル-カルバモイルオキシ基(例、メチルカルバモイルオキシ、エチルカルバモイルオキシ、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ)、
(15)C6-14アリール-カルバモイルオキシ基(例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ)、
(16)5ないし14員芳香族複素環カルボニルオキシ基(例、ニコチノイルオキシ)、
(17)3ないし14員非芳香族複素環カルボニルオキシ基(例、モルホリニルカルボニルオキシ、ピペリジニルカルボニルオキシ)、
(18)ハロゲン化されていてもよいC1-6アルキルスルホニルオキシ基(例、メチルスルホニルオキシ、トリフルオロメチルスルホニルオキシ)、
(19)C1-6アルキル基で置換されていてもよいC6-14アリールスルホニルオキシ基(例、フェニルスルホニルオキシ、トルエンスルホニルオキシ)、
(20)ハロゲン化されていてもよいC1-6アルキルチオ基、
(21)5ないし14員芳香族複素環基、
(22)3ないし14員非芳香族複素環基、
(23)ホルミル基、
(24)カルボキシ基、
(25)ハロゲン化されていてもよいC1-6アルキル-カルボニル基、
(26)C6-14アリール-カルボニル基、
(27)5ないし14員芳香族複素環カルボニル基、
(28)3ないし14員非芳香族複素環カルボニル基、
(29)C1-6アルコキシ-カルボニル基、
(30)C6-14アリールオキシ-カルボニル基(例、フェニルオキシカルボニル、1-ナフチルオキシカルボニル、2-ナフチルオキシカルボニル)、
(31)C7-16アラルキルオキシ-カルボニル基(例、ベンジルオキシカルボニル、フェネチルオキシカルボニル)、
(32)カルバモイル基、
(33)チオカルバモイル基、
(34)モノ-またはジ-C1-6アルキル-カルバモイル基、
(35)C6-14アリール-カルバモイル基(例、フェニルカルバモイル)、
(36)5ないし14員芳香族複素環カルバモイル基(例、ピリジルカルバモイル、チエニルカルバモイル)、
(37)3ないし14員非芳香族複素環カルバモイル基(例、モルホリニルカルバモイル、ピペリジニルカルバモイル)、
(38)ハロゲン化されていてもよいC1-6アルキルスルホニル基、
(39)C6-14アリールスルホニル基、
(40)5ないし14員芳香族複素環スルホニル基(例、ピリジルスルホニル、チエニルスルホニル)、
(41)ハロゲン化されていてもよいC1-6アルキルスルフィニル基、
(42)C6-14アリールスルフィニル基(例、フェニルスルフィニル、1-ナフチルスルフィニル、2-ナフチルスルフィニル)、
(43)5ないし14員芳香族複素環スルフィニル基(例、ピリジルスルフィニル、チエニルスルフィニル)、
(44)アミノ基、
(45)モノ-またはジ-C1-6アルキルアミノ基(例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミノ、N-エチル-N-メチルアミノ)、
(46)モノ-またはジ-C6-14アリールアミノ基(例、フェニルアミノ)、
(47)5ないし14員芳香族複素環アミノ基(例、ピリジルアミノ)、
(48)C7-16アラルキルアミノ基(例、ベンジルアミノ)、
(49)ホルミルアミノ基、
(50)C1-6アルキル-カルボニルアミノ基(例、アセチルアミノ、プロパノイルアミノ、ブタノイルアミノ)、
(51)(C1-6アルキル)(C1-6アルキル-カルボニル)アミノ基(例、N-アセチル-N-メチルアミノ)、
(52)C6-14アリール-カルボニルアミノ基(例、フェニルカルボニルアミノ、ナフチルカルボニルアミノ)、
(53)C1-6アルコキシ-カルボニルアミノ基(例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ、tert-ブトキシカルボニルアミノ)、
(54)C7-16アラルキルオキシ-カルボニルアミノ基(例、ベンジルオキシカルボニルアミノ)、
(55)C1-6アルキルスルホニルアミノ基(例、メチルスルホニルアミノ、エチルスルホニルアミノ)、
(56)C1-6アルキル基で置換されていてもよいC6-14アリールスルホニルアミノ基(例、フェニルスルホニルアミノ、トルエンスルホニルアミノ)、
(57)ハロゲン化されていてもよいC1-6アルキル基、
(58)C2-6アルケニル基、
(59)C2-6アルキニル基、
(60)C3-10シクロアルキル基、
(61)C3-10シクロアルケニル基、及び
(62)C6-14アリール基。
本明細書中、「複素環基」(「置換されていてもよい複素環基」における「複素環基」を含む)としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる1ないし4個のヘテロ原子をそれぞれ含有する、(i)芳香族複素環基、(ii)非芳香族複素環基および(iii)7ないし10員複素架橋環基が挙げられる。
該「芳香族複素環基」の好適な例としては、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、1,2,4-チアジアゾリル、1,3,4-チアジアゾリル、トリアゾリル、テトラゾリル、トリアジニルなどの5ないし6員単環式芳香族複素環基;
ベンゾチオフェニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾトリアゾリル、イミダゾピリジニル、チエノピリジニル、フロピリジニル、ピロロピリジニル、ピラゾロピリジニル、オキサゾロピリジニル、チアゾロピリジニル、イミダゾピラジニル、イミダゾピリミジニル、チエノピリミジニル、フロピリミジニル、ピロロピリミジニル、ピラゾロピリミジニル、オキサゾロピリミジニル、チアゾロピリミジニル、ピラゾロトリアジニル、ナフト[2,3-b]チエニル、フェノキサチイニル、インドリル、イソインドリル、1H-インダゾリル、プリニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β-カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルなどの8ないし14員縮合多環式(好ましくは2または3環式)芳香族複素環基が挙げられる。
該「非芳香族複素環基」の好適な例としては、アジリジニル、オキシラニル、チイラニル、アゼチジニル、オキセタニル、チエタニル、テトラヒドロチエニル、テトラヒドロフラニル、ピロリニル、ピロリジニル、イミダゾリニル、イミダゾリジニル、オキサゾリニル、オキサゾリジニル、ピラゾリニル、ピラゾリジニル、チアゾリニル、チアゾリジニル、テトラヒドロイソチアゾリル、テトラヒドロオキサゾリル、テトラヒドロイソオキサゾリル、ピペリジニル、ピペラジニル、テトラヒドロピリジニル、ジヒドロピリジニル、ジヒドロチオピラニル、テトラヒドロピリミジニル、テトラヒドロピリダジニル、ジヒドロピラニル、テトラヒドロピラニル、テトラヒドロチオピラニル、モルホリニル、チオモルホリニル、アゼパニル、ジアゼパニル、アゼピニル、オキセパニル、アゾカニル、ジアゾカニルなどの3ないし8員単環式非芳香族複素環基;
ジヒドロベンゾフラニル、ジヒドロベンゾイミダゾリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾチアゾリル、ジヒドロベンゾイソチアゾリル、ジヒドロナフト[2,3-b]チエニル、テトラヒドロイソキノリル、テトラヒドロキノリル、4H-キノリジニル、インドリニル、イソインドリニル、テトラヒドロチエノ[2,3-c]ピリジニル、テトラヒドロベンゾアゼピニル、テトラヒドロキノキサリニル、テトラヒドロフェナントリジニル、ヘキサヒドロフェノチアジニル、ヘキサヒドロフェノキサジニル、テトラヒドロフタラジニル、テトラヒドロナフチリジニル、テトラヒドロキナゾリニル、テトラヒドロシンノリニル、テトラヒドロカルバゾリル、テトラヒドロ-β-カルボリニル、テトラヒドロアクリジニル、テトラヒドロフェナジニル、テトラヒドロチオキサンテニル、オクタヒドロイソキノリルなどの9ないし14員縮合多環式(好ましくは2または3環式)非芳香族複素環基が挙げられる。
本明細書中、「含窒素複素環基」としては、「複素環基」のうち、環構成原子として少なくとも1個以上の窒素原子を含有するものが挙げられる。
本明細書中、「置換されていてもよい複素環基」としては、例えば、前記した置換基群Aから選ばれる置換基を有していてもよい複素環基が挙げられる。
「置換されていてもよい複素環基」における置換基の数は、例えば、1ないし3個である。置換基数が2個以上の場合、各置換基は同一であっても異なっていてもよい。
また、「アシル基」としては、炭化水素-スルホニル基、複素環-スルホニル基、炭化水素-スルフィニル基、複素環-スルフィニル基も挙げられる。
ここで、炭化水素-スルホニル基とは、炭化水素基が結合したスルホニル基を、複素環-スルホニル基とは、複素環基が結合したスルホニル基を、炭化水素-スルフィニル基とは、炭化水素基が結合したスルフィニル基を、複素環-スルフィニル基とは、複素環基が結合したスルフィニル基を、それぞれ意味する。
「アシル基」の好適な例としては、ホルミル基、カルボキシ基、C1-6アルキル-カルボニル基、C2-6アルケニル-カルボニル基(例、クロトノイル)、C3-10シクロアルキル-カルボニル基(例、シクロブタンカルボニル、シクロペンタンカルボニル、シクロヘキサンカルボニル、シクロヘプタンカルボニル)、C3-10シクロアルケニル-カルボニル基(例、2-シクロヘキセンカルボニル)、C6-14アリール-カルボニル基、C7-16アラルキル-カルボニル基、5ないし14員芳香族複素環カルボニル基、3ないし14員非芳香族複素環カルボニル基、C1-6アルコキシ-カルボニル基、C6-14アリールオキシ-カルボニル基(例、フェニルオキシカルボニル、ナフチルオキシカルボニル)、C7-16アラルキルオキシ-カルボニル基(例、ベンジルオキシカルボニル、フェネチルオキシカルボニル)、カルバモイル基、モノ-またはジ-C1-6アルキル-カルバモイル基、モノ-またはジ-C2-6アルケニル-カルバモイル基(例、ジアリルカルバモイル)、モノ-またはジ-C3-10シクロアルキル-カルバモイル基(例、シクロプロピルカルバモイル)、モノ-またはジ-C6-14アリール-カルバモイル基(例、フェニルカルバモイル)、モノ-またはジ-C7-16アラルキル-カルバモイル基、5ないし14員芳香族複素環カルバモイル基(例、ピリジルカルバモイル)、チオカルバモイル基、モノ-またはジ-C1-6アルキル-チオカルバモイル基(例、メチルチオカルバモイル、N-エチル-N-メチルチオカルバモイル)、モノ-またはジ-C2-6アルケニル-チオカルバモイル基(例、ジアリルチオカルバモイル)、モノ-またはジ-C3-10シクロアルキル-チオカルバモイル基(例、シクロプロピルチオカルバモイル、シクロヘキシルチオカルバモイル)、モノ-またはジ-C6-14アリール-チオカルバモイル基(例、フェニルチオカルバモイル)、モノ-またはジ-C7-16アラルキル-チオカルバモイル基(例、ベンジルチオカルバモイル、フェネチルチオカルバモイル)、5ないし14員芳香族複素環チオカルバモイル基(例、ピリジルチオカルバモイル)、スルフィノ基、C1-6アルキルスルフィニル基(例、メチルスルフィニル、エチルスルフィニル)、スルホ基、C1-6アルキルスルホニル基、C6-14アリールスルホニル基、ホスホノ基、モノ-またはジ-C1-6アルキルホスホノ基(例、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ)が挙げられる。
置換されていてもよいアミノ基の好適な例としては、アミノ基、モノ-またはジ-(ハロゲン化されていてもよいC1-6アルキル)アミノ基(例、メチルアミノ、トリフルオロメチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ、プロピルアミノ、ジブチルアミノ)、モノ-またはジ-C2-6アルケニルアミノ基(例、ジアリルアミノ)、モノ-またはジ-C3-10シクロアルキルアミノ基(例、シクロプロピルアミノ、シクロヘキシルアミノ)、モノ-またはジ-C6-14アリールアミノ基(例、フェニルアミノ)、モノ-またはジ-C7-16アラルキルアミノ基(例、ベンジルアミノ、ジベンジルアミノ)、モノ-またはジ-(ハロゲン化されていてもよいC1-6アルキル)-カルボニルアミノ基(例、アセチルアミノ、プロピオニルアミノ)、モノ-またはジ-C6-14アリール-カルボニルアミノ基(例、ベンゾイルアミノ)、モノ-またはジ-C7-16アラルキル-カルボニルアミノ基(例、ベンジルカルボニルアミノ)、モノ-またはジ-5ないし14員芳香族複素環カルボニルアミノ基(例、ニコチノイルアミノ、イソニコチノイルアミノ)、モノ-またはジ-3ないし14員非芳香族複素環カルボニルアミノ基(例、ピペリジニルカルボニルアミノ)、モノ-またはジ-C1-6アルコキシ-カルボニルアミノ基(例、tert-ブトキシカルボニルアミノ)、5ないし14員芳香族複素環アミノ基(例、ピリジルアミノ)、カルバモイルアミノ基、(モノ-またはジ-C1-6アルキル-カルバモイル)アミノ基(例、メチルカルバモイルアミノ)、(モノ-またはジ-C7-16アラルキル-カルバモイル)アミノ基(例、ベンジルカルバモイルアミノ)、C1-6アルキルスルホニルアミノ基(例、メチルスルホニルアミノ、エチルスルホニルアミノ)、C6-14アリールスルホニルアミノ基(例、フェニルスルホニルアミノ)、(C1-6アルキル)(C1-6アルキル-カルボニル)アミノ基(例、N-アセチル-N-メチルアミノ)、(C1-6アルキル)(C6-14アリール-カルボニル)アミノ基(例、N-ベンゾイル-N-メチルアミノ)が挙げられる。
置換されていてもよいカルバモイル基の好適な例としては、カルバモイル基、モノ-またはジ-C1-6アルキル-カルバモイル基、モノ-またはジ-C2-6アルケニル-カルバモイル基(例、ジアリルカルバモイル)、モノ-またはジ-C3-10シクロアルキル-カルバモイル基(例、シクロプロピルカルバモイル、シクロヘキシルカルバモイル)、モノ-またはジ-C6-14アリール-カルバモイル基(例、フェニルカルバモイル)、モノ-またはジ-C7-16アラルキル-カルバモイル基、モノ-またはジ-C1-6アルキル-カルボニル-カルバモイル基(例、アセチルカルバモイル、プロピオニルカルバモイル)、モノ-またはジ-C6-14アリール-カルボニル-カルバモイル基(例、ベンゾイルカルバモイル)、5ないし14員芳香族複素環カルバモイル基(例、ピリジルカルバモイル)が挙げられる。
置換されていてもよいチオカルバモイル基の好適な例としては、チオカルバモイル基、モノ-またはジ-C1-6アルキル-チオカルバモイル基(例、メチルチオカルバモイル、エチルチオカルバモイル、ジメチルチオカルバモイル、ジエチルチオカルバモイル、N-エチル-N-メチルチオカルバモイル)、モノ-またはジ-C2-6アルケニル-チオカルバモイル基(例、ジアリルチオカルバモイル)、モノ-またはジ-C3-10シクロアルキル-チオカルバモイル基(例、シクロプロピルチオカルバモイル、シクロヘキシルチオカルバモイル)、モノ-またはジ-C6-14アリール-チオカルバモイル基(例、フェニルチオカルバモイル)、モノ-またはジ-C7-16アラルキル-チオカルバモイル基(例、ベンジルチオカルバモイル、フェネチルチオカルバモイル)、モノ-またはジ-C1-6アルキル-カルボニル-チオカルバモイル基(例、アセチルチオカルバモイル、プロピオニルチオカルバモイル)、モノ-またはジ-C6-14アリール-カルボニル-チオカルバモイル基(例、ベンゾイルチオカルバモイル)、5ないし14員芳香族複素環チオカルバモイル基(例、ピリジルチオカルバモイル)が挙げられる。
置換されていてもよいスルファモイル基の好適な例としては、スルファモイル基、モノ-またはジ-C1-6アルキル-スルファモイル基(例、メチルスルファモイル、エチルスルファモイル、ジメチルスルファモイル、ジエチルスルファモイル、N-エチル-N-メチルスルファモイル)、モノ-またはジ-C2-6アルケニル-スルファモイル基(例、ジアリルスルファモイル)、モノ-またはジ-C3-10シクロアルキル-スルファモイル基(例、シクロプロピルスルファモイル、シクロヘキシルスルファモイル)、モノ-またはジ-C6-14アリール-スルファモイル基(例、フェニルスルファモイル)、モノ-またはジ-C7-16アラルキル-スルファモイル基(例、ベンジルスルファモイル、フェネチルスルファモイル)、モノ-またはジ-C1-6アルキル-カルボニル-スルファモイル基(例、アセチルスルファモイル、プロピオニルスルファモイル)、モノ-またはジ-C6-14アリール-カルボニル-スルファモイル基(例、ベンゾイルスルファモイル)、5ないし14員芳香族複素環スルファモイル基(例、ピリジルスルファモイル)が挙げられる。
置換されていてもよいヒドロキシ基の好適な例としては、ヒドロキシ基、C1-6アルコキシ基、C2-6アルケニルオキシ基(例、アリルオキシ、2-ブテニルオキシ、2-ペンテニルオキシ、3-ヘキセニルオキシ)、C3-10シクロアルキルオキシ基(例、シクロヘキシルオキシ)、C6-14アリールオキシ基(例、フェノキシ、ナフチルオキシ)、C7-16アラルキルオキシ基(例、ベンジルオキシ、フェネチルオキシ)、C1-6アルキル-カルボニルオキシ基(例、アセチルオキシ、プロピオニルオキシ、ブチリルオキシ、イソブチリルオキシ、ピバロイルオキシ)、C6-14アリール-カルボニルオキシ基(例、ベンゾイルオキシ)、C7-16アラルキル-カルボニルオキシ基(例、ベンジルカルボニルオキシ)、5ないし14員芳香族複素環カルボニルオキシ基(例、ニコチノイルオキシ)、3ないし14員非芳香族複素環カルボニルオキシ基(例、ピペリジニルカルボニルオキシ)、C1-6アルコキシ-カルボニルオキシ基(例、tert-ブトキシカルボニルオキシ)、5ないし14員芳香族複素環オキシ基(例、ピリジルオキシ)、カルバモイルオキシ基、C1-6アルキル-カルバモイルオキシ基(例、メチルカルバモイルオキシ)、C7-16アラルキル-カルバモイルオキシ基(例、ベンジルカルバモイルオキシ)、C1-6アルキルスルホニルオキシ基(例、メチルスルホニルオキシ、エチルスルホニルオキシ)、C6-14アリールスルホニルオキシ基(例、フェニルスルホニルオキシ)が挙げられる。
置換されていてもよいスルファニル基の好適な例としては、スルファニル(-SH)基、C1-6アルキルチオ基、C2-6アルケニルチオ基(例、アリルチオ、2-ブテニルチオ、2-ペンテニルチオ、3-ヘキセニルチオ)、C3-10シクロアルキルチオ基(例、シクロヘキシルチオ)、C6-14アリールチオ基(例、フェニルチオ、ナフチルチオ)、C7-16アラルキルチオ基(例、ベンジルチオ、フェネチルチオ)、C1-6アルキル-カルボニルチオ基(例、アセチルチオ、プロピオニルチオ、ブチリルチオ、イソブチリルチオ、ピバロイルチオ)、C6-14アリール-カルボニルチオ基(例、ベンゾイルチオ)、5ないし14員芳香族複素環チオ基(例、ピリジルチオ)、ハロゲン化チオ基(例、ペンタフルオロチオ)が挙げられる。
置換されていてもよいシリル基の好適な例としては、トリ-C1-6アルキルシリル基(例、トリメチルシリル、tert-ブチル(ジメチル)シリル)が挙げられる。
式(I)で表される化合物が、式:
で表される化合物であり;且つ
式(II)で表される化合物が、式:
で表される化合物である。
式(I)で表される化合物が、式(I’)で表される化合物であり;且つ
式(II)で表される化合物が、式(II’)で表される化合物である。
式(I)で表される化合物が、1,4,5,6-テトラヒドロピリジン-3-カルボキサミドであり;且つ
式(II)で表される化合物が、ピペリジン-3-カルボキサミドである。
式:
RbSO3H (VII)
[式中、Rbは、置換されていてもよい炭化水素基を示す。]
で表される化合物との塩である。
上記式(VII)中、Rbは、好ましくは、置換されていてもよいC6-14アリール基であり;より好ましくは、置換されていてもよいフェニル基であり;さらに好ましくは、C1-6アルキル基で置換されていてもよいフェニル基であり;特に好ましくは、メチルで置換されていてもよいフェニル基である。
式(I)および(II)で表される化合物は、それぞれ、溶媒和物(例、水和物、エタノール和物等)であっても、無溶媒和物(例、非水和物等)であってもよく、いずれも化合物(I)および(II)に包含される。
同位元素等で標識された化合物も、式(I)および(II)で表される化合物に包含される。
1Hを2H(D)に変換した重水素変換体も、式(I)および(II)で表される化合物に包含される。
Rは、特に好ましくは、メチルで置換されていてもよいフェニル基である。
式(XIII)の好ましい実施態様では、式(XIII)で表される化合物が、下記式:
R2’およびR3’、あるいはR3’およびR4’が形成する「5ないし8員環」の好適なものとしては、R2およびR3、あるいはR3およびR4が形成する「5ないし8員環」の好適なものと同様のものが挙げられる。
R7の好適な具体例としては、シアノ基で置換されたフェニル基、シアノ基およびフッ素原子で置換されたフェニル基が挙げられる。なかでも、シアノ基で置換されたフェニル基が好ましい。
R8は、好ましくは、水素原子またはC1-6アルキル基であり;より好ましくは、C1-6アルキル基であり;さらに好ましくは、メチル基である。
式(I’)で表される化合物が、1,4,5,6-テトラヒドロピリジン-3-カルボキサミドであり;
式(II’)で表される化合物が、ピペリジン-3-カルボキサミドであり;
式(IV)で表される化合物が、式:
で表される化合物であり;
式(V)で表される化合物が、式:
で表される化合物である。
式(III)で表される化合物が、式:
で表される化合物であり;
式(IV)で表される化合物が、式:
で表される化合物であり;
式(V)で表される化合物が、式:
で表される化合物である。
式(I’)で表される化合物が、1,4,5,6-テトラヒドロピリジン-3-カルボキサミドであり;
式(II’)で表される化合物が、ピペリジン-3-カルボキサミドであり;
式(III)で表される化合物が、式:
で表される化合物であり;
式(IV)で表される化合物が、式:
で表される化合物であり;
式(V)で表される化合物が、式:
で表される化合物である。
REは、特に好ましくは水素原子である。
式(I’)、(II’)、(III)、(IV)および(V)で表される化合物は、それぞれ、溶媒和物(例、水和物、エタノール和物等)であっても、無溶媒和物(例、非水和物等)であってもよく、いずれも式(I’)、(II’)、(III)、(IV)および(V)で表される化合物に包含される。
同位元素等で標識された化合物も、式(I’)、(II’)、(III)、(IV)および(V)で表される化合物に包含される。
1Hを2H(D)に変換した重水素変換体も、式(I’)、(II’)、(III)、(IV)および(V)で表される化合物に包含される。
ロジウム錯体:[RhCl(L)]2、[RhBr(L)]2、[RhI(L)]2、[RhCp*(L)]2、[Rh(cod)(L)]OTf、[Rh(cod)(L)]BF4、[Rh(cod)(L)]ClO4、[Rh(cod)(L)]PF6、[Rh(cod)(L)]SbF6、[Rh(cod)(L)]BPh4、[Rh(cod)(L)]B{3,5-(CF3)2C6H3}4、[Rh(nbd)(L)]OTf、[Rh(nbd)(L)]BF4、[Rh(nbd)(L)]ClO4、[Rh(nbd)(L)]PF6、[Rh(nbd)(L)]SbF6、[Rh(nbd)(L)]BPh4、[Rh(nbd)(L)]B{3,5-(CF3)2C6H3}4、[Rh(L)(CH3OH)2]OTf、[Rh(L)(CH3OH)2]BF4、[Rh(L)(CH3OH)2]ClO4、[Rh(L)(CH3OH)2]PF6、[Rh(L)(CH3OH)2]BPh4;
ルテニウム錯体:[RuCl2(L)]n、[RuBr2(L)]n、[RuI2(L)]n、[Ru(OAc)2(L)]、[Ru(OCOCF3)2(L)]、(NH2Me2)[{RuCl(L)}2(μ-Cl)3]、(NH2Et2)[{RuCl(L)}2(μ-Cl)3]、(NH2Me2)[{RuBr(L)}2(μ-Br)3]、(NH2Et2)[{RuBr(L)}2(μ-Br)3]、(NH2Me2)[{RuI(L)}2(μ-I)3]、(NH2Et2)[{RuI(L)}2(μ-I)3]、[Ru2Cl4(L)2(NEt3)]、[RuCl2(L)(dmf)n]、[Ru(2-methylallyl)2(L)]、[RuCl(Ar)(L)]Cl、[RuCl(Ar)(L)]Br、[RuCl(Ar)(L)]I、[RuCl(Ar)(L)]OTf、[RuCl(Ar)(L)]ClO4、[RuCl(Ar)(L)]PF6、[RuCl(Ar)(L)]BF4、[RuCl(Ar)(L)]BPh4、[RuBr(Ar)(L)]Cl、[RuBr(Ar)(L)]Br、[RuBr(Ar)(L)]I、[RuI(Ar)(L)]Cl、[RuI(Ar)(L)]Br、[RuI(Ar)(L)]I、[Ru(L)](OTf)2、[Ru(L)](BF4)2、[Ru(L)](ClO4)2、[Ru(L)](PF6)2、[Ru(L)](BPh4)2、[RuH(L)2]Cl、[RuH(L)2]OTf、[RuH(L)2]BF4、[RuH(L)2]ClO4、[RuH(L)2]PF6、[RuH(L)2]BPh4、[RuH(CH3CN)(L)]Cl、[RuH(CH3CN)(L)]OTf、[RuH(CH3CN)(L)]BF4、[RuH(CH3CN)(L)]ClO4、[RuH(CH3CN)(L)]PF6、[RuH(CH3CN)(L)]BPh4、[RuCl(L)]OTf、[RuCl(L)]BF4、[RuCl(L)]ClO4、[RuCl(L)]PF6、[RuCl(L)]BPh4、[RuBr(L)]OTf、[RuBr(L)]BF4、[RuBr(L)]ClO4、[RuBr(L)]PF6、[RuBr(L)]BPh4、[RuI(L)]OTf、[RuI(L)]BF4、[RuI(L)]ClO4、[RuI(L)]PF6、[RuI(L)]BPh4、[RuCl2(L)(en)]、[RuCl2(L)(dpen)]、[RuCl2(L)(daipen)]、[RuH(η1-BH4)(L)(en)]、[RuH(η1-BH4)(L)(daipen)]、[RuH(η1-BH4)(L)(dpen)]
(前記の[RuCl2(L)(en)]、[RuCl2(L)(dpen)]および[RuCl2(L)(daipen)]中のジアミン配位子であるen、dpenおよびdaipenに相当するジアミン配位子の例として、これらの他にも、1,2-シクロヘキサンジアミン、1,2-シクロヘプタンジアミン、2,3-ジメチルブタンジアミン、1-メチル-2,2-ジフェニル-1,2-エチレンジアミン、1-イソブチル-2,2-ジフェニル-1,2-エチレンジアミン、1-イソプロピル-2,2-ジフェニル-1,2-エチレンジアミン、1,1-ジ(4-アニシル)-2-メチル-1,2-エチレンジアミン、1,1-ジ(4-アニシル)-2-イソブチル-1,2-エチレンジアミン、1,1-ジ(4-アニシル)-2-ベンジル-1,2-エチレンジアミン、1-メチル-2,2-ジナフチル-1,2-エチレンジアミン、1-イソブチル-2,2-ジナフチル-1,2-エチレンジアミン、1-イソプロピル-2,2-ジナフチル-1,2-エチレンジアミン、プロパンジアミン、ブタンジアミン、フェニレンジアミンなどを用いることができる。);
イリジウム錯体:[IrCl(L)]2、[IrBr(L)]2、[IrI(L)]2、[IrCp*(L)]2、[Ir(cod)(L)]OTf、[Ir(cod)(L)]BF4、[Ir(cod)(L)]ClO4、[Ir(cod)(L)]PF6、[Ir(cod)(L)]SbF6、[Ir(cod)(L)]BPh4、[Ir(nbd)(L)]B{3,5-(CF3)2C6H3}4、[Ir(nbd)(L)]OTf、[Ir(nbd)(L)]BF4、[Ir(nbd)(L)]ClO4、[Ir(nbd)(L)]PF6、[Ir(nbd)(L)]SbF6、[Ir(nbd)(L)]BPh4、[Ir(nbd)(L)]B{3,5-(CF3)2C6H3}4;
パラジウム錯体:[PdCl2(L)]、[PdBr2(L)]、[PdI2(L)]、[Pd(π-allyl)(L)]Cl、[Pd(π-allyl)(L)]OTf、[Pd(π-allyl)(L)]BF4、[Pd(π-allyl)(L)]ClO4、[Pd(π-allyl)(L)]PF6、[Pd(π-allyl)(L)]BPh4、[Pd(L)](OTf)2、[Pd(L)](BF4)2、[Pd(L)](ClO4)2、[Pd(L)](PF6)2、[Pd(L)](BPh4)2、[Pd(L)2]、[Pd(L)2](OAc)2、[Pd(L)(H2O)2](OTf)2、[Pd(L)(H2O)2](BF4)2、[Pd(L)(H2O)2](ClO4)2、Pd(L)(H2O)2](PF6)2、[Pd(L)(H2O)2](BPh4)2、[{Pd(L)}2(μ-OH)2](OTf)2、[{Pd(L)}2(μ-OH)2](BF4)2、[{Pd(L)}2(μ-OH)2](ClO4)2、[{Pd(L)}2(μ-OH)2](PF6)2、[{Pd(L)}2(μ-OH)2](BPh4)2;
ニッケル錯体:[NiCl2(L)]、[NiBr2(L)]、[NiI2(L)]、[Ni(π-allyl)(L)]Cl、[Ni(cod)(L)]、[Ni(nbd)(L)];
銅錯体:[CuCl(L)]、[CuBr(L)]、[CuI(L)]、[CuH(L)]、[Cu(η1-BH4)(L)]、[Cu(Cp)(L)]、[Cu(Cp*)(L)]、[Cu(L)(CH3CN)2]OTf、[Cu(L)(CH3CN)2]BF4、[Cu(L)(CH3CN)2]ClO4、[Cu(L)(CH3CN)2]PF6、[Cu(L)(CH3CN)2]BPh4
BINAPのナフチル環にC1-6アルキル基やC6-14アリール基等の置換基をもつBINAP誘導体、例えば、2,2’-ビス(ジフェニルホスフィノ)-6,6’-ジメチル-1,1’-ビナフチル;
BINAPのナフチル環が部分的に水素化されたBINAP誘導体、例えば、2,2’-ビス(ジフェニルホスフィノ)-5,6,7,8,5’,6’,7’,8’-オクタヒドロ-1,1’-ビナフチル(H8BINAP);
BINAPのリン原子上のベンゼン環にC1-6アルキル基、ハロゲン原子、モノ又はジ-C1-6アルキルアミノ基、C1-6アルコキシ基、ピロリジニル基などの置換基を1ないし5個有するBINAP誘導体、例えば、2,2’-ビス[ビス(4-クロロフェニル)ホスフィノ)-1,1’-ビナフチル、2,2’-ビス(ジ-p-トリルホスフィノ)-1,1’-ビナフチル(tol-BINAP)、2,2’-ビス[ビス(3,5-ジメチルフェニル)ホスフィノ]-1,1’-ビナフチル(xyl-BINAP)、2,2’-ビス[ビス(3,5-ジエチルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジイソプロピルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジ-tert-ブチルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジメチルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジエチルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジイソプロピルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス[ビス(4-ジエチルアミノフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス[4-(ピロリジン-1-イル)フェニル]ホスフィノ]-1,1’-ビナフチル、2,2’-ビス(ジ-p-メトキシフェニルホスフィノ)-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジメチル-4-メトキシフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィノ]-1,1’-ビナフチル(DTBM-BINAP);
2,2’-ビス(ジシクロヘキシルホスフィノ)-6,6’-ジメチル-1,1’-ビフェニル(BICHEP),2,2’-ビス(ジフェニルホスフィノ)-6,6’-ジメトキシビフェニル(MeO-BIPHEP),2,3-ビス(ジフェニルホスフィノ)ブタン(CHIRAPHOS)、1-シクロヘキシル-1,2-ビス(ジフェニルホスフィノ)エタン(CYCPHOS)、1,2-ビス[(2-メトキシフェニル)フェニルホスフィノ]エタン(DIPAMP)、1,2-ビス(ジフェニルホスフィノ)プロパン(PROPHOS)、2,4-ビス(ジフェニルホスフィノ)ペンタン(SKEWPHOS)、SKEWPHOSのリン原子上のベンゼン環にC1-6アルキル基などの置換基を1ないし5個有するSKEWPHOS誘導体、1-[1’,2-ビス(ジフェニルホスフィノ)フェロセニル]エチレンジアミン(BPPFA)、1-置換-3,4-ビス(ジフェニルホスフィノ)ピロリジン(DEGPHOS)、2,3-O-イソプロピリデン-2,3-ジヒドロキシ-1,4-ビス(ジフェニルホスフィノ)ブタン(DIOP)、置換-1,2-ビスホスホラノベンゼン(DuPHOS)、置換-1,2-ビスホスホラノエタン(BPE)、5,6-ビス(ジフェニルホスフィノ)-2-ノルボルネン(NORPHOS)、N,N’-ビス(ジフェニルホスフィノ)-N,N’-ビス(1-フェニルエチル)エチレンジアミン(PNNP)、2,2’-ジフェニルホスフィノ-1,1’-ビシクロペンチル(BICP)、4,12-ビス(ジフェニルホスフィノ)-[2,2]-パラシクロファン(PhanePHOS)、N-置換-N-ジフェニルホスフィノ-1-[2-(ジフェニルホスフィノ)フェロセニル]エチルアミン(BoPhoz)、1-[2-(2置換ホスフィノ)フェロセニル]エチル-2置換ホスフィン(Josiphos)、1-[2-(2’-2置換ホスフィノフェニル)フェロセニル]エチル-2置換ホスフィン(Walphos)、2,2’-ビス(α-N,N-ジメチルアミノフェニルメチル)-1,1’-ビス(2置換ホスフィノ)フェロセン(Mandyphos)、2置換ホスフィノ-2-[α-(N,N-ジメチルアミノ)-o-2置換ホスフィノフェニル-メチル]フェロセン(Taniaphos)、1,1-ビス(2置換-ホスホタノ)フェロセン(FerroTANE)、7,7’-ビス(ジフェニルホスフィノ)-3,3’,4,4’-テトラヒドロ-4,4’-ジメチル-8,8’-ビ(2H-1,4-ベンゾオキサジン)(Solphos)などが挙げられる。
「遷移金属錯体」に用いる「配位子」として光学活性な配位子を使用する。
Lで表される「ジホスフィン配位子」のうち、SKEWPHOSのリン原子上の1個のベンゼン環にC1-6アルキル基などの置換基を1ないし5個有するSKEWPHOS誘導体は、特許文献WO2013/146987に記載する方法で合成することができる。
例えば、Lで表される「ジホスフィン配位子」のうち、SKEWPHOSのリン原子上の1個のベンゼン環にC1-6アルキル基などの置換基を1ないし5個有するSKEWPHOS誘導体のロジウム錯体は、特許文献WO2013/146987に記載する方法で合成することができる。
式:
[Ru(OCORa)2La] (VIII)
[式中、Raは、置換されていてもよいC1-3アルキル基を;Laはジホスフィン配位子を示す。]
で表されるルテニウム錯体が好ましい。
Raで表される「置換されていてもよいC1-3アルキル基」における「C1-3アルキル基」として好適なものは、メチル、エチル、イソプロピルであり、特に好ましくは、メチルである。
Raで表される「置換されていてもよいC1-3アルキル基」における「C1-3アルキル基」は、それぞれ、置換可能な位置に1ないし5個(好ましくは1ないし3個)の置換基を有していてもよい。このような置換基としては、例えば、上記置換基群Aが挙げられる。該置換基は、ハロゲン原子が好ましく、フッ素原子がより好ましい。置換基が複数存在する場合、各置換基は、同一でも異なっていてもよい。
Raで表される「置換されていてもよいC1-3アルキル基」は、好ましくは、メチルまたはトリフルオロメチルであリ、より好ましくはトリフルオロメチルである。
Laで表されるジホスフィン配位子としては、例えば、Lで例示したものと同様のものが挙げられ;中でも好ましくは、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(以下、BINAPと略記することがある);BINAPのナフチル環にC1-6アルキル基やC6-14アリール基等の置換基をもつBINAP誘導体、例えば、2,2’-ビス(ジフェニルホスフィノ)-6,6’-ジメチル-1,1’-ビナフチル;BINAPのナフチル環が部分的に水素化されたBINAP誘導体、例えば、2,2’-ビス(ジフェニルホスフィノ)-5,6,7,8,5’,6’,7’,8’-オクタヒドロ-1,1’-ビナフチル(H8BINAP);BINAPのリン原子上の1個のベンゼン環にC1-6アルキル基などの置換基を1ないし5個有するBINAP誘導体、例えば、2,2’-ビス(ジ-p-トリルホスフィノ)-1,1’-ビナフチル(tol-BINAP)、2,2’-ビス[ビス(3,5-ジメチルフェニル)ホスフィノ]-1,1’-ビナフチル(xyl-BINAP)、2,2’-ビス[ビス(3,5-ジエチルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジイソプロピルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジ-tert-ブチルフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジメチルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジエチルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス〔ビス(4-ジメチルアミノ-3,5-ジイソプロピルフェニル)ホスフィノ〕-1,1’-ビナフチル、2,2’-ビス[ビス(4-ジエチルアミノフェニル)ホスフィノ]-1,1’-ビナフチルおよび2,2’-ビス[ビス[4-(ピロリジン-1-イル)フェニル]ホスフィノ]-1,1’-ビナフチル、2,2’-ビス(ジ-p-メトキシフェニルホスフィノ)-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジメチル-4-メトキシフェニル)ホスフィノ]-1,1’-ビナフチル、2,2’-ビス[ビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィノ]-1,1’-ビナフチル(DTBM-BINAP)、4,12-ビス(ジフェニルホスフィノ)-[2,2]-パラシクロファン(PhanePHOS)、2,2’-ビス(α-N,N-ジメチルアミノフェニルメチル)-1,1’-ビス(2置換ホスフィノ)フェロセン(Mandyphos)であり;
より好ましくは、2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2,2’-ビス[ビス(4-クロロフェニル)ホスフィノ)-1,1’-ビナフチル、2,2’-ビス(α-N,N-ジメチルアミノフェニルメチル)-1,1’-ビス(2置換ホスフィノ)フェロセン(Mandyphos)であり;
さらに好ましくは、2,2’-ビス[ビス(4-クロロフェニル)ホスフィノ)-1,1’-ビナフチル、2,2’-ビス(α-N,N-ジメチルアミノフェニルメチル)-1,1’-ビス(2置換ホスフィノ)フェロセン(Mandyphos)である。
式:
[Ru(OCORa’)2La’] (VIII’)
[式中、Ra’は、トリフルオロメチル基を;La’は、ジホスフィン配位子の光学活性体であり、
(1)式:
式:
(2)式:
で表される化合物の光学活性体から選ばれる。]
で表されるルテニウム錯体である。
なお、前記した混合物からなる光学活性体とは、La’が式(IX- a)で表される化合物の光学活性体であるルテニウム錯体(VIII’)とLa’が式(IX-b)で表される化合物の光学活性体であるルテニウム錯体(VIII’)との混合物(但し、1モル:1モルの混合物は除く)をルテニウム錯体として用いる態様を意味する。
これらルテニウム錯体は、製造法(A)などの各種水素化反応において、反応選択性の高い触媒として有用である。
ルテニウム錯体の好適な具体例としては、以下の錯体が挙げられる。[Ru(OCOCF3)2{(S)-p-Cl-binap}]、[Ru(OCOCF3)2{(S)-(R)-mandyphos}]、[RuCl2(S)-binap]、[Ru(OCOCF3)2{(S)-binap}]、[Ru(OCOCF3)2{(S)-phanephos}]。好ましくは、[Ru(OCOCF3)2{(S)-binap}]および[Ru(OCOCF3)2{(S)-(R)-mandyphos}]である。
無機塩基としては、例えば、水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水酸化セシウムなどの水酸化アルカリ金属;リチウムメトキシド、ナトリウムメトキシド、カリウムメトキシド、リチウムエトキシド、ナトリウムエトキシド、カリウムエトキシド、リチウムプロポキシド、ナトリウムプロポキシド、カリウムプロポキシド、リチウムイソプロポキシド、ナトリウムイソプロポキシド、カリウムイソプロポキシド、カリウムtert-ブトキシドなどの炭素数1ないし6のアルカリ金属アルコキシド;ナトリウムチオメトキシドなどの炭素数1ないし6のアルカリ金属チオアルコキシド;炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸塩;炭酸水素ナトリウム、炭酸水素カリウム等の炭酸水素塩;酢酸ナトリウム、酢酸カリウム等の酢酸塩;リン酸三カリウム、リン酸ナトリウム等のリン酸塩;リン酸一水素カリウム、リン酸一水素ナトリウム等のリン酸一水素塩が挙げられる。
塩基の使用量は、溶媒の種類、その他の反応条件により異なるが、通常、基質である式(I)で表される化合物またはその塩1モルに対して、約0.01モル以上であり、溶媒として用いることもできる。
スルホン酸とは、1個以上のスルホ基を有する化合物を示し、中でも好ましくは、上記式(VII)で表されるスルホン酸であり;より好ましくは、メタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸であり;特に好ましくはp-トルエンスルホン酸である。
酸の使用量は、溶媒の種類、その他の反応条件により異なるが、通常、基質である式(I)で表される化合物またはその塩1モルに対して、約0.01モル以上であり、溶媒として用いることもできる。好ましくは0.05~1.5モルである。
製造法(A)における「水素化反応」に添加してもよい塩としては、上記の「無機塩基」で例示した塩に加え、例えば、「水素化反応」に用いることのできる上記の「酸」を酸成分とする塩が挙げられ、中でもハロゲン陰イオンを有する塩が好ましく、例えば、ハロゲン化アルカリ金属および
式:
で表される化合物などが挙げられる。
以下に、製造法(A)を用いた式(V)で表される化合物の光学活性体またはその塩の製造法を説明する。
式(V)で表される化合物の光学活性体またはその塩は、下記の反応式に示す製造法(B)によって製造することができる。
工程B-1は、下記の反応式に示すように式(I’)で表される化合物またはその塩を不斉水素化反応に付することにより、式(II’)で表される化合物の光学活性体またはその塩を製造する工程である。
工程B-2は、下記の反応式に示すように工程B-1で得られた式(II’)で表される化合物の光学活性体またはその塩と式(III)で表される化合物またはその塩を縮合反応に付することにより、式(IV)で表される化合物の光学活性体またはその塩を製造する工程である。
無機塩基としては、例えば、水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水酸化セシウムなどの水酸化アルカリ金属;リチウムメトキシド、ナトリウムメトキシド、カリウムメトキシド、リチウムエトキシド、ナトリウムエトキシド、カリウムエトキシド、リチウムプロポキシド、ナトリウムプロポキシド、カリウムプロポキシド、リチウムイソプロポキシド、ナトリウムイソプロポキシド、カリウムイソプロポキシド、カリウムtert-ブトキシドなどの炭素数1ないし6のアルカリ金属アルコキシド;ナトリウムチオメトキシドなどの炭素数1ないし6のアルカリ金属チオアルコキシド;炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸塩;炭酸水素ナトリウム、炭酸水素カリウム等の炭酸水素塩;酢酸ナトリウム、酢酸カリウム等の酢酸塩;リン酸三カリウム、リン酸ナトリウム等のリン酸塩;リン酸一水素カリウム、リン酸一水素ナトリウム等のリン酸一水素塩が挙げられる。
工程B-2で用いてもよい塩基としては、炭酸カリウムが特に好ましい。
工程B-3は、下記の反応式に示すように化合物(IV)で表される化合物の光学活性体またはその塩を転位反応に付することにより、化合物(V)で表される化合物の光学活性体またはその塩を製造する工程である。
酸化剤の使用量は、溶媒の種類、その他の反応条件により異なるが、式(IV)で表される化合物の光学活性体またはその塩1モルに対して、通常、0.01~100モルであり、好ましくは、0.1~10モルであり、より好ましくは、0.9~2モルである。
塩基の使用量は、溶媒の種類、その他の反応条件により異なるが、通常、基質である式(IV)で表される化合物の光学活性体またはその塩1モルに対して、約0.001モル以上であり、好ましくは、0.001~10モルであり、より好ましくは0.01~2モルであり、溶媒として用いることもできる。
酸の使用量は、溶媒の種類、その他の反応条件により異なるが、式(IV)で表される化合物の光学活性体またはその塩1モルに対して、通常、0.001モル以上であり、好ましくは、0.001~10モルであり、より好ましくは0.01~2モルであり、溶媒として用いることもできる。
工程B-3の転位反応に添加してもよい塩としては、上記の「無機塩基」で例示した塩の他に、例えば、本転位反応に用いることのできる上記の「酸」を酸成分とする塩が挙げられ、中でもハロゲン陰イオンを有する塩が好ましい。ハロゲン陰イオンを有する塩としては、例えば、上記で示したようなハロゲン化アルカリ金属、上記式(VI)で表されるアンモニウム塩などが挙げられる。
鏡像体過剰率(% e.e.)=100 X [(R)-(S)]/[(R)+(S)] または100 X [(S)-(R)]/[(R)+(S)](式中、(R)および(S)は各鏡像体の高速液体クロマトグラフィーにおける面積を示す。)
また、クロマトグラフィーで用いられる溶媒は体積%を、その他は重量%を示す。
プロトンNMRスペクトルで、OHやNHプロトンなどブロードで確認できないものについて
は、データに記載していない。
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)
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
DMSO-d6: 重ジメチルスルホキシド
CD3OD : 重メタノール
1H-NMR : プロトン核磁気共鳴
13C-NMR : 13C核磁気共鳴
19F-NMR : 19F核磁気共鳴
31P-NMR : 31P核磁気共鳴
RuCl2{(S)-binap}: ジクロロ[(S)-(-)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル]ルテニウム(II)
1H核磁気共鳴スペクトル(1H-NMR):ブルカー社製BRUKER AVANCE 500(500MHz)、内部標準物質:テトラメチルシラン
13C核磁気共鳴スペクトル(13C-NMR):ブルカー社製BRUKER AVANCE 500(125MHz)、内部標準物質:CDCl3
19F核磁気共鳴スペクトル(19F-NMR):ブルカー社製BRUKER AVANCE 500(202MHz)、外部標準物質:トリフルオロ酢酸
31P核磁気共鳴スペクトル(31P-NMR):ブルカー社製BRUKER AVANCE 500(471MHz)、外部標準物質:85%-H3PO4水溶液
1,4,5,6-テトラヒドロピリジン-3-カルボキサミドの合成
1H-NMR (500MHz, CDCl3, TMS) δ (ppm) 1.72-1.76 (m, 2H), 2.15 (t,J=6.31Hz, 2H), 3.05-3.15 (m, 2H), 7.38 (s, 1H).
(NH, OH, COOH由来のプロトンは未検出)
13C-NMR (125MHz, CDCl3, CDCl3) δ(ppm) 20.03, 39.75, 94.15, 143.62, 173.99.
Anal. Calcd for C6H10N2O:C,57.12;H,7.99;N,22.21.Found:C,57.11;H,8.09;N,22.10.
ESI-MS:m/z 127.0873 [M+H]+.
IR(ATR, cm-1):3300 (νNH), 3201 (νNH), 3000-2800(νCH), 1622 (νC=O), 1506 (νC=C), 1423 (δCH), 1362 (δCH).
1,4,5,6-テトラヒドロピリジン-3-カルボキサミドパラトルエンスルホン酸塩0.85エタノール和物の合成
1H-NMR (500MHz, D2O) δ(ppm) 1.72-1.76 (m, 2H), 2.15 (t,J=6.31Hz, 2H), 3.05-3.15 (m, 2H), 7.38 (s, 1H).
(NH, OH, COOH由来のプロトンは未検出)
13C-NMR (125MHz, D2O) δ(ppm) 20.03, 39.75, 94.15, 143.62, 173.99.
Anal. Calcd for C6H10N2O:C,57.12;H,7.99;N,22.21.Found:C,57.11;H,8.09;N,22.10.
ESI-MS:m/z 127.0873 [M+H]+.
IR(ATR, cm-1):3300 (νNH), 3201 (νNH), 3000-2800(νCH), 1622 (νC=O), 1506 (νC=C), 1423 (δCH), 1362 (δCH).
ジトリフルオロアセタト[(S)-(-)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル]ルテニウム(II)錯体の合成
1H-NMR (500MHz, CDCl3, TMS) δ (ppm) 6.35-6.40 (m, 2H), 6.55 (br, 4H), 6.68 (br, 2H), 6.88 (br, 2H), 7.11 (br, 4H), 7.30 (br, 2H), 7.44 (br, 4H), 7.52 (br, 2H), 7.68 (br, 8H), 7.88 (br, 2H).
19F-NMR (471MHz, CDCl3, TFA) δ (ppm) -76.88 (s).
31P-NMR (202MHz, CDCl3, H3PO4) δ (ppm) 56.46 (s).
ジトリフルオロアセタト[(S)-(-)-2,2'-ビス(ビス(4-クロロフェニル)ホスフィノ)-1,1'-ビナフチル]ルテニウム(II)錯体の合成
1H-NMR (500MHz, CD3OD, TMS) δ (ppm) 6.25-6.36 (m, 2H), 6.40-6.55 (m, 4H), 6.84-7.03 (m, 6H), 7.28-7.39 (m, 2H), 7.41-7.52 (m, 4H), 7.62-7.75 (m, 6H), 7.76-7.89 (m, 4H).
31P-NMR (202MHz, CD3OD, H3PO4) δ (ppm) 55.42 (s).
ジトリフルオロアセタト[(RP,R'P)-1,1'-ビス[(S)-α-(ジメチルアミノ)ベンジル]-2,2'-ビス(ジフェニルホスフィノ)フェロセン]ルテニウム(II)錯体の合成
31P-NMR (202MHz, CD3OD, H3PO4) δ (ppm) 63.14 (s).
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(工程1) 粗(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
1H-NMR (500MHz, D2O) δ(ppm) 1.55-1.72 (m, 2H), 1.76-1.97 (m, 2H), 2.29 (s, 3H), 2.65-2.76 (m, 1H), 2.88-2.99 (m, 1H), 3.00-3.07 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.29 (m, 1H), 7.27 (d, J=7.88Hz, 2H), 7.62(d, J=7.88Hz, 2H). (NH, OH, COOH由来のプロトンは未検出)
13C-NMR (125MHz, D2O) δ(ppm) 20.58, 25.57, 38.42, 43.93, 44.77, 125.45, 129.55, 139.74, 142.48, 177.26.
Anal. Calcd for C13H20N2O4S:C,51.98;H,6.71;N,9.33;S,10.68.Found:C,51.20;H,6.73;N,9.02;S,11.14.
ESI-MS:m/z 129.1033(C6H12N2O) [M+H]+, m/z 171.0135(C7H8O3S) [M-H]-.
IR(ATR, cm-1):3163 (νNH), 2900-2800(νCH), 1670 (νC=O), 1435 (δCH), 1170 (νS=O).
(高速液体クロマトグラフィー条件)
カラム:CD-Ph (資生堂株式会社製)
移動相:0.1mol/L-ヘキサフルオロリン酸カリウム水溶液/アセトニトリル(容積比:95/5)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(S)体15.2min、(R)体17.0min.
1H-NMR (500MHz, D2O) δ(ppm) 1.55-1.71 (m, 2H), 1.76-1.87 (m, 1H), 1.86-1.96 (m, 1H), 2.28 (s, 3H), 2.65-2.75 (m, 1H), 2.88-2.99 (m, 1H), 3.00-3.07 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.29 (m, 1H), 7.26 (d, J=8.20Hz, 2H), 7.60 (d, J=8.51Hz, 2H).
13C-NMR (125MHz, D2O) δ(ppm) 20.55, 25.55, 38.39, 43.89, 44.72, 125.42, 129.51, 139.64, 142.47, 177.28.
Anal. Calcd for C13H20N2O4S:C,51.98;H,6.71;N,9.33;S,10.68.Found:C,51.90;H,6.79;N,9.24;S,10.65.
ESI-MS:m/z 129.1035(C6H12N2O) [M+H]+, m/z 171.0134(C7H8O3S) [M-H]-.
IR(ATR, cm-1):3159 (νNH), 2950-2800(νCH), 1670 (νC=O), 1435 (δCH), 1171 (νS=O).
[α] (c 0.98, MeOH, 25oC)=-0.45o.
(高速液体クロマトグラフィー条件)
カラム:CD-Ph (資生堂株式会社製)
移動相:0.1mol/L-ヘキサフルオロリン酸カリウム水溶液/アセトニトリル(容積比:95/5)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(S)体15.2min、(R)体17.0min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CD-Ph (資生堂株式会社製)
移動相:0.1mol/L-ヘキサフルオロリン酸カリウム水溶液/アセトニトリル(容積比:95/5)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(S)体15.2min、(R)体17.0min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CD-Ph (資生堂株式会社製)
移動相:0.1mol/L-ヘキサフルオロリン酸カリウム水溶液/アセトニトリル(容積比:95/5)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(S)体15.2min、(R)体17.0min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:IC(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(R)体12.6min、(S)体16.4min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CD-Ph (資生堂株式会社製)
移動相:0.1mol/L-ヘキサフルオロリン酸カリウム水溶液/アセトニトリル(容積比:95/5)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(S)体15.2min、(R)体17.0min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CHIRALPAK AD-H (ダイセル化学社製)
移動相:n-ヘプタン/エタノール/メタノール/ジエチルアミン混液 (容積比: 800/150/50/1)
流速:0.8mL/min
検出:UV220nm
温度:40℃
保持時間:(S)体11.3min、(R)体12.2min.
粗(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CHIRALPAK AD-H (ダイセル化学社製)
移動相:n-ヘプタン/エタノール/メタノール/ジエチルアミン混液 (容積比: 800/150/50/1)
流速:0.8mL/min
検出:UV220nm
温度:40℃
保持時間:(S)体11.3min、(R)体12.2min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(工程1) 粗(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:CHIRALPAK AD-H (ダイセル化学社製)
移動相:n-ヘプタン/エタノール/メタノール/ジエチルアミン混液 (容積比: 800/150/50/1)
流速:0.8mL/min
検出:UV220nm
温度:40℃
保持時間:(S)体11.3min、(R)体12.2min.
(高速液体クロマトグラフィー条件)
カラム:CHIRALPAK AD-H (ダイセル化学社製)
移動相:n-ヘプタン/エタノール/メタノール/ジエチルアミン混液 (容積比: 800/150/50/1)
流速:0.8mL/min
検出:UV220nm
温度:40℃
保持時間:(S)体11.3min、(R)体12.2min.
(R)-1-(3-(2-シアノベンジル)-1-メチル-2,6-ジオキソ-1,2,3,6-テトラヒドロピリミジン-4-イル)ピペリジン-3-カルボキサミドの合成
1H-NMR (500MHz, CDCl3, TMS) δ(ppm) 1.46 (qt, J=13.0, 3.5Hz, 1H), 1.70 (dt, J=13.5, 4.0Hz, 1H), 1.91 (dd, J=13.0,3.5Hz, 1H), 2.47 (tt, J=11.5, 3.5Hz, 1H), 2.55 (t, J=11.5Hz, 1H), 2.72 (t, J=11.5Hz, 1H), 2.88 (d, J=11.5Hz, 1H), 3.12-3.20 (dm, 1H), 3.25 (s, 3H), 5.13 (d, J=16.0Hz, 1H), 5.32 (d, J=16.0Hz, 1H), 5.34 (s, 1H), 5.67 (bs, 1H), 5.73 (bs, 1H), 7.11 (d, J=8.0Hz, 1H), 7.32 (t, J=7.5Hz,1H), 7.51 (td, J=8.0, 1.5Hz, 1H), 7.61 (dd, J=7.5, 1.5Hz, 1H).
13C-NMR (125MHz, CDCl3, CDCl3) δ(ppm) 24.28, 27.30, 28.20, 42.46, 46.43, 51.91, 54.01, 91.27, 110.74, 117.68, 127.18, 128.18, 133.28, 133.61, 141.01, 152.99, 159.80, 163.01, 174.80.
ESI-MS:m/z 368.1731[M+H]+, 390.1557[M+Na]+, 406.1262 [M+H]+.
IR(ATR, cm-1):3387, 3319, 3202 (νNH), 2941, 2853 (νCH), 2226 (νCN), 1690, 1676, 1628 (δCH).
[α] (c 0.98, MeOH, 25oC)=-21.4o.
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾニトリルの合成
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾニトリル安息香酸塩の合成
(R)-1-(3-(2-シアノ-5-フルオロベンジル)-1-メチル-2,6-ジオキソ-1,2,3,6-テトラヒドロピリミジン-4-イル)ピペリジン-3-カルボキサミドの合成
1H-NMR (500MHz, CDCl3) δ (ppm) 1.45-1.60 (m, 1H) 1.62-1.72 (m, 1H) 1.80 (m, 1H) 1.92-2.07 (m, 1H) 2.49-2.59 (m, 1H) 2.64 (t, J=10.88 Hz,1H) 2.82 (t, J=10.56 Hz, 1H) 2.94 (d, J=11.98 Hz, 1H) 3.14-3.28 (m, 1H) 3.34 (s, 3H) 5.17 (d, J=16.39 Hz,1H) 5.38 (d, 1H, J=16.08 Hz, 1H) 5.42 (s, 1H) 5.48 (brs, 1H) 5.66 (brs, 1H) 6.90 (dd, J=9.14 Hz, 2.52 Hz, 1H) 7.10 (td, J=8.04 Hz, 2.52 Hz, 1H) 7.70 (dd, J=8.67 Hz, 5.20 Hz, 1H).
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-4-フルオロベンゾニトリルの合成
1H-NMR (500MHz, CDCl3) δ (ppm) 1.23 (d, J=11.03 Hz, 1H) 1.30 (brs, 2H) 1.56-1.67 (m, 1H) 1.72-1.83 (m, 1H) 1.95 (dd, J=12.77 Hz, 3.94 Hz, 1H) 2.41 (m,1H) 2.61 (m, 1H) 2.87-2.98 (m, 2H) 2.99-3.05 (m, 1H) 3.32 (s, 3H) 5.23-5.32 (m, 2H) 5.39 (s, 1H) 6.86 (dd, J=8.99 Hz, 2.36 Hz, 1H) 7.09 (td, J=8.04 Hz, 2.52 Hz, 1H) 7.69 (dd, J=8.51 Hz, 5.36 Hz, 1H).
13C NMR (126 MHz, CDCl3) δppm 28.0, 33.4, 46.1, 51.9, 59.7, 90.8, 114.6,114.7, 115.6, 115.8, 116.4, 135.4, 135.5, 144.6, 152.7, 159.5, 162.9.
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)-4-フルオロベンゾニトリルコハク酸塩の合成
1H-NMR (500MHz, DMSO) δ (ppm) 1.35 (d, J=8.83 Hz, 1H) 1.42-1.57 (m, 1H) 1.66-1.97 (m, 2H) 2.54-2.77 (m, 2H) 2.91 (d, J=11.35 Hz, 1H) 3.00-3.07 (m, 1H) 3.08 (m, 1H) 3.09 (s, 3H) 3.14 (m, 1H) 5.12 (d, J=16.08 Hz, 1H) 5.20 (d, J=16.39 Hz, 1H) 5.38 (s, 1H) 7.17 (dd, J=9.62 Hz, 2.36 Hz, 1H) 7.35 (td, J=8.51 Hz, 2.52 Hz, 1H) 7.95 (dd, J=8.67 Hz, 5.52 Hz, 1H).
13C NMR (126 MHz, DMSO) δ ppm 27.9, 31.6, 46.3, 47.0, 51.7, 55.8, 90.3, 106.9, 115.7, 117.1, 136.45, 136.53, 145.8, 152.3, 159.7, 162.7, 164.1, 166.1, 175.2.
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾニトリル安息香酸塩の合成
(R)-2-((6-(3-アミノピペリジン-1-イル)-3-メチル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メチル)ベンゾニトリル安息香酸塩の合成
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:IC(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(R)体12.6min、(S)体16.4min.
(R)-ピペリジン-3-カルボキサミドパラトルエンスルホン酸塩の合成
(高速液体クロマトグラフィー条件)
カラム:IC(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV200nm
温度:25℃
保持時間:(R)体12.6min、(S)体16.4min.
(R)-ピペリジン-3-カルボキサミドの合成
(高速液体クロマトグラフィー条件)
カラム:AD-RH(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV220nm
温度:25℃
保持時間: (S)体12.7min、(R)体14.2min.
(R)-ピペリジン-3-カルボキサミドの合成
(高速液体クロマトグラフィー条件)
カラム:AD-RH(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV220nm
温度:25℃
保持時間:(S)体12.7min、 (R)体14.2min.
(S)-ピペリジン-3-カルボキサミドの合成
(高速液体クロマトグラフィー条件)
カラム:AD-RH(ダイセル化学社製)
移動相:
0.020mol/L-リン酸水溶液/アセトニトリル(容積比:7/3)
流速:0.5mL/min
検出:UV220nm
温度:25℃
保持時間:(S)体12.7min、(R)体14.2min.
Claims (11)
- 式:
で表される化合物またはその塩を有機金属錯体の存在下で水素化反応に付すことを特徴とする、
式:
で表される化合物の光学活性体またはその塩の製造法。 - 有機金属錯体が遷移金属錯体である、請求項1記載の製造法。
- 遷移金属錯体がルテニウム錯体である、請求項2記載の製造法。
- ルテニウム錯体が、
式:
[Ru(OCORa)2La] (VIII)
[式中、Raは、置換されていてもよいC1-3アルキル基を;Laはジホスフィン配位子を示す。]
で表される請求項3記載の製造法。 - 式:
で表される化合物の光学活性体またはその塩と、
式:
で表される化合物またはその塩とを反応させることを特徴とする、
式:
で表される化合物の光学活性体またはその塩の製造法。 - (1)式:
で表される化合物またはその塩を有機金属錯体の存在下で水素化反応に付すことにより、
式:
で表される化合物の光学活性体またはその塩を製造する工程;および
(2)式:
で表される化合物の光学活性体またはその塩と、式:
で表される化合物またはその塩とを反応させることにより、
式:
で表される化合物の光学活性体またはその塩を製造する工程を含む、請求項9記載の製造法。
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JP2016507852A JPWO2015137496A1 (ja) | 2014-03-14 | 2015-03-13 | 複素環化合物の製造法 |
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Cited By (2)
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CN110669046A (zh) * | 2019-09-10 | 2020-01-10 | 武汉大学 | 具有多个手性中心的多取代四氢-γ-咔啉类衍生物及其立体多样性的制备方法 |
CN110753689A (zh) * | 2017-02-28 | 2020-02-04 | 武田药品工业株式会社 | 用于生产杂环化合物的方法 |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09502459A (ja) * | 1994-06-23 | 1997-03-11 | フイルメニツヒ ソシエテ アノニム | (+)−(1r)−シス−3−オキソ−2−ペンチル−1−シクロペンタン酢酸の製造法 |
JP2002179692A (ja) * | 2000-09-11 | 2002-06-26 | Bayer Ag | ジホスフィン |
JP2002537305A (ja) * | 1999-02-19 | 2002-11-05 | ロディア・シミ | キラルジホスフィンの製造方法 |
JP2003231691A (ja) * | 2001-12-07 | 2003-08-19 | Takeda Chem Ind Ltd | ジホスフィン化合物の製造法およびその製造中間体 |
WO2003072197A1 (en) * | 2002-02-27 | 2003-09-04 | Pfizer Products Inc. | Acc inhibitors |
JP2009508873A (ja) * | 2005-09-16 | 2009-03-05 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
JP2012521385A (ja) * | 2009-03-24 | 2012-09-13 | エフ.ホフマン−ラ ロシュ アーゲー | プロピオン酸誘導体の調製方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE438653T1 (de) * | 2001-12-07 | 2009-08-15 | Takeda Pharmaceutical | Verfahren zur herstellung von diphosphinverbindungen und zwischenprodukte für das verfahren |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
GB0622202D0 (en) * | 2006-11-07 | 2006-12-20 | Addex Pharmaceuticals Sa | Novel compounds |
JP5265513B2 (ja) | 2007-02-19 | 2013-08-14 | 株式会社カネカ | 光学活性3−アミノピペリジン又はその塩の製造方法 |
WO2009015179A1 (en) * | 2007-07-23 | 2009-01-29 | Syndax Pharmaceuticals, Inc. | Novel compounds and methods of using them |
WO2010131146A1 (en) * | 2009-05-12 | 2010-11-18 | Pfizer Limited | Cyclobutenedione derivatives |
CN102471267A (zh) | 2009-07-21 | 2012-05-23 | 住友化学株式会社 | 光学活性3-哌啶甲酰胺的制造方法 |
-
2015
- 2015-03-13 CN CN201580024934.1A patent/CN106458897A/zh active Pending
- 2015-03-13 WO PCT/JP2015/057541 patent/WO2015137496A1/ja active Application Filing
- 2015-03-13 JP JP2016507852A patent/JPWO2015137496A1/ja not_active Abandoned
- 2015-03-13 EP EP15762433.9A patent/EP3118192A4/en not_active Withdrawn
- 2015-03-13 CA CA2942631A patent/CA2942631A1/en not_active Abandoned
- 2015-03-13 US US15/125,299 patent/US9809569B2/en not_active Expired - Fee Related
-
2017
- 2017-10-18 US US15/786,953 patent/US20180079741A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09502459A (ja) * | 1994-06-23 | 1997-03-11 | フイルメニツヒ ソシエテ アノニム | (+)−(1r)−シス−3−オキソ−2−ペンチル−1−シクロペンタン酢酸の製造法 |
JP2002537305A (ja) * | 1999-02-19 | 2002-11-05 | ロディア・シミ | キラルジホスフィンの製造方法 |
JP2002179692A (ja) * | 2000-09-11 | 2002-06-26 | Bayer Ag | ジホスフィン |
JP2003231691A (ja) * | 2001-12-07 | 2003-08-19 | Takeda Chem Ind Ltd | ジホスフィン化合物の製造法およびその製造中間体 |
WO2003072197A1 (en) * | 2002-02-27 | 2003-09-04 | Pfizer Products Inc. | Acc inhibitors |
JP2009508873A (ja) * | 2005-09-16 | 2009-03-05 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
JP2012521385A (ja) * | 2009-03-24 | 2012-09-13 | エフ.ホフマン−ラ ロシュ アーゲー | プロピオン酸誘導体の調製方法 |
Non-Patent Citations (9)
Title |
---|
ANDERSON, B. D. ET AL.: "Shio Keisei ni yoru Suiyosei Yuki Kagobutsu no Chosei, Saishin Soyaku Kagaku last volume", TECHNOMICS, no. 34, 25 September 1999 (1999-09-25), pages 347 - 365, XP008185726 * |
DATABASE REGISTRY 16 November 1984 (1984-11-16), XP055359312, retrieved from STN Database accession no. 7032-11-3 * |
DATABASE REGISTRY 26 March 2010 (2010-03-26), XP055359320, retrieved from STN Database accession no. 1214903-21-5 * |
DATABASE REGISTRY 28 March 2008 (2008-03-28), XP055359331, retrieved from STN Database accession no. 1010645-58-5 * |
DATABASE REGISTRY 8 June 2008 (2008-06-08), XP055359326, retrieved from STN Database accession no. 1026661-43-7 * |
ICHIKAWA, E. ET AL.: "New Entries in Lewis Acid- Lewis Base Bifunctional Asymmetric Catalyst: Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives", J. AM. CHEM. SOC., vol. 126, no. 38, 2004, pages 11808 - 11809, XP055224653, ISSN: 0002-7863 * |
LEI, A. ET AL.: "Asymmetric Hydrogenation of Pyridines: Enantioselective Synthesis of Nipecotic Acid Derivatives", EUR. J. ORG. CHEM., no. 19, 2006, pages 4343 - 4347, XP055224651, ISSN: 1434-193x * |
See also references of EP3118192A4 * |
TROXLER, F.: "29. Elektrophile und nucleophile Substitution partiell hydrierter Nicotinsaure- Derivate 11.Mitt. uber synthetische Indol- Verbindungen[1", HELVETICA CHIMICA ACTA, vol. 56, no. 1, 1973, pages 374 - 389, XP055224652, ISSN: 0018-019x * |
Cited By (4)
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CN110753689A (zh) * | 2017-02-28 | 2020-02-04 | 武田药品工业株式会社 | 用于生产杂环化合物的方法 |
CN110753689B (zh) * | 2017-02-28 | 2024-01-26 | 武田药品工业株式会社 | 用于生产杂环化合物的方法 |
CN110669046A (zh) * | 2019-09-10 | 2020-01-10 | 武汉大学 | 具有多个手性中心的多取代四氢-γ-咔啉类衍生物及其立体多样性的制备方法 |
CN110669046B (zh) * | 2019-09-10 | 2021-07-06 | 武汉大学 | 具有多个手性中心的多取代四氢-γ-咔啉类衍生物及其立体多样性的制备方法 |
Also Published As
Publication number | Publication date |
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US9809569B2 (en) | 2017-11-07 |
EP3118192A4 (en) | 2017-12-13 |
US20170081305A1 (en) | 2017-03-23 |
EP3118192A1 (en) | 2017-01-18 |
CA2942631A1 (en) | 2015-09-17 |
JPWO2015137496A1 (ja) | 2017-04-06 |
CN106458897A (zh) | 2017-02-22 |
US20180079741A1 (en) | 2018-03-22 |
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