JP2011207768A - (アリール)ジフルオロ酢酸エステル誘導体及びその製造方法 - Google Patents
(アリール)ジフルオロ酢酸エステル誘導体及びその製造方法 Download PDFInfo
- Publication number
- JP2011207768A JP2011207768A JP2010074026A JP2010074026A JP2011207768A JP 2011207768 A JP2011207768 A JP 2011207768A JP 2010074026 A JP2010074026 A JP 2010074026A JP 2010074026 A JP2010074026 A JP 2010074026A JP 2011207768 A JP2011207768 A JP 2011207768A
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- JP
- Japan
- Prior art keywords
- group
- ethyl
- aryl
- nmr
- iron
- Prior art date
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- -1 difluoroacetic acid ester Chemical class 0.000 title claims abstract description 197
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims abstract description 8
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 35
- 150000002978 peroxides Chemical class 0.000 claims description 32
- 150000002506 iron compounds Chemical class 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 20
- 150000003462 sulfoxides Chemical class 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 8
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 8
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 229910021575 Iron(II) bromide Inorganic materials 0.000 claims description 4
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 4
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims description 4
- LFKXWKGYHQXRQA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;iron Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LFKXWKGYHQXRQA-FDGPNNRMSA-N 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 3
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 7
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 92
- 238000005481 NMR spectroscopy Methods 0.000 description 70
- XYZWMVYYUIMRIZ-UHFFFAOYSA-N 4-bromo-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(Br)C=C1 XYZWMVYYUIMRIZ-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 22
- NZFLWVDXYUGFAV-UHFFFAOYSA-N 1-methyl-2-acetylpyrrole Chemical compound CC(=O)C1=CC=CN1C NZFLWVDXYUGFAV-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- JJHHIJFTHRNPIK-UHFFFAOYSA-N Diphenyl sulfoxide Chemical compound C=1C=CC=CC=1S(=O)C1=CC=CC=C1 JJHHIJFTHRNPIK-UHFFFAOYSA-N 0.000 description 12
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical class OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012300 argon atmosphere Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- PBWZKZYHONABLN-UHFFFAOYSA-M difluoroacetate Chemical compound [O-]C(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-M 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- RIKMMFOAQPJVMX-UHFFFAOYSA-N fomepizole Chemical compound CC=1C=NNC=1 RIKMMFOAQPJVMX-UHFFFAOYSA-N 0.000 description 8
- 229960004285 fomepizole Drugs 0.000 description 8
- BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 7
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 7
- GEZGAZKEOUKLBR-UHFFFAOYSA-N 1-phenylpyrrole Chemical compound C1=CC=CN1C1=CC=CC=C1 GEZGAZKEOUKLBR-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 5
- HGWXXIZVRRTDKT-UHFFFAOYSA-N ethyl 2,2-difluoro-2-iodoacetate Chemical compound CCOC(=O)C(F)(F)I HGWXXIZVRRTDKT-UHFFFAOYSA-N 0.000 description 5
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 4
- LCFFREMLXLZNHE-GBOLQPHISA-N (e)-2-[(3r)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Chemical compound C12=C(N)N=CN=C2N([C@@H]2CCCN(C2)C(=O)C(/C#N)=C/C(C)(C)N2CCN(CC2)C2COC2)N=C1C(C(=C1)F)=CC=C1OC1=CC=CC=C1 LCFFREMLXLZNHE-GBOLQPHISA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- LOWMYOWHQMKBTM-UHFFFAOYSA-N 1-butylsulfinylbutane Chemical compound CCCCS(=O)CCCC LOWMYOWHQMKBTM-UHFFFAOYSA-N 0.000 description 3
- SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 2
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 2
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- BQMPGKPTOHKYHS-UHFFFAOYSA-N 1h-pyrrole-2-carbonitrile Chemical compound N#CC1=CC=CN1 BQMPGKPTOHKYHS-UHFFFAOYSA-N 0.000 description 2
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 2
- VUPXKQHLZATXTR-UHFFFAOYSA-N 2,4-diphenyl-1,3-oxazole Chemical compound C=1OC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 VUPXKQHLZATXTR-UHFFFAOYSA-N 0.000 description 2
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- YLMFXCIATJJKQL-UHFFFAOYSA-N 2-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Br YLMFXCIATJJKQL-UHFFFAOYSA-N 0.000 description 2
- UVRRJILIXQAAFK-UHFFFAOYSA-N 2-bromo-4-methylaniline Chemical compound CC1=CC=C(N)C(Br)=C1 UVRRJILIXQAAFK-UHFFFAOYSA-N 0.000 description 2
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 2
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 2
- HLPIHRDZBHXTFJ-UHFFFAOYSA-N 2-ethylfuran Chemical compound CCC1=CC=CO1 HLPIHRDZBHXTFJ-UHFFFAOYSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- CXNVOWPRHWWCQR-UHFFFAOYSA-N 4-Chloro-ortho-toluidine Chemical compound CC1=CC(Cl)=CC=C1N CXNVOWPRHWWCQR-UHFFFAOYSA-N 0.000 description 2
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 2
- GGUOCFNAWIODMF-UHFFFAOYSA-N 4-chloroacetanilide Chemical compound CC(=O)NC1=CC=C(Cl)C=C1 GGUOCFNAWIODMF-UHFFFAOYSA-N 0.000 description 2
- HRXZRAXKKNUKRF-UHFFFAOYSA-N 4-ethylaniline Chemical compound CCC1=CC=C(N)C=C1 HRXZRAXKKNUKRF-UHFFFAOYSA-N 0.000 description 2
- XHLKOHSAWQPOFO-UHFFFAOYSA-N 5-phenyl-1h-imidazole Chemical compound N1C=NC=C1C1=CC=CC=C1 XHLKOHSAWQPOFO-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- 125000004226 phenanthren-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(C([H])=C([H])C3=C(*)C([H])=C([H])C([H])=C23)=C1[H] 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000004544 purin-8-yl group Chemical group N1=CN=C2N=C(NC2=C1)* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 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
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Abstract
【解決手段】下記一般式(1a)(式中、Araは、オキサゾール−5−イル基、2,4−ジフェニルオキサゾール−5−イル基、チアゾール−5−イル基、2−アセチルアミノチアゾール−5−イル基または2−アミノ−1,3,4−チアジアゾール−5−イル基を示す。R1は、炭素数1〜4のアルキル基を示す。)で表される(アリール)ジフルオロ酢酸エステル誘導体である。
【選択図】なし
Description
すなわち本発明は、一般式(1a)
また、本発明は、一般式(2)
一般式(3)
一般式(4)
Araは、Arに全て包含される。従って、一般式(1a)で表される(アリール)ジフルオロ酢酸エステル誘導体は、一般式(1)で表される(アリール)ジフルオロ酢酸エステル誘導体に全て包含される。
アリール類(2a)は、全てアリール類(2)に包含される。
ジフルオロ酢酸エステル類(3)、スルホキシド類(4)、鉄化合物、過酸化物、酸や反応条件などは、全て後述する(アリール)ジフルオロ酢酸エステル類(1)の製造方法の場合と同様である。
(アリール)ジフルオロ酢酸エステル誘導体(1)は、アリール類(2)とジフルオロ酢酸エステル類(3)を、スルホキシド類(4)、鉄化合物、過酸化物および場合によっては酸の存在下に反応させることにより製造することができる(工程1)。
(アリール)ジフルオロ酢酸エステル誘導体(1a)は、ArがAraであることを除けば、工程1の同様の方法により製造することができる(工程1a)。
製造方法の原料であるアリール類(2)に特に制限はなく、市販品さらには既知の方法で製造することができる化合物を使用することができる。
Arは、下記(i)〜(vii)で置換されていてもよいアリール基である。
(i)ハロゲン原子
(ii)炭素数1〜4のアルキル基
(iii)(炭素数1〜4のアルキル)カルボニル基
(iv)(炭素数1〜4のアルコキシ)カルボニル基
(v)シアノ基
(vi)炭素数1〜4のアルキル基もしくは(炭素数1〜4のアルキル)カルボニル基で置換されていてもよいアミノ基
(vii)フェニル基
その中でも、ピロール−2−イル基、インドール−2−イル基、オキサゾール−5−イル基、ピラゾール−5−イル基、イミダゾール−5−イル基、チアゾール−5−イル基、1,3,4−チアジアゾール−2−イル基、チオフェン−2−イル基またはフェニル基であることが好ましい。
ジフルオロ酢酸エステル類(3)のR1で示される炭素数1〜4のアルキル基は、直鎖状または分岐状のいずれでもよく、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基が例示できる。収率が良く入手容易な点で、メチル基またはエチル基が好ましく、エチル基がさらに好ましい。
(アリール)ジフルオロ酢酸エステル誘導体(1)としては、具体的には、ジフルオロ(1−フェニルピロール−2−イル)酢酸エチル、ジフルオロ(インドール−2−イル)酢酸エチル、(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル、ジフルオロ(オキサゾール−5−イル)酢酸エチル、ジフルオロ(チアゾール−5−イル)酢酸エチル、ジフルオロ(4−フェニルイミダゾール−5−イル)酢酸エチル、ジフルオロ(2,4−ジフェニルオキサゾール−5−イル)酢酸エチル、(2−アセチルアミノチアゾール−5−イル)ジフルオロ酢酸エチル、(5−アミノ−1,3,4−チアジアゾール−2−イル)ジフルオロ酢酸エチル、ジフルオロ(チオフェン−2−イル)酢酸エチル、(5−ブロモチオフェン−2−イル)ジフルオロ酢酸エチル、(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル、(2−アセチルアミノ−4−ブロモフェニル)ジフルオロ酢酸エチル、(2−アミノ−3,5−ジクロロフェニル)ジフルオロ酢酸エチル、(2−アミノ−3−ブロモ−5−メチルフェニル)ジフルオロ酢酸エチル、(2−アミノ−4−エトキシカルボニルフェニル)ジフルオロ酢酸エチル、(4−アセチル−2−アミノフェニル)ジフルオロ酢酸エチル、(2−アミノ−4−シアノフェニル)ジフルオロ酢酸エチル、(2−アセチルアミノ−4−クロロフェニル)ジフルオロ酢酸エチルなどが挙げられる。
工程1(及び工程1a)は、スルホキシド類(4)の存在下に反応を行うことが必須である。R3aおよびR3bは、各々、独立して、炭素数1〜4のアルキル基またはフェニル基を示す。スルホキシド類(4)のR3aおよびR3bで示される炭素数1〜4のアルキル基は、直鎖状または分岐状のいずれでもよく、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec−ブチル基、tert−ブチル基等が例示できる。その中でも、メチル基、ブチル基またはフェニル基であることが好ましい。
工程1(及び工程1a)は、鉄化合物の存在下に反応を行うことが必須である。用いることができる鉄化合物としては、収率が良い点で鉄(II)塩が好ましく、例えば、硫酸鉄(II)、硫酸鉄(II)アンモニウム、テトラフルオロホウ酸鉄(II)、塩化鉄(II)、臭化鉄(II)、ヨウ化鉄(II)等の無機酸塩や、酢酸鉄(II)、シュウ酸鉄(II)、ビス(アセチルアセトナト)鉄(II)、フェロセン、ビス(η5−ペンタメチルシクロペンタジエニル)鉄(II)等の有機金属化合物を例示することができ、これらを適宜組み合わせて用いても良い。また、工程1は過酸化物の存在下で行うため、鉄粉末、鉄(0)塩または鉄(I)塩を用いても、系内で鉄(II)塩が発生し、これを用いることもできる。その中でも、収率が良い点で、硫酸鉄(II)、塩化鉄(II)、臭化鉄(II)、鉄粉、ビス(アセチルアセトナト)鉄(II)またはフェロセンを用いることが好ましい。鉄化合物の使用量に特に制限はなく、アリール類(2)に対していわゆる触媒量でも良く、好ましくは、アリール類(2)に対して0.05〜1等量添加することにより、収率良く目的物を得ることができる。
工程1(及び工程1a)は、過酸化物の存在下に反応を行うことが必須である。本発明で用いることができる過酸化物としては、具体的には、過酸化水素、過酸化水素−尿素複合体、tert−ブチルペルオキシド、過酢酸等を例示することができ、これらを必要に応じて組み合わせて用いても良い。その中でも、収率が良い点で、過酸化水素または過酸化水素−尿素複合体、tert−ブチルペルオキシドを用いるのが好ましく、過酸化水素がさらに好ましい。
工程1(及び工程1a)は、さらに酸を添加することにより目的物の収率を向上させることができる場合がある。用いることのできる酸としては、硫酸、塩酸、臭化水素、ヨウ化水素、硝酸、リン酸、ヘキサフルオロリン酸、テトラフルオロホウ酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、p−トルエンスルホン酸、トリフルオロメタンスルホン酸、トリフルオロ酢酸等の有機酸を例示することができ、適宜これらを組み合わせて用いても良い。その中でも、収率が良い点で、硫酸または酢酸を用いることが好ましい。酸の使用量に特に制限はなく、アリール類(2)に対していわゆる触媒量でも良く、好ましくは、アリール類(2)に対して0.05〜2等量添加することにより、収率良く目的物を得ることができる。
よって、本発明に係る製造方法(工程1及び工程1a)では、アリール類(2)とジフルオロ酢酸エステル類(3)を、スルホキシド類(4)、鉄化合物、過酸化物の存在下で反応させることを必須とするが、さらに酸を存在させることができる。
工程1(及び工程1a)の反応溶媒は、反応に害を及ぼさない溶媒であれば、特に規定はない。具体的には、水、N,N−ジメチルホルムアミド、テトラヒドロフラン、ジエチルエーテル、1,4−ジオキサン、アセトン、アセトニトリル、酢酸エチル、酢酸、トリフルオロ酢酸、tert−ブチルアルコール、イソプロピルアルコール、エタノール、メタノール、トリフルオロエタノール、ヘキサメチルリン酸トリアミド、N−メチル−2−ピロリドン、N,N,N’,N’−テトラメチル尿素、N,N’−ジメチルプロピレン尿素等を例示することができ、適宜これらを組み合わせて用いても良い。工程1(及び工程1a)は、有機溶媒中で行うことができる。スルホキシド類(4)をそのまま溶媒として用いても良い。その中でも、収率が良い点で、スルホキシド類(4)または、スルホキシド類(4)とアセトニトリル、エタノールまたはアセトンの混合溶媒を用いることが好ましい。溶媒の使用量は特に制限はない。
1H−NMR(重クロロホルム):δ1.21(3H,t,J=7.1Hz),4.14(2H,q,J=7.1Hz),6.26−6.29(1H,m),6.61−6.64(1H,m),6.85−6.88(1H,m),7.34−7.45(5H,m).
19F−NMR(重ジメチルスルホキシド):δ−90.9.
MS(m/z):265[M]+.
1H−NMR(重クロロホルム):δ1.37(3H,t,J=7.1Hz),4.38(2H,q,J=7.1Hz),6.86−6.89(1H,m),7.14−7.19(1H,m),7.27−7.32(1H,m),7.40−7.44(1H,m),7.64−7.68(1H,m),8.56(1H,brs).
19F−NMR(重ジメチルスルホキシド):δ−97.8.
MS(m/z):239[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.26(3H,t,J=7.1Hz),2.43(3H,s),3.89(3H,s),4.39(2H,q,J=7.1Hz),6.51(1H,d,J=4.3Hz),7.12(1H,d,J=4.3Hz).
13C−NMR(重クロロホルム):δ13.8,27.8,34.7(t,JCF=3.0Hz),63.6,110.5(t,JCF=249.3Hz),110.6(t,JCF=5.5Hz),117.9,130.4(t,JCF=29.4Hz),133.7,162.7(t,JCF=34.2Hz),189.6.
19F−NMR(重ジメチルスルホキシド):δ−97.7.
MS(m/z):245[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.28(3H,t,J=7.1Hz),4.40(2H,q,J=7.1Hz),7.83(3H,t,JHF=2.2Hz),8.69(1H,s).
19F−NMR(重ジメチルスルホキシド):δ−101.3.
MS(m/z):191[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.27(3H,t,J=7.1Hz),4.38(2H,q,J=7.1Hz),8.32(1H,s),9.391H,s).
19F−NMR(重ジメチルスルホキシド):δ−90.5.
MS(m/z):207[M]+.
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、硫酸鉄(II)水溶液(鉄化合物)(1.0mol/L、0.15mL)、ジメチルスルホキシド(4)(2.5mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.00mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で1時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率48%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、硫酸鉄(II)水溶液(鉄化合物)(1.0mol/L、0.15mL)、ジメチルスルホキシド(4)(2.0mL)、硫酸(酸)のジメチルスルホキシド溶液(4)(1.0mol/L、0.5mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.00mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で1時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率52%)。
ブロモジフルオロ酢酸エチルをジフルオロヨード酢酸エチル(3)(147μL、1.00mmol)に換えた以外は実施例−6と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率60%)。
ブロモジフルオロ酢酸エチルをジフルオロヨード酢酸エチル(3)(147μL、1.00mmol)に換えた以外は実施例−7と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率74%)。
硫酸鉄(II)水溶液を塩化鉄(II)水溶液(鉄化合物)(1.0mol/L、0.15mL)に換えた以外は実施例−6と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率45%)。
硫酸鉄(II)水溶液を臭化鉄(II)水溶液(鉄化合物)(1.0mol/L、0.15mL)に換えた以外は実施例−6と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率27%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、鉄粉末(鉄化合物)(8mg、0.15mmol)、ジメチルスルホキシド(4)(2.0mL)、硫酸(酸)のジメチルスルホキシド溶液(4)(1.0mol/L、0.5mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.00mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率19%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、ビス(アセチルアセトナト)鉄(II)(鉄化合物)(38mg、0.15mmol)、ジメチルスルホキシド(4)(2.0mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.0mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率25%)。
空気中で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、フェロセン(鉄化合物)(28mg、0.15mmol)、ジメチルスルホキシド(4)(2.5mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.00mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率57%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、フェロセン(鉄化合物)(28mg、0.15mmol)、ジメチルスルホキシド(4)(2.0mL)、酢酸(酸)のジメチルスルホキシド溶液(4)(1.0mol/L、0.5mL)およびブロモジフルオロ酢酸エチル(3)(128μL、1.00mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率53%)。
ブロモジフルオロ酢酸エチル(256μL、2.00mmol)をジフルオロヨード酢酸エチル(3)(147μL、1.00mmol)に換えた以外は実施例−13と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率83%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、フェロセン(鉄化合物)(9mg、0.05mmol)、ジメチルスルホキシド(4)(2.5mL)およびブロモジフルオロ酢酸エチル(3)(192μL、1.50mmol)を混合した後、混合物に過酸化水素−尿素複合体(過酸化物)(94mg、1.0mmol)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率77%)。
過酸化水素−尿素複合体を70%tert−ブチルペルオキシド水溶液(過酸化物)(0.14mL)に換えた以外は実施例−17と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率11%)。
過酸化水素−尿素複合体を30%過酸化水素水(過酸化物)(0.1mL)に換え、ジメチルスルホキシド(4)の量を25mLに換えた以外は実施例−17と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率84%)。
過酸化水素−尿素複合体を30%過酸化水素水(過酸化物)(0.1mL)に換え、ジメチルスルホキシドをジメチルスルホキシド(4)(1.5mL)とアセトニトリル(1.0mL)の混合溶媒に換えた以外は実施例−17と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率64%)。
過酸化水素−尿素複合体を30%過酸化水素水(過酸化物)(0.1mL)に換え、ジメチルスルホキシドをジメチルスルホキシド(4)(2.0mL)とエタノール(0.5mL)の混合溶媒に換えた以外は実施例−17と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率57%)。
アルゴン雰囲気下で、2−アセチル−1−メチルピロール(2)(59μL、0.50mmol)、フェロセン(鉄化合物)(9mg、0.05mmol)、アセトン(5.0mL)、ジフェニルスルホキシド(4)(1.01g、5.0mmol)およびブロモジフルオロ酢酸エチル(3)(192μL、1.50mmol)を混合した後、混合物に30%過酸化水素水(過酸化物)(0.1mL)を加えた。室温で12時間撹拌後、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率10%)。
アセトンをN,N−ジメチルホルムアミド(5.0mL)に換え、ジフェニルスルホキシドをジブチルスルホキシド(4)(811mg、5.00mmol)に換えた以外は実施例−22と同じ操作を行い、19F−NMRにより(5−アセチル−1−メチルピロール−2−イル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率13%)。
1H−NMR(重ジメチルスルホキシド):δ1.25(3H,t,J=7.1Hz),2.10(3H,s),4.33(2H,q,J=7.1Hz),7.67(1H,s),13.06(1H,brs).
13C−NMR(重ジメチルスルホキシド):δ8.1,13.9,63.2,112.9(t,JCF=243.3Hz),114.0,130.0,141.9(t,JCF=26.4Hz),163.3(t,JCF=32.6Hz).
19F−NMR(重ジメチルスルホキシド):δ−98.7.
MS(m/z):204[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.18(3H,t,J=7.1Hz),4.23(2H,q,J=7.1Hz),7.38−7.43(1H,m),7.44−7.50(2H,m),7.51−7.56(2H,m),7.81(1H,s),13.00(1H,brs).
13C−NMR(重ジメチルスルホキシド):δ13.9,63.0,113.2(t,JCF=243.3Hz),128.4,128.6,128.7,128.8,129.1,131.1,136.1,163.4(t,JCF=32.9Hz).
19F−NMR(重ジメチルスルホキシド):δ−94.9.
MS(m/z):266[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.16(3H,t,J=7.1Hz),4.29(2H,q,J=7.1Hz),7.50−7.56(3H,m),7.58−7.64(3H,m),7.68−7.72(2H,m),8.03−8.07(2H,m).
13C−NMR(重クロロホルム):δ13.6,63.7,109.1(t,JCF=248.8Hz),126.2,126.9,128.4,128.6,128.8,129.3,129.9,131.3,136.1(t,JCF=34.1Hz),142.6(t,JCF=2.5Hz),161.6,161.8(t,JCF=33.4Hz).
19F−NMR(重ジメチルスルホキシド):δ−99.1.
MS(m/z):343[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.27(3H,t,J=7.1Hz),2.17(3H,s),4.37(2H,q,J=7.1Hz),7.83(1H,s),12.54(1H,brs).
13C−NMR(重ジメチルスルホキシド):δ13.8,22.5,64.1,111.8(t,JCF=248.1Hz),120.7(t,JCF=29.1Hz),139.9(t,JCF=6.6Hz),161.1,162.4(t,JCF=34.4Hz),169.5.
19F−NMR(重ジメチルスルホキシド):δ−90.6.
MS(m/z):264[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.27(3H,t,J=7.1Hz),4.38(2H,q,J=7.1Hz),7.91(2H,brs).
13C−NMR(重ジメチルスルホキシド):δ13.8,64.2,110.2(t,JCF=248.2Hz),148.2(t,JCF=31.0Hz),161.2(t,JCF=31.7Hz),171.6.
19F−NMR(重ジメチルスルホキシド):δ−94.9.
MS(m/z):223[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.26(3H,t,J=7.1Hz),4.36(2H,q,J=7.1Hz),7.16−7.20(1H,m),7.48−7.51(1H,m),7.88−7.91(1H,m).
13C−NMR(重クロロホルム):δ13.8,63.4,111.7(t,JCF=250.4Hz),127.1,128.4(t,JCF=5.6Hz),129.0(t,JCF=1.5Hz),134.0(t,JCF=30.1Hz),163.3(t,JCF=35.1Hz).
19F−NMR(重ジメチルスルホキシド):δ−90.8.
MS(m/z):206[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.27(3H,t,J=7.1Hz),4.37(2H,q,J=7.1Hz),7.32−7.35(1H,m),7.36−7.39(1H,m).
13C−NMR(重ジメチルスルホキシド):δ13.7,64.2,110.9(t,JCF=249.6Hz),116.8,130.5(t,JCF=5.9Hz),131.3,134.0(t,JCF=30.2Hz),162.0(t,JCF=34.2Hz).
19F−NMR(重ジメチルスルホキシド):δ−91.6.
MS(m/z):284[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.21(3H,t,J=7.1Hz),2.47(6H,s),4.25(2H,q,J=7.1Hz),7.49−7.53(1H,m),7.76−7.80(2H,m).
13C−NMR(重クロロホルム):δ14.0,45.2,62.3,111.6(t,JCF=247.5Hz),118.4,124.5,129.4(t,JCF=6.4Hz),132.9(t,JCF=24.0Hz),134.9,151.5(t,JCF=4.9Hz),163.4(t,JCF=32.5Hz).
19F−NMR(重ジメチルスルホキシド):δ−97.7.
MS(m/z):321[M]+.
ブロモジフルオロ酢酸エチルをジフルオロヨード酢酸エチル(2)(294μL、2.00mmol)に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率33%)。
フェロセンを硫酸鉄(II)水溶液(鉄化合物)(1.0mol/L、0.3mL)に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率55%)。
フェロセンを塩化鉄(II)水溶液(鉄化合物)(1.0mol/L、0.3mL)に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率35%)。
30%過酸化水素水溶液を過酸化水素−尿素複合体(過酸化物)(188mg、2.00mmol)に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率55%)。
30%過酸化水素水溶液を70%tert−ブチルヒドロペルオキシド水溶液(過酸化物)(0.28mL)に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率10%)。
ジメチルスルホキシドをジメチルスルホキシド(2)(4.0mL)とN,N−ジメチルホルムアミド(4.0mL)の混合溶媒に換えた以外は実施例−31と同じ操作を行い、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率46%)。
アルゴン雰囲気下で、4−ブロモ−N,N−ジメチルアニリン(2)(200mg、1.00mmol)、硫酸(酸)のジメチルスルホキシド溶液(4)(1.0mol/L、1.0mL)、硫酸鉄(II)水溶液(鉄化合物)(1.0mol/L、0.3mL)、ジメチルスルホキシド(4)(5.0mL)およびブロモジフルオロ酢酸エチル(3)(385μL、3.00mmol)を混合した後、混合物に30%過酸化水素水(0.2mL)を加えた。室温で12時間撹拌後、19F−NMRにより(4−ブロモ−2−ジメチルアミノフェニル)ジフルオロ酢酸エチル(1)の生成を確認した(NMR収率59%)。
1H−NMR(重ジメチルスルホキシド):δ1.16(3H,t,J=7.1Hz),1.96(3H,s),4.21(2H,q,J=7.1Hz),7.28−7.33(1H,m),7.76−7.81(2H,m),9.49(1H,brs).
13C−NMR(重ジメチルスルホキシド):δ13.7,22.9,63.6,112.0(t,JCF=250.1Hz),119.0,128.7(t,JCF=8.4Hz),130.6(t,JCF=23.5Hz),131.7,134.9,135.1,162.5(t,JCF=33.8Hz),169.4.
19F−NMR(重ジメチルスルホキシド):δ−99.5.
MS(m/z):335[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.22(3H,t,J=7.1Hz),4.33(2H,q,J=7.1Hz),5.43(2H,brs),7.28−7.31(1H,m),7.63−7.66(1H,m).
13C−NMR(重ジメチルスルホキシド):δ13.7,64.0,113.0(t,JCF=251.8Hz),117.0(t,JCF=24.3Hz),119.7,120.7,124.8(t,JCF=8.8Hz),131.8,141.1(t,JCF=2.9Hz),162.6(t,JCF=34.5Hz).
19F−NMR(重ジメチルスルホキシド):δ−103.1.
MS(m/z):283[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.21(3H,t,J=7.1Hz),2.20(3H,s),4.31(2H,q,J=7.1Hz),4.96(2H,brs),7.13−7.16(1H,m),7.46−7.49(1H,m).
13C−NMR(重ジメチルスルホキシド):δ13.8,19.5,63.7,110.6,113.8(t,JCF=250.6Hz),116.4(t,JCF=23.5Hz),126.1(t,JCF=8.1Hz),127.1,136.0,140.3(t,JCF=2.9Hz),163.2(t,JCF=34.8Hz).
19F−NMR(重ジメチルスルホキシド):δ−102.6.
MS(m/z):307[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.23(3H,t,J=7.1Hz),1.27(3H,t,J=7.1Hz),4.23(2H,q,J=7.1Hz),4.33(2H,q,J=7.1Hz),6.08(2H,brs),6.81−6.85(1H,m),7.74−7.81(2H,m).
13C−NMR(重ジメチルスルホキシド):δ13.8,14.4,60.3,63.7,112.9(t,JCF=24.1Hz),114.3(t,JCF=250.3Hz),116.5,116.7,128.4(t,JCF=8.2Hz),133.2,150.4,163.2(t,JCF=35.0Hz),165.2.
19F−NMR(重ジメチルスルホキシド):δ−103.0.
MS(m/z):287[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.23(3H,t,J=7.1Hz),2.43(3H,s),4.32(2H,q,J=7.1Hz),6.11(2H,brs),6.80−6.85(1H,m),7.77−7.84(2H,m).
13C−NMR(重ジメチルスルホキシド):δ13.8,26.0,63.7,112.9(t,JCF=24.1Hz),114.3(t,JCF=250.3Hz),116.2,125.0,127.6(t,JCF=8.0Hz),132.8,150.5,163.3(t,JCF=35.1Hz),195.0.
19F−NMR(重ジメチルスルホキシド):δ−102.8.
MS(m/z):257[M]+.
1H−NMR(重ジメチルスルホキシド,TMS):δ1.22(3H,t,J=7.1Hz),4.32(2H,q,J=7.1Hz),6.24(2H,brs),6.84−6.89(1H,m),7.55−7.62(2H,m).
13C−NMR(重ジメチルスルホキシド):δ13.8,63.9,96.8,113.6(t,JCF=250.9Hz),113.7(t,JCF=24.4Hz),117.2,119.5,131.3(t,JCF=8.4Hz),135.5,150.162.8(t,JCF=34.8Hz).
19F−NMR(重ジメチルスルホキシド):δ−103.1.
MS(m/z):240[M]+.
1H−NMR(重ジメチルスルホキシド):δ1.16(3H,t,J=7.1Hz),1.96(3H,s),4.21(2H,q,J=7.1Hz),7.34−7.39(1H,m),7.63−7.68(2H,m),9.50(1H,brs).
13C−NMR(重ジメチルスルホキシド):δ13.7,22.9,63.6,112.0(t,JCF=250.1Hz),125.9(t,JCF=8.4Hz),130.4(t,JCF=23.4Hz),131.0,131.5,131.9,134.6,162.5(t,JCF=33.8Hz),169.4.
19F−NMR(重ジメチルスルホキシド):δ−99.6.
MS(m/z):291[M]+.
Claims (7)
- 一般式(1a)
- 一般式(2)
一般式(3)
一般式(4)
一般式(1)
- Arが、ピロール−2−イル基、インドール−2−イル基、オキサゾール−5−イル基、ピラゾール−5−イル基、イミダゾール−5−イル基、チアゾール−5−イル基、1,3,4−チアジアゾール−2−イル基、チオフェン−2−イル基またはフェニル基である請求項2に記載の(アリール)ジフルオロ酢酸エステル誘導体の製造方法。
- R3aおよびR3bが、メチル基、ブチル基またはフェニル基である請求項2または3に記載の(アリール)ジフルオロ酢酸エステル誘導体の製造方法。
- 鉄化合物が、硫酸鉄(II)、塩化鉄(II)、臭化鉄(II)、鉄粉、ビス(アセチルアセトナト)鉄(II)またはフェロセンである請求項2から4のいずれかに記載の(アリール)ジフルオロ酢酸エステル誘導体の製造方法。
- 過酸化物が、過酸化水素である請求項2から5のいずれかに記載の(アリール)ジフルオロ酢酸エステル誘導体の製造方法。
- 酸が、硫酸または酢酸である請求項2から6のいずれかに記載の(アリール)ジフルオロ酢酸エステル誘導体の製造方法。
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JP2006522809A (ja) * | 2003-04-10 | 2006-10-05 | 3−ディメンショナル ファーマシューティカルズ, インコーポレイテッド | 置換フェニルアセトアミおよびプロテアーゼインヒビターとしてのその使用 |
WO2007109459A2 (en) * | 2006-03-21 | 2007-09-27 | Janssen Pharmaceutica, Nv | Pyridines and pyridine n-oxides as modulators of thrombin |
JP2008524139A (ja) * | 2004-12-15 | 2008-07-10 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | メタ置換チアゾリノン類、それらの製造及び医薬としての使用 |
JP2009502977A (ja) * | 2005-08-03 | 2009-01-29 | メルク フロスト カナダ リミテツド | Ep4受容体アゴニスト、この組成物および方法 |
JP2009525960A (ja) * | 2006-01-18 | 2009-07-16 | アムジエン・インコーポレーテツド | プロテインキナーゼb(pkb)阻害剤としてのチアゾール化合物 |
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JP2006522809A (ja) * | 2003-04-10 | 2006-10-05 | 3−ディメンショナル ファーマシューティカルズ, インコーポレイテッド | 置換フェニルアセトアミおよびプロテアーゼインヒビターとしてのその使用 |
JP2008524139A (ja) * | 2004-12-15 | 2008-07-10 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | メタ置換チアゾリノン類、それらの製造及び医薬としての使用 |
JP2009502977A (ja) * | 2005-08-03 | 2009-01-29 | メルク フロスト カナダ リミテツド | Ep4受容体アゴニスト、この組成物および方法 |
JP2009525960A (ja) * | 2006-01-18 | 2009-07-16 | アムジエン・インコーポレーテツド | プロテインキナーゼb(pkb)阻害剤としてのチアゾール化合物 |
WO2007109459A2 (en) * | 2006-03-21 | 2007-09-27 | Janssen Pharmaceutica, Nv | Pyridines and pyridine n-oxides as modulators of thrombin |
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