JP6317367B2 - フルオロラクトン誘導体の製造方法 - Google Patents
フルオロラクトン誘導体の製造方法 Download PDFInfo
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- JP6317367B2 JP6317367B2 JP2015552063A JP2015552063A JP6317367B2 JP 6317367 B2 JP6317367 B2 JP 6317367B2 JP 2015552063 A JP2015552063 A JP 2015552063A JP 2015552063 A JP2015552063 A JP 2015552063A JP 6317367 B2 JP6317367 B2 JP 6317367B2
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- formula
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- derivative
- fluorolactone
- mixture
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- 238000004519 manufacturing process Methods 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims description 45
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- HPKZHKRTMMLVBQ-UHFFFAOYSA-N fluoro propanoate Chemical class CCC(=O)OF HPKZHKRTMMLVBQ-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- MVLMPMUGCWJDLE-UHFFFAOYSA-M dibutylboron trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[B+]CCCC MVLMPMUGCWJDLE-UHFFFAOYSA-M 0.000 claims description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- -1 fluoro lactone Chemical class 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- FLALGSYYVIWTFQ-UHFFFAOYSA-K propan-2-olate;titanium(4+);trichloride Chemical compound [Cl-].[Cl-].[Cl-].CC(C)O[Ti+3] FLALGSYYVIWTFQ-UHFFFAOYSA-K 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- VNCJYMKHJWVTPK-WVOWXROLSA-N (3r,4r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one Chemical compound C[C@@]1(F)[C@H](O)C(CO)OC1=O VNCJYMKHJWVTPK-WVOWXROLSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- YSGPYVWACGYQDJ-YFKPBYRVSA-N (4r)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde Chemical compound CC1(C)OC[C@H](C=O)O1 YSGPYVWACGYQDJ-YFKPBYRVSA-N 0.000 description 6
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 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
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- PHTOJBANGYSTOH-INIZCTEOSA-N (4s)-5,5-diphenyl-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@@H]1NC(=O)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 PHTOJBANGYSTOH-INIZCTEOSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 4
- SEZRREGFJFZQQD-UHFFFAOYSA-N 2-fluoropropanoyl chloride Chemical compound CC(F)C(Cl)=O SEZRREGFJFZQQD-UHFFFAOYSA-N 0.000 description 4
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 description 4
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 4
- YSGPYVWACGYQDJ-UHFFFAOYSA-N D-glyceraldehyde acetonide Natural products CC1(C)OCC(C=O)O1 YSGPYVWACGYQDJ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- PIUDLVMICXVHIF-COBSHVIPSA-N (4s)-3-(2-fluoropropanoyl)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)C(C)F PIUDLVMICXVHIF-COBSHVIPSA-N 0.000 description 3
- WEDFGMJDAGTUAF-PKHIMPSTSA-N (4s)-3-(2-fluoropropanoyl)-5,5-diphenyl-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@@H]1N(C(=O)C(C)F)C(=O)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 WEDFGMJDAGTUAF-PKHIMPSTSA-N 0.000 description 3
- PIBGZOZKKVEPEL-UYUMYWFVSA-N (4s)-3-[(2r,3r)-3-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-3-hydroxy-2-methylpropanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)[C@](C)(F)[C@H](O)[C@@H]1OC(C)(C)OC1 PIBGZOZKKVEPEL-UYUMYWFVSA-N 0.000 description 3
- KDAPHHXSTOOVML-UXGLMHHASA-N (4s)-3-[(2r,3r)-3-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-3-hydroxy-2-methylpropanoyl]-5,5-diphenyl-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound C([C@@H]1[C@@H](O)[C@@](C)(F)C(=O)N2[C@H](C(OC2=O)(C=2C=CC=CC=2)C=2C=CC=CC=2)C(C)C)OC(C)(C)O1 KDAPHHXSTOOVML-UXGLMHHASA-N 0.000 description 3
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 description 3
- MXTLPVDYOVDQHW-UMJHXOGRSA-N (4s)-4-benzyl-3-(2-fluoropropanoyl)-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)C(F)C)[C@H]1CC1=CC=CC=C1 MXTLPVDYOVDQHW-UMJHXOGRSA-N 0.000 description 3
- MCFZKYAFROCMAI-NRTGNBEESA-N (4s)-4-benzyl-3-[(2r,3r)-3-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-3-hydroxy-2-methylpropanoyl]-1,3-oxazolidin-2-one Chemical compound C([C@@H]1[C@@H](O)[C@](F)(C)C(=O)N2C(OC[C@@H]2CC=2C=CC=CC=2)=O)OC(C)(C)O1 MCFZKYAFROCMAI-NRTGNBEESA-N 0.000 description 3
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4s)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 3
- 0 C[C@@](CC(CO*)O1)(C1=O)F Chemical compound C[C@@](CC(CO*)O1)(C1=O)F 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- XCJLIYKAMLUDGN-QMMMGPOBSA-N methyl (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound COC(=O)[C@H](C(C)C)NC(=O)OC(C)(C)C XCJLIYKAMLUDGN-QMMMGPOBSA-N 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FCZMSASMHPDGEJ-IBGZPJMESA-N tert-butyl n-[(2s)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl]carbamate Chemical compound C=1C=CC=CC=1C(O)([C@@H](NC(=O)OC(C)(C)C)C(C)C)C1=CC=CC=C1 FCZMSASMHPDGEJ-IBGZPJMESA-N 0.000 description 2
- 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 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- ODYBCPSCYHAGHA-YDYPAMBWSA-N (1s,2s)-1,2-bis(2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol Chemical compound O1C(C)(C)OCC1[C@@H](O)[C@H](O)C1OC(C)(C)OC1 ODYBCPSCYHAGHA-YDYPAMBWSA-N 0.000 description 1
- WOMGQJDMFFMWEC-UHFFFAOYSA-N 1,6-dimethyl-2h-pyridine Chemical compound CN1CC=CC=C1C WOMGQJDMFFMWEC-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- STVVMTBJNDTZBF-UHFFFAOYSA-N 2-amino-3-phenylpropan-1-ol Chemical compound OCC(N)CC1=CC=CC=C1 STVVMTBJNDTZBF-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- DJYHWUZNQDCXSW-UHFFFAOYSA-N CC(C)CCC(CO1)NC1=O Chemical compound CC(C)CCC(CO1)NC1=O DJYHWUZNQDCXSW-UHFFFAOYSA-N 0.000 description 1
- KVCOVVVFOUBSDA-BAFYGKSASA-N C[C@@](CC(CO)O1)(C1=O)F Chemical compound C[C@@](CC(CO)O1)(C1=O)F KVCOVVVFOUBSDA-BAFYGKSASA-N 0.000 description 1
- VJVVGWJHRWQZJV-INMPXNLMSA-N C[C@@]([C@@H]([C@@H]1OC(C)(C)OC1)O)(C(N(C(Cc1ccccc1)CO1)C1=O)O)F Chemical compound C[C@@]([C@@H]([C@@H]1OC(C)(C)OC1)O)(C(N(C(Cc1ccccc1)CO1)C1=O)O)F VJVVGWJHRWQZJV-INMPXNLMSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical compound CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
及び式
のそのアシル化された誘導体
の新規な製造方法に関する。
本発明の方法は、式
a)式
[式中、Aはキラル部分
と反応させ、式
のアルドール付加物を形成させること;及び
b)式Iのフルオロラクトン誘導体を得るために、式IVのアルドール付加物を加水分解に付すこと;
の工程を含む。
工程a)
工程a)は、式IVのアルドール付加物を形成するための、式IIのアルデヒドと式IIIのフルオロプロピオネート誘導体の反応を必要とする。
式IIIのフルオロプロピオネート誘導体は下のスキーム
Aがキラル部分
スキーム1a(A=A1であるA−H)
具体的な態様においては、AがA3である式IIIのフルオロプロピオネート誘導体が用いられる。
式III
のフルオロプロピオネート誘導体は現在までのところ当技術分野において説明されておらず、それ故に本発明の具体的な態様を表す。
反応は、トリフルオロメタンスルホン酸ジブチルボロン、塩化チタン、チタン(IV)トリクロリドイソプロポキシド、チタンイソプロポキシド、塩化マグネシウム、マグネシウムトリフレート又は塩化亜鉛から選択される触媒の存在下で行われる。
通例、第3級アミンのような塩基は、2,6−ルチジン、2,3−ルチジン、2,4−ルチジン、2,5−ルチジン、3,4−ルチジン、3,5−ルチジン、トリエチルアミン、ジイソプロピルエチルアミン、ジエチルアミン、ピリジン又は1,6−ジメチルピリジンから選択され、そして適切な有機溶媒は、例えば塩化メチレン、1,2−ジクロロエタン、クロロホルム、アセトニトリル、トルエン、キシレン、クロロベンゼン、テトラヒドロフラン、2−メチルテトラヒドロフラン又はメチルイソブチルエーテル、又はそれらの混合物が提示される。
反応温度は、通常−78℃から50℃に維持される。
より具体的なアルドール付加物は、式
で表される。
工程b)は、式Iのフルオロラクトン誘導体を得るために、式IVのアルドール付加物を加水分解に付すことを必要とする。
加水分解は、通例、塩基として水酸化リチウム、水酸化ナトリウム又は水酸化カリウムから選択されるアルカリ水酸化物の存在下、過酸化水素、m−クロロパーオキシ安息香酸、次亜塩素酸ナトリウム、過塩素酸ナトリウム又はエチレンオキシドから選択される酸化剤を用いて行われる。
加水分解は、通常、−30℃から50℃の反応温度で行われる。
キラルアミンA−Hは、当業者に知られた方法によって、例えば、キラルアミンA13aの場合は、単に反応混合物からろ過することによって、反応混合物から単離し、回収することができる。
のアシル化フルオロラクトンを形成する。
アシル化は、塩化ベンゾイル、塩化アセチル、塩化ピバロイル、塩化トリメチルシリル、tert-ブチルジメチルシリルクロリド、3,4−ジヒドロ−2H−ピランから選択される適切なアシル化剤、具体的には、塩化ベンゾイルを用いて、第3級アミン、例えば、トリエチルアミン、ジイソプロピルエチルアミン、2,3−ルチジン、2,4−ルチジン、2,5−ルチジン、3,4−ルチジン、3,5−ルチジン、ピリジン、1,6−ジメチルピリジン又は1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン又はその混合物の存在下、具体的には、トリエチルアミンの存在下、行われる。
適切な有機溶媒、例えば、テトラヒドロフラン、2−メチルテトラヒドロフラン、ジクロロメタン、1,2−ジクロロエタン、アセトニトリル、トルエン、キシレン、メチルイソブチルケトン、メチルtert−ブチルエーテル又はアセトン、しかし、具体的には、テトラヒドロフランが提示され、反応温度は、通例、−20℃から80℃に維持される。
で表される。
適切なヒドロキシ保護基R1は、ベンジル、アセチル、トリメチルシリル、tert−ブチル、tert−ブチルジメチルシリル又はジヒドロピラニルであり、しかし、具体的には、ベンジルである。
EA 酢酸エチル
HE ヘキサン
MeOH メタノール
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
出発原料:
A.(R)−2,2−ジメチル−1,3−ジオキソラン−4−カルボアルデヒドの製造
B1.(S)−4−ベンジルオキサゾリジン−2−オンの製造
C1.(4S)−3−(2−フルオロプロパノイル)−4−ベンジルオキサゾリジン−2−オン
(式IIIにおいてA=A1a)
C2.(4S)−3−(2−フルオロプロパノイル)−4−イソプロピルオキサゾリジン−2−オン
(式IIIにおいてA=A2a)
C3.(4S)−3−(2−フルオロプロパノイル)−4−イソプロピル−5,5−ジフェニルオキサゾリジン−2−オン
(式IIIにおいてA=A3a)
D1.(S)−3−((2R,3R)−3−((R)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−フルオロ−3−ヒドロキシ−2−メチルプロパノイル)−4−ベンジルオキサゾリジン−2−オン(式IVにおいてA=A1a)
(3R,4R)−3−フルオロ−4−ヒドロキシ−5−(ヒドロキシメチル)−3−メチルジヒドロフラン−2(3H)−オンの製造(実施例D1のアルドール付加物から)
実施例2
(3R,4R)−3−フルオロ−4−ヒドロキシ−5−(ヒドロキシメチル)−3−メチルジヒドロフラン−2(3H)−オンの製造(実施例D2のアルドール付加物から)
(3R,4R)−3−フルオロ−4−ヒドロキシ−5−(ヒドロキシメチル)−3−メチルジヒドロフラン−2(3H)−オンの製造(実施例D3のアルドール付加物から)
湿ったケーキ(上記参照)を水(375ml)に溶解させ、混合物を30分間撹拌し、ろ過し、そしてろ過ケーキを水(100ml×2)で2回洗浄した。湿ったケーキを真空下50℃で24時間乾燥させ、白色の固体(35.2g)を得た。減圧下エバポレーションを行って、有機層(上記参照)を乾固させ、残渣をメタノール(25ml)に溶解させ、ろ過し、そしてメタノール(5ml)で洗浄した。湿ったケーキを真空下50℃で24時間乾燥させ、白色の固体(6.3g)を得た。回収されたキラルアミンの合計は41.5g、回収率95%であった。
((3R,4R)−3−(ベンゾイルオキシ)−4−フルオロ−4−メチル−5−オキソテトラヒドロフラン−2−イル)メチルベンゾエートの製造
1H-NMR (CDCl3, 400 MHz): δ8.10 (d, J=7.6 Hz, 2H), 8.00 (d, J=7.6 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 5.53 (dd, J=17.6, 5.6 Hz, 1H), 5.02 (m, 1H), 4.77 (dd, J=12.8, 3.6 Hz, 1H), 4.62 (dd, J=12.8, 5.2 Hz, 1H), 1.77(d, J=23.2 Hz, 3H)。
本明細書は以下の発明の開示を包含する:
[1]式
a)式
[式中、Aはキラル部分
と反応させ、式
のアルドール付加物を形成させること;及び
b)式Iのフルオロラクトン誘導体を得るために、式IVのアルドール付加物を加水分解に付すこと;
の工程を含む、前記方法。
[2]式IIIのフルオロプロピオネート誘導体におけるキラル部分AがA3である、[1]に記載の方法。
[3]フルオロラクトン誘導体が式
[4]式IIIのフルオロプロピオネート誘導体におけるキラル部分AがA3aである、[3]に記載の方法。
[5]式Iのフルオロラクトン誘導体がアシル化され、式
のアシル化フルオロラクトンを形成する、[1]に記載の方法。
[6]アシル化フルオロラクトンが式
で表される、[5]に記載の方法。
[7]ヒドロキシ保護基R 1 がベンジルを表す、[5]又は[6]に記載の方法。
[8]キラル部分Aが式
[9]工程a)において反応が、トリフルオロメタンスルホン酸ジブチルボロン、塩化チタン、チタン(IV)トリクロリドイソプロポキシド、チタンイソプロポキシド、塩化マグネシウム、マグネシウムトリフレート又は塩化亜鉛から選択される触媒の存在下で行われる、[1]に記載の方法。
[10]触媒が、トリフルオロメタンスルホン酸ジブチルボロンである、[9]に記載の方法。
[11]工程a)において反応が、塩基及び有機溶媒の存在下、−78℃から50℃の反応温度で行われる、[1]、[9]又は[10]に記載の方法。
[12]工程b)において加水分解が、アルカリ水酸化物の塩基の存在下、酸化剤を用いて行われる、[1]に記載の方法。
[13]工程b)において加水分解が、酸化剤として過酸化水素、及びアルカリ水酸化物の塩基として水酸化リチウムを用いて行われる、[12]に記載の方法。
[14]工程b)において加水分解が、−30℃から50℃の反応温度で行われる、[1]、[12]又は[13]に記載の方法。
[15]アシル化が、第3級アミンの存在下、−20℃から80℃の反応温度で行われる、[5]の方法。
[16]アシル化剤が塩化ベンゾイルである、[15]の方法。
[17]式
のフルオロプロピオネート誘導体。
[18]Aが
[19]AがA3aである、[17]に記載のフルオロプロピオネート誘導体。
[20]式
のアルドール付加物。
[21]式
の[20]に記載のアルドール付加物。
[22]Aが
である、[20]又は[21]に記載のアルドール付加物。
[23]AがA3aである、[20]から[22]のいずれかに記載のアルドール付加物。
Claims (22)
- 式IIIのフルオロプロピオネート誘導体におけるキラル部分AがA3である、請求項1に記載の方法。
- 式IIIのフルオロプロピオネート誘導体におけるキラル部分AがA3aである、請求項3に記載の方法。
- アシル基R1がベンゾイルを表す、請求項5又は6に記載の方法。
- 工程a)において反応が、トリフルオロメタンスルホン酸ジブチルボロン、塩化チタン、チタン(IV)トリクロリドイソプロポキシド、チタンイソプロポキシド、塩化マグネシウム、マグネシウムトリフレート又は塩化亜鉛から選択される触媒の存在下で行われる、請求項1に記載の方法。
- 触媒が、トリフルオロメタンスルホン酸ジブチルボロンである、請求項9に記載の方法。
- 工程a)において反応が、塩基及び有機溶媒の存在下、−78℃から50℃の反応温度で行われる、請求項1、9又は10に記載の方法。
- 工程b)において加水分解が、アルカリ水酸化物の塩基の存在下、酸化剤を用いて行われる、請求項1に記載の方法。
- 工程b)において加水分解が、酸化剤として過酸化水素、及びアルカリ水酸化物の塩基として水酸化リチウムを用いて行われる、請求項12に記載の方法。
- 工程b)において加水分解が、−30℃から50℃の反応温度で行われる、請求項1、12又は13に記載の方法。
- アシル化が、第3級アミンの存在下、−20℃から80℃の反応温度で行われる、請求項5の方法。
- アシル化剤が塩化ベンゾイルである、請求項15の方法。
- AがA3aである、請求項19から21のいずれか1項に記載のアルドール付加物。
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RU2422454C2 (ru) | 2005-12-09 | 2011-06-27 | Ф. Хоффманн-Ля Рош Аг | Антивирусные нуклеозиды |
KR101118413B1 (ko) * | 2006-12-18 | 2012-03-07 | 에프. 호프만-라 로슈 아게 | 3,5-다이-o-아실-2-플루오로-2-c-메틸-d-리보노-감마-락톤의 제조 방법 |
WO2008090046A1 (en) * | 2007-01-23 | 2008-07-31 | F. Hoffmann-La Roche Ag | Alternate process for preparing 3,5-di-omicron-acyl-2-fluoro-2-c-methyl-d-ribono-gamma-lactone |
AR094466A1 (es) | 2013-01-14 | 2015-08-05 | Hoffmann La Roche | Proceso para la obtención de un derivado de fluorlactona |
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2014
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- 2014-01-13 KR KR1020157021634A patent/KR102187280B1/ko active IP Right Grant
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US9624183B2 (en) | 2017-04-18 |
EP2943475B1 (en) | 2017-10-25 |
US9845299B2 (en) | 2017-12-19 |
KR20200138424A (ko) | 2020-12-09 |
WO2014108525A1 (en) | 2014-07-17 |
MX2015008661A (es) | 2015-10-05 |
AR094466A1 (es) | 2015-08-05 |
BR112015016647A2 (pt) | 2017-07-11 |
IL239697A0 (en) | 2015-08-31 |
EP2943475A1 (en) | 2015-11-18 |
KR102187280B1 (ko) | 2020-12-07 |
JP2016508154A (ja) | 2016-03-17 |
PT2943475T (pt) | 2018-01-17 |
RU2015130337A (ru) | 2017-02-20 |
HK1219094A1 (zh) | 2017-03-24 |
IL239697A (en) | 2017-12-31 |
ES2655851T3 (es) | 2018-02-21 |
SG11201505455VA (en) | 2015-08-28 |
CA2896253C (en) | 2021-01-12 |
RU2656600C2 (ru) | 2018-06-06 |
CA2896253A1 (en) | 2014-07-17 |
HK1215020A1 (zh) | 2016-08-12 |
US20150315165A1 (en) | 2015-11-05 |
US20170183317A1 (en) | 2017-06-29 |
KR20150104205A (ko) | 2015-09-14 |
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