WO2001053305A1 - Procédés de préparation de dérivés de carbapenem - Google Patents
Procédés de préparation de dérivés de carbapenem Download PDFInfo
- Publication number
- WO2001053305A1 WO2001053305A1 PCT/JP2001/000439 JP0100439W WO0153305A1 WO 2001053305 A1 WO2001053305 A1 WO 2001053305A1 JP 0100439 W JP0100439 W JP 0100439W WO 0153305 A1 WO0153305 A1 WO 0153305A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- lower alkyl
- substituted
- formula
- alkyl group
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 19
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 125000005843 halogen group Chemical group 0.000 claims abstract description 58
- 238000001727 in vivo Methods 0.000 claims abstract description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 7
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 100
- 125000006239 protecting group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 150000002148 esters Chemical group 0.000 claims description 8
- 150000001768 cations Chemical class 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 125000002560 nitrile group Chemical group 0.000 claims 1
- -1 imidazo[5,1-b]thiazolyl groups Chemical group 0.000 abstract description 150
- 239000011541 reaction mixture Substances 0.000 abstract description 24
- 239000000543 intermediate Substances 0.000 abstract description 10
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 44
- 239000000243 solution Substances 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 4
- 239000012507 Sephadex™ Substances 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002523 gelfiltration Methods 0.000 description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- QXSZNDIIPUOQMB-UHFFFAOYSA-N 1,1,2,2-tetrabromoethane Chemical compound BrC(Br)C(Br)Br QXSZNDIIPUOQMB-UHFFFAOYSA-N 0.000 description 3
- AQFXIWDRLHRFIC-UHFFFAOYSA-N 1-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone Chemical compound CC(=O)N1N=C(C(F)(F)F)C=C1C1=CC=CC=C1 AQFXIWDRLHRFIC-UHFFFAOYSA-N 0.000 description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
- RVGLUKRYMXEQAH-UHFFFAOYSA-N 3,3-dimethyloxetane Chemical compound CC1(C)COC1 RVGLUKRYMXEQAH-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-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
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- ZYWYUYRYYGYFPI-UHFFFAOYSA-N 7-methylsulfanylimidazo[5,1-b][1,3]thiazole Chemical compound C1=CSC2=C(SC)N=CN21 ZYWYUYRYYGYFPI-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-NJFSPNSNSA-N carbane Chemical class [14CH4] VNWKTOKETHGBQD-NJFSPNSNSA-N 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229960003750 ethyl chloride Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- IIUBFCZXGSJIJX-UHFFFAOYSA-N imidazo[5,1-b][1,3]thiazole Chemical group C1=NC=C2SC=CN21 IIUBFCZXGSJIJX-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GNLJBJNONOOOQC-UHFFFAOYSA-N $l^{3}-carbane;magnesium Chemical compound [Mg]C GNLJBJNONOOOQC-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- SGAAGTUHTZAXEI-UHFFFAOYSA-N 1,2,4-trioxolan-3-one Chemical compound C1OC(=O)OO1 SGAAGTUHTZAXEI-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NJXLTCRWGNHYAI-UHFFFAOYSA-N 1-chloroethyl 2-cyclohexylethyl carbonate Chemical compound CC(Cl)OC(=O)OCCC1CCCCC1 NJXLTCRWGNHYAI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- ZDMPJRXTMWNNMF-UHFFFAOYSA-N 2-bromo-7-methylsulfanylimidazo[5,1-b][1,3]thiazole Chemical compound CSC1=C2N(C=C(S2)Br)C=N1 ZDMPJRXTMWNNMF-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 1
- MDKAAWDKKBFSTK-UHFFFAOYSA-N 2-ethoxybenzoyl chloride Chemical compound CCOC1=CC=CC=C1C(Cl)=O MDKAAWDKKBFSTK-UHFFFAOYSA-N 0.000 description 1
- IEOIHFQCFYIXDQ-UHFFFAOYSA-N 2-iodo-7-methylsulfanylimidazo[5,1-b][1,3]thiazole Chemical compound C1=C(I)SC2=C(SC)N=CN21 IEOIHFQCFYIXDQ-UHFFFAOYSA-N 0.000 description 1
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YDIYEOMDOWUDTJ-UHFFFAOYSA-N 4-(dimethylamino)benzoic acid Chemical compound CN(C)C1=CC=C(C(O)=O)C=C1 YDIYEOMDOWUDTJ-UHFFFAOYSA-N 0.000 description 1
- XLWQUESMILVIPR-UHFFFAOYSA-N 4-ethoxybenzoyl chloride Chemical compound CCOC1=CC=C(C(Cl)=O)C=C1 XLWQUESMILVIPR-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZVERWTXKKWSSHH-UHFFFAOYSA-N 4-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC=C(C(O)=O)C=C1 ZVERWTXKKWSSHH-UHFFFAOYSA-N 0.000 description 1
- USRKDQLKRQMYKX-UHFFFAOYSA-N 4-propan-2-yloxybenzoyl chloride Chemical compound CC(C)OC1=CC=C(C(Cl)=O)C=C1 USRKDQLKRQMYKX-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100025142 Beta-microseminoprotein Human genes 0.000 description 1
- BNIKYPHBIQYTOT-UHFFFAOYSA-N CCOOC(=O)C(C)Cl Chemical compound CCOOC(=O)C(C)Cl BNIKYPHBIQYTOT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920001393 Crofelemer Polymers 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000662429 Fenerbahce Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 101100185029 Homo sapiens MSMB gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241001080173 Ridens Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical group C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- IDDTZZTYVODXHH-UHFFFAOYSA-N chloromethyl (5-methyl-2-propan-2-ylcyclohexyl) carbonate Chemical compound CC(C)C1CCC(C)CC1OC(=O)OCCl IDDTZZTYVODXHH-UHFFFAOYSA-N 0.000 description 1
- BOXZXICVMMSYPE-UHFFFAOYSA-N chloromethyl benzoate Chemical compound ClCOC(=O)C1=CC=CC=C1 BOXZXICVMMSYPE-UHFFFAOYSA-N 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 101150116596 dhp-1 gene Proteins 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- SGZHLLQPCVCEDC-UHFFFAOYSA-L magnesium;bromide;chloride Chemical compound Cl[Mg]Br SGZHLLQPCVCEDC-UHFFFAOYSA-L 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- RHBWCWDSCYBXFD-UHFFFAOYSA-M potassium 2-butyloctanoate Chemical compound CCCCCCC(CCCC)C(=O)[O-].[K+] RHBWCWDSCYBXFD-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl 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
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- 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
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
Definitions
- the present invention provides a novel process for producing 2- (7-methylthioimidazo [5,1-b] thiazolyl-2-yl) capilluvanem derivatives having excellent antibacterial activity and a wide spectrum, and intermediates thereof. About.
- a carbenem derivative having a substituted imidazo [5,11b] thiazolyl group at the 2-position on the carbamine ring is a laculinase-producing bacterium, MRS A (methicillin-resistant It has strong antibacterial activity against Staphylococcus aureus, resistant Pseudomonas aeruginosa, PRSP (benicillin-resistant pneumococcus), enterococci and Haemophilus influenzae, and high against DHP-1 (renal dehydrobeptidase-1) It has been reported that it has stability. The following methods are disclosed as methods for producing these derivatives.
- R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
- R 3 represents a protecting group for a carboxyl group or a group capable of being hydrolyzed in a living body
- R 1 represents a lower alkyl group.
- R represents also represent a group in vivo can be hydrolyzed, refers to salts of Cal Bokishiru group or Anion-carboxylic acid as _C0 2 R.
- the compound of the formula (X) and the reagent such as trialkyltin chloride used for preparing the compound belong to the organotin compound and have high toxicity. Further, the palladium catalyst and the phosphine ligand used in the reaction of the compound of the formula (IX) with the compound of the formula (X) were expensive.
- the present invention is directed to a method for advantageously producing a lubabenem derivative having a substituted imidazo [5,1-b] thiazole group at the 2-position on the lavenenem ring in terms of safety and economy, and its production. Its purpose is to provide intermediates used in the method.
- the present inventors have treated certain substituted imidazo [5,1-b] thiazols, which are intermediates for the production of sorbanem derivatives, with a Grignard reagent and combined the resulting mixture with other intermediates for the production. By reacting, we have found that carbane derivatives can be produced efficiently, safely and inexpensively.
- the present invention is based on this finding.
- the process according to the invention comprises a compound of the formula (III):
- R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
- R 2 is substituted by a lower alkyl group optionally substituted by one or more halogen atoms, or a halogen atom or lower alkyl group (this alkyl group may be substituted by one or more halogen atoms)
- R 3 represents a carboxyl protecting group or a group that can be hydrolyzed in vivo.
- X represents a halogen atom.
- IT is a lower alkyl group optionally substituted with one or more halogen atoms, or a halogen atom, a lower alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
- a lower alkoxy group optionally substituted by an atom and one NR 5 R 6 (R 5 and R 6 may be the same or different and represent a lower alkyl group, or R 5 and R f Together represent a — (C IL) lake—group (n is an integer from 2 to 6) which may be substituted with one or more groups which may be the same or different and are selected from the group consisting of Represents a phenyl group, and I 1 , R 2 and R 3 have the same meanings as defined in the formula (II I).
- R 1 represents a hydrogen atom or a hydroxyl-protecting group
- R represents a hydrogen atom or a group capable of being hydrolyzed in a living body, or forms a pharmaceutically acceptable salt.
- R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
- Lower alkyl group lower alkyl group, lower alkyl group, lower alkyl group, lower alkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower cycloalkyl group, lower alkyloxy group, lower alkyloxy group, lower alkyloxy group Cycloalkyloxycarbonyloxy lower alkyl group, lower cycloalkyloxycarbonyloxy (lower cycloalkyl) methyl group, lower cycloalkyl lower alkyloxycarbonyloxy lower alkyl group Group, adamantyloxycarbonyloxy lower alkyl group, 2-indaniloxycarbonyloxy lower alkyl group which may have a substituent on the aromatic ring, aryl lower alkyloxycarbonyl group Xyl-lower alkyl group, aryloxy lower alkyl group, ponyloxy-lower alky
- R 4 is a substituted lower alkyl group, or a halogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, wherein one or more hydrogen atoms on the ring are the same or different, —NR S R 6 (R s and R f may be the same or different and each represents a lower alkyl group, or R s and R 6 together form a — (CH 2 ) group (n is an integer of 2 to 6)
- a production method characterized by representing a phenyl group which may be substituted with a group selected from the group consisting of the group represented by.
- Preferred specific examples of the compound of the formula (I) include:
- the compound of formula (I) is dissolved or suspended in an inert solvent such as tetrahydrofuran, getyl ether, dioxane, dimethoxetane, toluene, benzene, dichloromethane, hexamethylphosphoric acid triamide, and the like. 70 ° C., preferably at 180 ° C.
- alkyl magnesium chloride alkyl magnesium bromide, alkyl magnesium oxide, aryl magnesium bromide, etc., preferably methyl magnesium
- a Grignard reagent such as chloride and ethylmagnesium bromide
- the mixture was mixed with tetrahydrofuran, getyl ether, dioxane, dimethyloxetane, toluene, benzene, dichloromethane, and hexamethyl phosphate triamide.
- a compound of formula (I) such as alkyl magnesium chloride, alkyl magnesium bromide, alkyl magnesium chloride, aryl magnesium bromide, etc., preferably methyl magnesium chloride, ethyl magnesium bromide.
- a compound of formula (III) can be obtained.
- the obtained compound of the formula (III) may be purified, if necessary, by precipitation, crystallization, or gel filtration using Sephadex or the like, or silica gel column chromatography, and used in the next step.
- the compound of formula (III) is then subjected to the steps of forming an ordinary ring of pentane, removing the protecting group if necessary, introducing an ester residue which can be hydrolyzed in vivo, and Z Alternatively, the compound can be converted to a compound of the formula (IV) by performing a step of forming a pharmaceutically acceptable salt in CO 2 R.
- the step of forming the carbane ring is carried out under Wittig cyclization conditions well known in the art, that is, the compound represented by the formula (III) dissolved in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, or dioxane, If necessary, the reaction can be carried out by adding a catalytic amount of an additive (preferably hydroquinone) and reacting at room temperature to reflux temperature for 10 minutes to 24 hours.
- an additive preferably hydroquinone
- the step of removing the protecting group is performed by performing the deprotection reaction of the protecting groups R 1 and R 3 in one or more steps before or after performing the above-mentioned ring closing reaction depending on the type of the protecting group. Become.
- a mineral acid such as hydrochloric acid
- an organic acid such as formic acid, acetic acid or citric acid
- a Lewis acid such as aluminum chloride
- R 1 is a silyl protecting group (for example, t-butyldimethylsilyl group, trimethylsilyl group, or triethylsilyl group)
- a fluorine ion reagent for example, tetrabutylammonium fluoride
- R ′ is an aryloxycarbonyl group and R 3 is an aryl group
- it can be easily removed by using various palladium complexes (for example, tetrakis (triphenylphosphine) palladium (0) and the like). it can.
- R 3 to produce a compound of formula (IV) is an ester residue which can be hydrolyzed in vivo may be prepared according to the following steps.
- bases in this reaction include organic bases such as diisoprovirethylamine, diazabicyclo [2,2,2] indene and 2,6-lutidine, and inorganic bases such as sodium hydroxide, Examples include potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
- R "_Y is, for example, benzoyloxymethyl chloride, 11- (benzoyloxy) ethyl chloride, 11- (2-methylbenzoyloxy) ethyl chloride, 4-t-butylbenzoyl chloride 2,4,6-trimethylbenzoyloxymethyl chloride, 4- (N, N-di-n-propylaminosulfonyl) ben Vyloxymethyl chloride 1- [4- (N, N-di-n-propylaminosulfonyl) benzoyloxy] ethyl chloride, 2-naphthylcarboxyloxymethyl chloride, 1-adamantylcarbonyloxymethyl chloride 1- (1-adamantylcarbonyloxy) ethyl, cyclohexyl (cyclohexyloxycarbonyloxy) methylo-dide, (1R, 2S, 5R)-( 1) 1-menthyloxycarbonyloxymethyl chloride, (1
- the compound represented by the formula (XII) thus obtained can be isolated and purified by precipitation, crystallization or gel filtration using Sephadex or the like, or silica gel column chromatography. can do.
- Kiichi C 0 2 step of forming a pharmaceutically acceptable salt thereof in R can therefore performed with conventional methods.
- a compound represented by the formula (XII) is suspended in water, and under ice-cooling, 1.0 equivalent of an aqueous solution of sodium hydrogencarbonate or potassium hydrogencarbonate is added. And then freeze-dried as it is or by precipitation or crystallization using an organic solvent such as acetonitrile or acetone.
- an organic solvent such as acetonitrile or acetone.
- Example 1 2- Mode 7-methylthioimidazo "5, 1-b] thiazol 2- (tree n-butylsyl)-7-methylthioimidazo [5, 1-b] thiazole 0. Cool 2.5 g of 23 g of tetrahydrofuran to 150 ° C, 0.11 g of N-succinimide was added. After stirring at the same temperature for 4 hours, 50 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a dilute aqueous sodium bicarbonate solution, a dilute aqueous sodium thiosulfate solution, and a saturated aqueous sodium chloride solution.
- This reaction mixture was added to 100 ml of a saturated aqueous solution of ammonium chloride, and extracted with 100 ml of ethyl acetate.
- the organic layer was sequentially washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
- the residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate) to obtain 0.39 g of the title compound.
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Abstract
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AU2001227095A AU2001227095A1 (en) | 2000-01-24 | 2001-01-24 | Processes for the preparation of carbapenem derivatives |
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JP2000-15105 | 2000-01-24 | ||
JP2000015105A JP2005231997A (ja) | 2000-01-24 | 2000-01-24 | カルバペネム誘導体の製造法 |
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WO2001053305A1 true WO2001053305A1 (fr) | 2001-07-26 |
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PCT/JP2001/000439 WO2001053305A1 (fr) | 2000-01-24 | 2001-01-24 | Procédés de préparation de dérivés de carbapenem |
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JP (1) | JP2005231997A (fr) |
AU (1) | AU2001227095A1 (fr) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004055027A1 (fr) * | 2002-12-13 | 2004-07-01 | Meiji Seika Kaisha, Ltd. | Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production |
WO2006077919A1 (fr) * | 2005-01-19 | 2006-07-27 | Meiji Seika Kaisha, Ltd. | Dérivé d'imidazothiazole et méthode de synthèse dudit dérivé |
US7482445B2 (en) | 2003-06-18 | 2009-01-27 | Meiji Seika Kaisha, Ltd. | Crystalline carbapenem intermediate |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0010316A1 (fr) * | 1978-10-24 | 1980-04-30 | Merck & Co. Inc. | Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0089139A2 (fr) * | 1982-03-16 | 1983-09-21 | Beecham Group Plc | Antibiotiques, leur préparation et leur utilisation |
EP0760370A1 (fr) * | 1995-03-10 | 1997-03-05 | Meiji Seika Kabushiki Kaisha | Nouveaux derives de carbapeneme |
WO1998032760A1 (fr) * | 1997-01-28 | 1998-07-30 | Meiji Seika Kaisha, Ltd. | Nouveaux derives de carbapenem |
WO2000006581A1 (fr) * | 1998-07-27 | 2000-02-10 | Meiji Seika Kaisha, Ltd. | Nouveaux derives de carbapenem |
-
2000
- 2000-01-24 JP JP2000015105A patent/JP2005231997A/ja not_active Withdrawn
-
2001
- 2001-01-24 WO PCT/JP2001/000439 patent/WO2001053305A1/fr active Application Filing
- 2001-01-24 AU AU2001227095A patent/AU2001227095A1/en not_active Abandoned
Patent Citations (5)
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EP0010316A1 (fr) * | 1978-10-24 | 1980-04-30 | Merck & Co. Inc. | Acides 1-carba-2-pénem-3-carboxyliques 1-, 6- et 2-substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0089139A2 (fr) * | 1982-03-16 | 1983-09-21 | Beecham Group Plc | Antibiotiques, leur préparation et leur utilisation |
EP0760370A1 (fr) * | 1995-03-10 | 1997-03-05 | Meiji Seika Kabushiki Kaisha | Nouveaux derives de carbapeneme |
WO1998032760A1 (fr) * | 1997-01-28 | 1998-07-30 | Meiji Seika Kaisha, Ltd. | Nouveaux derives de carbapenem |
WO2000006581A1 (fr) * | 1998-07-27 | 2000-02-10 | Meiji Seika Kaisha, Ltd. | Nouveaux derives de carbapenem |
Non-Patent Citations (1)
Title |
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GUTHIKONDA R.N. ET AL.: "Structure-activity relationships in the 2-arylcarbapenem series: synthesis of 1-methyl-2-aryl-cabapenems", J. MED. CHEM., vol. 30, no. 5, 1987, pages 871 - 880, XP002942200 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004055027A1 (fr) * | 2002-12-13 | 2004-07-01 | Meiji Seika Kaisha, Ltd. | Intermediaire pour derive de carbapeneme substitue en position 2 et son procede de production |
US7524951B2 (en) | 2002-12-13 | 2009-04-28 | Meiji Seika Kaisha, Ltd. | Intermediates of 2-substituted carbapenem derivatives and process for production thereof |
US7563901B2 (en) | 2002-12-13 | 2009-07-21 | Meiji Seika Kaisha, Ltd. | Intermediates of 2-substituted carbapenem derivatives and process for production thereof |
US7482445B2 (en) | 2003-06-18 | 2009-01-27 | Meiji Seika Kaisha, Ltd. | Crystalline carbapenem intermediate |
WO2006077919A1 (fr) * | 2005-01-19 | 2006-07-27 | Meiji Seika Kaisha, Ltd. | Dérivé d'imidazothiazole et méthode de synthèse dudit dérivé |
US7662841B2 (en) | 2005-01-19 | 2010-02-16 | Meiji Seika Kaisha, Ltd. | Imidazothiazole derivatives and process for producing the same |
CN101137661B (zh) * | 2005-01-19 | 2011-06-15 | 明治制果株式会社 | 咪唑并噻唑衍生物及其制备方法 |
JP4964599B2 (ja) * | 2005-01-19 | 2012-07-04 | Meiji Seikaファルマ株式会社 | イミダゾチアゾール誘導体およびその製造方法 |
KR101344137B1 (ko) | 2005-01-19 | 2013-12-20 | 메이지 세이카 파루마 가부시키가이샤 | 이미다조티아졸 유도체 및 그의 제조방법 |
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Publication number | Publication date |
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JP2005231997A (ja) | 2005-09-02 |
AU2001227095A1 (en) | 2001-07-31 |
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