JPH0343272B2 - - Google Patents
Info
- Publication number
- JPH0343272B2 JPH0343272B2 JP57091471A JP9147182A JPH0343272B2 JP H0343272 B2 JPH0343272 B2 JP H0343272B2 JP 57091471 A JP57091471 A JP 57091471A JP 9147182 A JP9147182 A JP 9147182A JP H0343272 B2 JPH0343272 B2 JP H0343272B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- amino
- fluoromethyl
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 105
- -1 cyanomethyl group Chemical group 0.000 claims description 38
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 231100000252 nontoxic Toxicity 0.000 claims description 9
- 230000003000 nontoxic effect Effects 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 7
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- PWZPJYKKYSFZRH-UHFFFAOYSA-N 2-(fluoromethyl)-4-oxoazetidine-1-sulfonic acid Chemical compound OS(=O)(=O)N1C(CF)CC1=O PWZPJYKKYSFZRH-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 22
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 239000002253 acid Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000004473 Threonine Substances 0.000 description 10
- 229960002898 threonine Drugs 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- VBCJJOJFKPQKPM-RITPCOANSA-N (2s,3s)-4-fluoro-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)[C@H](O)CF VBCJJOJFKPQKPM-RITPCOANSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- UFKGHYDBMUTINA-WDSKDSINSA-N tert-butyl (2r,3s)-1-amino-2-(fluoromethyl)-4-oxoazetidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)[C@H]1[C@H](CF)N(N)C1=O UFKGHYDBMUTINA-WDSKDSINSA-N 0.000 description 8
- 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 8
- 238000001816 cooling Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 5
- POPMTCFTVLHAGX-UWVGGRQHSA-N benzyl (2r,3s)-1-amino-2-(fluoromethyl)-4-oxoazetidine-3-carboxylate Chemical compound O=C1N(N)[C@@H](CF)[C@@H]1C(=O)OCC1=CC=CC=C1 POPMTCFTVLHAGX-UWVGGRQHSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- WPVIUZQMFSKPMN-UHFFFAOYSA-N 1-hydroxyazetidin-2-one Chemical compound ON1CCC1=O WPVIUZQMFSKPMN-UHFFFAOYSA-N 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 208000022362 bacterial infectious disease Diseases 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- YZNZLZIBEXDZOX-LRDDRELGSA-N tert-butyl (2R,3S)-3-amino-2-(fluoromethyl)-4-oxo-1-phenylmethoxyazetidine-3-carboxylate Chemical compound C(=O)(OC(C)(C)C)[C@]1(C(N([C@H]1CF)OCC1=CC=CC=C1)=O)N YZNZLZIBEXDZOX-LRDDRELGSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000002904 solvent Substances 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
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- CDFGMYLBUSYTKQ-UHFFFAOYSA-N 2-oxoazetidine-1-sulfonic acid Chemical compound OS(=O)(=O)N1CCC1=O CDFGMYLBUSYTKQ-UHFFFAOYSA-N 0.000 description 2
- ZACYWSWFHQXKPR-UHFFFAOYSA-N 4-(fluoromethyl)azetidin-2-one Chemical compound FCC1CC(=O)N1 ZACYWSWFHQXKPR-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 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
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- QLHZECDNPPYKFB-UHFFFAOYSA-L potassium sodium hydrogen carbonate hydrogen sulfate Chemical compound [Na+].[K+].OC(O)=O.[O-]S([O-])(=O)=O QLHZECDNPPYKFB-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
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- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、細菌感染症治療剤として有用な新規
なアゼチジノン誘導体またはその医薬上許容され
る塩、その製造法およびその用途に関する。
従来の技術および発明が解決しようとする課題
最近、３位にアシルアミノ基および１位にスル
ホ基を有する２−アゼチジノン骨格の単環β−ラ
クタム抗菌性物質が、A.Imada et al.，Nature，
289，590（1981）、R.B.Sykes et al.，Nature，
291，489（1981）の２つのグループにより独立し
て発見された。
単環β−ラクタムの化学修飾された誘導体に関
する先行技術としては、特開昭55−164671号公
報、同55−164672号公報、同56−125362号公報、
同56−133259号公報、同−133260号公報、同56−
135465号公報、同56−138169号公報および同56−
139454号公報が挙げられる。上記の公開公報に
は、特開昭56−125362号公報を除き２−アゼチジ
ノン核の４位が無置換の化合物が記載されている
にすぎない。特開昭56−125362号公報の実施例
103には、２−アゼチジノン核の４位がメチル基
であり、本発明のＲが１−カルボキシ−１−メチ
ルエチル基に相当する、化合物［Azthreonam
（アズトレオナム）］が記載されている。しかしな
がら、その抗菌活性は十分でなく、β−ラクタマ
ーゼに対する安定性も満足できるものではない。
いずれの公開公報においても、本発明化合物の
特徴である２−アゼチジノン核の４位にフルオロ
メチル基を有する（3S，4R）−（−）トランス体
の単環β−ラクタム誘導体に関する示唆はされて
いない。
課題を解決するための手段
本発明は一般式
［式中、ＲはC1-3アルキル基、C2-3アルケニル
基、C2-3アルキニル基、C3-5シクロアルキル基、
シアノC1-3アルキル基、カルボキシC1-3アルキル
基、ベンジル基またはフエニル基を示す］で表さ
れる化合物またはその医薬上許容される無毒性
塩、その製造法およびその用途に関する。
本発明者らは、２−アゼチジノン核に、（3S，
4R）−トランス−３−アシルアミノ−４−フルオ
ロメチル基を有する化合物に関して鋭意研究し、
該化合物が強い抗菌活性を有し、医薬品として有
用であることを見出し、本発明を完成した。
次に本明細書で言及される各種用語について説
明する。
C1-3アルキル基とは、炭素数１ないし３個のア
ルキル基を意味し、例えばメチル基、エチル基、
プロピル基、イソプロピル基等が挙げられる。
C2-3アルケニル基とは、炭素数２ないし３個の
アルケニル基を意味し、例えばビニル基、２−プ
ロペニル基等が挙げられる。
C2-3アルキニル基とは、炭素数２ないし３個の
アルキニル基を意味し、例えば、エチニル基、２
−プロピニル基等が挙げられる。
C3-5シクロアルキル基とは、３員ないし５員の
環状アルキニル基を意味し、例えばシクロプロピ
ル基、シクロブチル基、シクロペンチル基等が挙
げられる。
シアノC1-3アルキル基とは、シアノ基が置換し
た前述のC1-3アルキル基を意味し、例えばシアノ
メチル基等が挙げられる。
カルボキシC1-3アルキル基とは、カルボキシル
基が置換した前述のC1-3アルキル基を意味し、例
えばカルボキシメチル基、１−カルボキシ−１−
メチルエチル等が挙げられる。
医薬上許容される無毒性塩とは、例えばナトリ
ウム塩、カリウム塩等のアルカリ金属塩；カルシ
ウム塩、マグネシウム塩等のアルカリ土類金属
塩；アンモニウム塩等の無機アミン塩；トリメチ
ルアミン塩、トリエチルアミン塩、Ｎ，N′−ジ
ベンジルエチレンジアミン塩、プロカイン塩等の
有機アミン塩；塩酸塩、臭化水素酸塩、硫酸塩、
燐酸塩、硝酸塩等の無機酸塩；酢酸塩、乳酸塩、
プロピオン酸塩、マレイン酸塩、りんご酸塩、酒
石酸塩、くえん酸塩、メタンスルホン酸塩、イセ
チオン酸塩等の有機酸塩；アルギニン塩、リジン
塩、アスパラギン酸塩、グルタミン酸塩等のアミ
ノ酸塩等が挙げられる。
本発明の一般式［］の化合物中、好適な化合
物としては、Ｒがメチル基、エチル基、プロピル
基、イソプロピル基、２−プロペニル基、２−プ
ロピニル基、カルボキシメチル基、シアノメチル
基、１−カルボキシ−１−メチルエチル基、シク
ロペンチル基、ベンジル基またはフエニル基の化
合物であり、特に１−カルボキシ−１−メチルエ
チル基の化合物が好適である。
次に本発明化合物の製造法について説明する。
本発明化合物は、
(イ) 一般式
［式中、R1は水素原子またはスルホ基を示
す］で表される化合物と
一般式
［式中、R2は水素原子またはアミノ基の保
護基、R3はC1-3アルキル基、C2-3アルケニル
基、C2-3アルキニル基、C3-5シクロアルキル
基、シアノC1-3アルキル基、保護されていても
よいカルボキシC1-3アルキル基、ベンジル基ま
たはフエニル基を示す］で表される化合物また
はその反応性誘導体とを反応させ、
(ロ) 次にR1が水素原子を示す場合は、工程(イ)で
得られた化合物をスルホン化し、
(ハ) 要すれば、保護基を除去し、そして
(ニ) 要すれば、このようにして得られた化合物を
その医薬上許容される無毒性の塩に変換するこ
とにより製造することができる。
一般式［］の化合物と一般式［］の化合物
との反応は、例えば塩化メチレン、クロロホル
ム、ジエチルエーテル、酢酸エチル、酢酸ブチ
ル、テトラヒドロフラン、アセトニトリル、Ｎ，
Ｎ−ジメチルホルムアミド、ジメチルスルホキシ
ドまたはこれらの混合溶媒中で、脱酸剤の存在下
または非存在下で行うことができる。脱酸剤とし
ては、例えば、炭酸ナトリウム、炭酸カリウム、
炭酸カルシウム、炭酸マグネシウム等の金属塩、
または例えばトリエチルアミン、Ｎ，Ｎ−ジイソ
プロピルエチルアミン、Ｎ−メチルモルホリン、
Ｎ，Ｎ−ジメチルアニリン等の有機アミンが挙げ
られる。反応は一般式［］の化合物１モルに対
して、一般式［］の化合物を等モル使用し、反
応温度および反応時間は特に限定されないが、通
常は０〜40℃で0.5〜５時間である。
一般式［］のR1が水素原子の場合、一般式
［］の化合物と一般式［］の化合物との反応
終了後、有機アミン−無水硫酸のコンプレツクス
を用いてスルホン化反応を行う。スルホン化反応
は、一般式［］の化合物と一般式［］の化合
物との縮合物１モルに対して、該コンプレツクを
１〜５モル使用し、反応温度および反応時間は、
特に限定されないが、通常、10〜30℃で５〜80時
間である。
一般式［］のR1がスルホ基である化合物は、
該化合物をテトラブチルアンモニウム塩（以下、
TBA塩と略す）として本反応で使用することも
できる。
一般式［］のアミノ基およびR3は必要に応
じて保護されていてもよく、保護基が存在する場
合は保護基を除去することにより、本発明化合物
［］得ることができる。
前記一般式におけるカルボキシル基およびアミ
ノ基の保護基としては、β−ラクタム合成の分野
で通常使用される保護基を適宜選択して使用する
ことができる。
アミノ基の保護基としては、例えばトリチル
基、tert−ブトキシカルボニル基、ベンジルオキ
シカルボニル基等が挙げられる。
カルボキシル基の保護基としては、例えばベン
ズヒドリル基、tert−ブチル基等が挙げられる。
本製造法を具体的に説明する前に本発明の原料
化合物の合成方法について説明する。
本発明化合物の重要な中間体である（3S，4R）
−（−）−３−tert−ブトキシカルボニルアミノ−
４−フルオロメチル−２−アゼチジノン(6)の合成
は、γ−フルオロ−Ｌ−トレオニン(1)｛［α］20 D−
18゜（ｃ＝５，H2O）｝を出発原料として、M.J.
Miller et al.，J.Am.Chem.Soc.，102，7026
（1980）の方法に従つて合成出来る。γ−フルオ
ロ−Ｌ−トレオニン(1)をジオキサン中で２−tert
−ブトキシカルボニルチオ−４，６−ジメチルピ
リミジン（以下、Bos−Ｓと略す）を用いて、
tert−ブトキシカルボニル（以下、Bocと略す）
化を行い、Ｎ−Boc−γ−フルオロトレオニン(2)
を得る。次に、化合物(2)を直接にＯ−ベンジルヒ
ドロキシルアミンとＮ，N′−ジシクロヘキシル
カルボジイミド（以下、DCCと略す）等の縮合
剤の存在下に反応させて、N1−ベンジルオキシ
−N2−Boc−γ−フルオロトレオニンアミド(3)
を得ることができる。また化合物(3)は、化合物(2)
とＮ−ヒドロキシスクシンイミド（以下、HOSu
と略す）もしくは１−ヒドロキシベンゾトリアゾ
ール（以下、HOBtと略す）とDCCとを反応させ
て、化合物(2)の活性エステルとした後、Ｏ−ベン
ジルヒドロキシルアミンと反応させても得ること
ができる。
次に、化合物(3)をトリフエニルホスフイン、四
塩化炭素およびトリエチルアミン（以下、TEA
と略す）の存在下に、またはジエチルアゾジカル
ボキシラート（以下、DEADと略す）とトリフ
エニルホスフインの存在下に閉環反応させて、
（3S，4R）−（−）−３−Boc−アミノ−１−ベン
ジルオキシ−４−フルオロメチル−２−オキソア
ゼチジン(4)に誘導する｛［α］20 D−44.5゜（ｃ＝１、
CH3OH）｝。化合物(4)をパラジウム炭素の存在下
に接触還元すると１−ヒドロキシアゼチジノン(5)
が得られる。化合物(5)を三塩化チタンで還元する
と、（3S，4R）−（−）−３−Boc−アミノ−４−
フルオロメチル−２−オキソアゼチジン(6)が得ら
れる｛［α］20 D−110.2゜（ｃ＝１、CH3OH）｝。
次に本発明の化合物の製造法を具体的に説明す
る。
本発明化合物［］は化合物(6)を用いて次のよ
うに合成することができる。
化合物(6)をトリフルオロ酢酸（以下、TFAと
略す）で処理すると、（3S，4R）−３−アミノ−
４−フルオロメチル−２−オキソアゼチジン(7)を
与える。一方、（Ｚ）−２−（２−トリチルアミノ
−４−チアゾリル）−２−置換オキシイミノ酢酸
(8)に五塩化燐を作用させて、酸クロリドに変換
し、該酸クロリドと化合物(7)とをTEAの存在下
に反応させて、（3S，4R）−３−｛（Ｚ）−２−（２
−トリチルアミノ−４−チアゾリル）−２−置換
オキシイミノアセトアミド｝−４−フルオロメチ
ル−２−オキソアゼチジン(9)が得られる。化合物
(9)をＮ，Ｎ−ジメチルホルムアミド（以下、
DMFと略す）中でピリジン−無水硫酸コンプレ
ツクスまたは２−ピコリン−無水硫酸コンプレツ
クスでスルホン化して、（3S，4R）−３−〔（Ｚ）−
２−（２−トリチルアミノ−４−チアゾリル）−２
−置換オキシイミノアセトアミド〕−４−フルオ
ロメチル−２−オキソ−１−アゼチジンスルホン
酸(10)を得る。化合物(10)を水を含むギ酸、TFAま
たはそれらの混合液で処理すると、アミノ保護基
のトリチル基はもちろんのことカルボキシル保護
基のtert−ブチル基またはベンズヒドリル基も除
去され、（3S，4R）−（−）−３−｛（Ｚ）−２−（２
−アミノ−４−チアゾリル）−２−置換オキシイ
ミノアセトアミド｝−４−フルオロメチル−２−
オキソ−１−アゼチジンスルホン酸［］の分子
内塩を得ることができる。この分子内塩を適当な
苛性アルカリまたは炭酸アルカリ等で中和して凍
結乾燥すると目的化合物［］のカリウム塩また
はナトリウム塩が得られる。
化合物(6)から出発して、２−アゼチジノン核の
１位のスルホン化を行い、次いでアシル化を行う
方法でも目的化合物［］は合成できる。
化合物(6)のアミノ保護基のBocをTFAで除去
し、化合物(7)に変換し、ベンジルクロロホルマー
トでアミノ基をベンジルオキシカルボニル（以
下、Cbzと略す）化し、（3S，4R）−３−Cbz−ア
ミノ−４−フルオロメチル−２−オキソアゼチジ
ン(11)を得る。化合物(11)をピリジン−無水硫酸コン
プレツクスまたは２−ピコリン−無水硫酸コンプ
レツクスでスルホン化して、（3S，4R）−（−）−
３−Cbz−アミノ−４−フルオロメチル−２−オ
キソ−１−アゼチジンスルホン酸とすることがで
きる。さらに該スルホン酸はTBA塩(12)として単
離することができる｛［α］20 D−12.1゜（ｃ＝１，
C2H5OH）｝。さらに化合物(12)をパラジウム炭素存
在下に接触還元して、（3S，4R）−３−アミノ−
４−フルオロメチル−２−オキソ−１−アゼチジ
ンスルホン酸TBA塩（13）とする。化合物（13）
と（Ｚ）−２−（２−アミノ−４−チアゾリル）−
２−置換オキシイミノ酢酸(8)の活性エステル、例
えば化合物(8)とHOBtからDCCの存在下に得られ
る活性エステルとを反応させて、（3S，4R）−３
−｛（Ｚ）−２−（２−アミノ−４−チアゾリル）２
−置換オキシイミノアセトアミド｝−４−フルオ
ロメチル−２−オキソ−１−アゼチジンスルホン
酸TBA塩（14）が得られる。
置換基R3が除去すべき保護基を含まない場合、
化合物（14）は目的化合物［］のTBA塩を与
える。更にこのTBA塩を水または含水メタノー
ルに溶かし強酸性イオン交換樹脂のカリウム塩
型、例えばダイヤイオン
SK−102（K+）で処理
し、凍結乾燥して［］のカリウム塩が得られ
る。また置換基R3の中にtert−ブチル基あるいは
ベンズヒドリル基等のカルボキシル基の保護基を
含む場合は、TFA−アニソールで処理し、TFA
を溜去後、酢酸エチル等の有機溶媒処理により目
的化合物［］の分子内塩が得られる。分子内塩
は適当な苛性アルカリあるいは炭酸アルカリで処
理し、次に凍結乾燥することによりナトリウム塩
またはカリウム塩に変換することができる。
化合物（13）はD.M.Floyd et al.，J.Org.
Chem.，47，176（1982）のＬ−トレオニンから
（3S，4R）−３−Cbz−アミノ−４−メチル−２
−オキソ−１−アゼチジンスルホン酸TBA塩の
製法に従つても合成できる。γ−フルオロ−Ｌ−
トレオニン(1)にベンジルクロロホルマートを作用
させてＮ−Cbz−γ−フルオロ−Ｌ−トレオニン
（15）に変換し、次にHOSuとDCCの存在下に反
応させ活性エステルとし、さらにアンモニアを作
用させて、N2−Cbz−γ−フルオロ−Ｌ−トレオ
ニンアミド（16）を得る。化合物（16）にピリジ
ン中、メタンスルホニルクロリドを反応させて、
N2−Cbz−Ｏ−メシル−γ−フルオロ−Ｌ−トレ
オニンアミド（17）に変換し、次にピリジン−無
水硫酸コンプレツクスまたは２−ピコリン−無水
硫酸コンプレツクスを用いて、アミドのスルホン
化を行い、N2−Cbz−Ｏ−メシル−N1−スルホ
ナート−γ−フルオロ−Ｌ−トレオニンアミド
TBA塩（18）に誘導する。化合物（18）は水−
１，２−ジクロロエタン中、炭酸カリウムの存在
下に閉環させて、化合物（12）を得ることができ
る。
本発明化合物［］は細菌による感染症の治療
および予防に有用である。
次の代表例の抗菌活性（MIC）を示す。
化合物Ａ：（3S，4R）−（−）−３−〔（Ｚ）−２−
（２−アミノ−４−チアゾリル）−２−メトキシイ
ミノアセトアミド〕−４−フルオロメチル−２−
オキソ−１−アゼチジンスルホン酸 カリウム塩
化合物Ｂ：（3S，4R）−（−）−３−〔（Ｚ）−２−
（２−アミノ−４−チアゾリル）−２−エトキシイ
ミノアセトアミド〕−４−フルオロメチル−２−
オキソ−１−アゼチジンスルホン酸 カリウム塩
化合物Ｃ：（3S，4R）−（−）−３−〔（Ｚ）−２−
（２−アミノ−４−チアゾリル）−２−カルボキシ
ラートメトキシイミノアセトアミド〕−４−フル
オロメチル−２−オキソ−１−アゼチジンスルホ
ン酸 ジカリウム塩
化合物Ｄ：（3S，4R）−（−）−３−〔（Ｚ）−２−
（２−アミノ−４−チアゾリル）−２−（１−カル
ボキシラート−１−メチルエトキシイミノ）アセ
トアミド〕−４−フルオロメチル−２−オキソ−
１−アゼチジンスルホン酸 ジカリウム塩
化合物Ｅ：（3S，4R）−（−）−３−〔（Ｚ）−２−
（２−アミノ−４−チアゾリル）−２−ベンジルオ
キシイミノアセトアミド〕−４−フルオロメチル
−２−オキソ−１−アゼチジンスルホン酸 カリ
ウム塩
【表】
上記の表から明らかなように、本発明化合物
は、優れた抗菌活性を示し、特に、グラム陰性菌
に対し、顕著な効果を有する。
本発明化合物［］を細菌感染症の予防または
治療に用いるには、そのまま、または医薬上許容
される塩として使用する、本発明化合物またはそ
の塩は単独または薬剤的に許容される担体と複合
して、投与に適した剤形で、経口または非経口的
に投与される。
本発明化合物の製剤として、例えば注射剤、錠
剤、カプセル剤、顆粒剤、細粒剤、粉末剤、液
剤、懸濁剤、乳剤、シロツプ剤、エリキシル剤、
レモネード剤、坐剤等が挙げられる。
さらに必要により前記製剤に溶解液、補助剤、
安定化剤、結合剤、湿潤剤、滑沢剤、崩壊剤等の
通常使用される添加剤を配合してもよく、例えば
注射剤には通常、注射用蒸留水、生理食塩水、ブ
ドウ糖注射液等の溶解液で用時調剤し、必要によ
りパラオキシ安息香酸メチル、ｐ−ヒドロキシ安
息香酸プロピル等の安定化剤を含有してもよい。
錠剤、顆粒剤、細粒剤およびカプセル剤には通
常、アラビアゴム、ゼラチン、ソルビツト、トラ
ガント、ポリビニルピロリドン、乳糖、しよ糖、
とうもろこしでんぷん、リン酸カルシウム、グリ
シン、ステアリン酸マグネシウム、タルク、ポリ
エチレングリコール、シリカ、ラウリル硫酸ナト
リウム等が用いられる。液状製剤には通常、ソル
ビツトシロツプ、メチルセルロース、グルコー
ス、しよ糖シロツプ、ゼラチン、ヒドロキシエチ
ルセルロース、カルボキシメチルセルロース、ス
テアリン酸アルミニウムゲル、食用油、レシチ
ン、ソルビタンモノオレエート、アラビアゴム、
扁桃油、ココナツ油、油性エステル、プロピレン
グリコール、エチルアルコール、ｐ−ヒドロキシ
安息香酸メチル、プロピオン酸、ソルビン酸等の
慣用の添加剤が用いられる。座剤には、例えばカ
カオ脂またはその他のグリセリドのような通常の
坐剤基剤を含有していてもよい。
本発明化合物およびその医薬上許容される塩の
投与量は患者の年令、症状、投与対象によつて異
なるが、一般的には患者の体重１Kgに対して１〜
100mg、好ましくは５〜30mgを１日に２〜４回に
分けて経口または非経口的に投与する。
本発明化合物は細菌感染治療、または細菌感染
症の予防のため、例えば哺乳動物の呼吸器感染
症、***症、化膿性疾患、胆道感染症、腸内
感染症、産婦人科感染症、外科感染症等の治療ま
たは予防に用いることができる。
次に実施例を挙げて本発明を更に詳細に説明す
るが、本発明はこれに限定されるものではない。
実施例 １
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−メトキシイミノア
セトアミド〕−４−フルオロメチル−２−オキ
ソ−１−アゼチジンスルホン酸
ａ （Ｚ）−２−（２−トリチルアミノ−４−チア
ゾリル）−２−メトキシイミノ酢酸610mg
（1.37mmol）を五塩化燐315mg（1.51mmol）の
メチレンクロリド15ml溶液中に−10℃に冷却下
に加えた。反応液を−５℃で30分間攪拌した
後、−10℃に冷却し、トリエチルアミン（以下、
TEAと略す）0.42ml（3.02mmol）と水５mlを
加えて、０℃で３分間攪拌した。有機層を分取
し、無水炭酸カリウム−硫酸ナトリウムで乾燥
して酸クロリド溶液を調製した。一方、（3S，
4R）−（−）−３−Boc−アミノ−４−フルオロ
メチル−２−オキソアゼチジン300mg
（1.37mmol）の冷トリフルオロ酢酸（以下、
TFAと略す）1.5ml溶液を氷冷下１時間攪拌し
た後、減圧下で蒸発させ、さらに酢酸エチル５
mlを加えて蒸発させた。残渣に酢酸エチル20ml
を加え−10℃に冷却し、TEA0.96ml
（6.88mmol）を加え、調製しておいた酸クロリ
ド溶液を10分間かけて滴下し、−10℃〜０℃で
30分間、さらに冷却水浴を除いて30分間攪拌し
た。反応液を減圧下に濃縮し、残渣に酢酸エチ
ルと水を加えて抽出した。有機層を分取し、無
水硫酸ナトリウムで乾燥後、減圧下で濃縮乾固
し、残渣をシリカゲルフラツシユカラムクロマ
トグラフイに付し、クロロホルム−メタノール
（97：３）を用いて溶離し、目的物を含むフラ
クシヨンを減圧下で濃縮し、エーテルを加えて
沈殿を濾取すると600mg（収率：80.3％）の
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−トリ
チルアミノ−４−チアゾリル）−２−メトキシ
イミノアセトアミド〕−４−フルオロメチル−
２−オキソアゼチジンが得られた。
ｂ 実施例１−ａで得られた化合物600mg
（1.1mmol）を含む無水Ｎ，Ｎ−ジメチルホル
ムアミド（以下、DMFと略す）10ml溶液にピ
リジン−無水硫酸コンプレツクス525mg
（3.3mmol）を加え、室温で３日間攪拌した後、
減圧下にDMFを蒸発させ、残渣を酢酸エチル
と水に分配し、有機層を分取した。該有機層を
無水硫酸ナトリウムで乾燥後、クロロホルム−
メタノール（97：３）を用いてシリカゲルフラ
ツシユカラムクロマトグラフイに付し、目的物
を含むフラクシヨンを減圧下に濃縮して（3S，
4R）−（−）−３−〔（Ｚ）−２−（２−トリチルア
ミノ−４−チアゾリル）−２−メトキシイミノ
アセトアミド〕−４−フルオロメチル−２−オ
キソ−１−アゼチジンスルホン酸を得た。
ｃ 実施例１−ｂで得られた化合物をギ酸10mlに
溶解させ、５℃で２日間放置した。反応液の溶
媒を減圧下に留去し、残渣にアセトンを加え粉
末化して濾取した。得られた粉末をクロロホル
ム−メタノール（６：４）を用いたシリカゲル
フラツシユカラムクロマトグラフイに付し、表
題の化合物65mg（スルホン化と脱トリチルの二
段階合わせた収率：15.4％）を得た。
IR（KBr）cm-1：3450，1770，1665，1625，
1530，1270，1240，1050
実施例 ２
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（１−カルボキシ−
１−メチルエトキシイミノ）アセトアミド〕−
４−フルオロメチル−２−オキソ−１−アゼチ
ジンスルホン酸
ａ （Ｚ）−２−（２−トリチルアミノ−４−チア
ゾリル）−２−（１−Boc−１−メチルエトキシ
イミノ）酢酸784mg（1.37mmol）を五塩化燐
315mg（1.51mmol）のメチレンクロリド15ml溶
液中に−10℃で加えた。反応液を−５℃で30分
間攪拌した後、−10℃に冷却し、水５mlと
TEA0.42ml（3.02mmol）を加えて、０℃で３
分間攪拌した。有機層を無水炭酸カリウム−硫
酸ナトリウムで乾燥して酸クロリド溶液を調製
した。
一方、（3S，4R）−（−）−３−Boc−アミノ
−４−フルオロメチル−２−オキソアゼチジン
300mg（1.37mmol）の冷TFA1.5ml溶液を氷冷
下１時間攪拌した。反応液を減圧下に濃縮し、
残渣に酢酸エチル５mlを加えて更に濃縮した。
残渣に酢酸エチル20mlを加え、−10℃で
TEA0.96ml（6.88mmol）を加え、さらに上記
の酸クロリド溶液を10分間で滴下した。−10〜
０℃で30分間、さらに室温で30分間攪拌した
後、反応液を減圧下に濃縮した。残渣に酢酸エ
チルと水を加えて抽出し、有機層を分取し無水
硫酸ナトリウムで乾燥し、減圧下で濃縮した。
残渣をクロロホルム−メタノール（97：３）を
用いたシリカゲルフラツシユカラムクロマトグ
ラフイに付し、（3S，4R）−（−）−３−〔（Ｚ）−
２−（２−トリチルアミノ−４−チアゾリル）−
２−（１−Boc−１−メチルエトキシイミノ）
アセトアミド〕−４−フルオロメチル−２−オ
キソアゼチジン340mg（収率：36.8％）を得た。
IR（KBr）cm-1：3400，1770，1740，1670，
1590，1570，1200，1190，1040，995
ｂ 実施例２−ａで得られた化合物340mg
（0.51mmol）の無水DMF6ml溶液に、ピリジン
−無水硫酸コンプレツクス240mg（1.5mmol）
を加えて室温で３日間攪拌した。反応液を減圧
下で濃縮し、酢酸エチル−水を加え抽出し、有
機層を分取後、有機層を無水硫酸ナトリウムで
乾燥し、減圧下で濃縮乾固、残渣をクロロホル
ム−メタノール（95：５）を溶媒とするシリカ
ゲルフラツシユカラムクロマトグラフイに付
し、（3S，4R）−（−）−３−〔（Ｚ）−２−（２−
トリチルアミノ−４−チアゾリル）−２−（１−
Boc−１−メチルエトキシイミノ）アセトアミ
ド〕−４−フルオロメチル−２−オキソ−１−
アゼチジンスルホン酸180mg（収率：47.3％）
を得た。
IR（KBr）cm-1：3400，1755，1725，1670，
1590，1570，1280，1245，1200，1140，1045
ｃ 実施例２−ｂで得られた化合物180mg
（0.24mmol）のギ酸５mlの溶液を５℃で４日間
放置した後、減圧下に濃縮し、残渣にアセトン
を加え粉末化して濾取した。この粉末をクロロ
ホルム−メタノ−ル（７：３）を用いたシリカ
ゲルフラツシユカラムクロマトグラフイに付
し、目的物を含むフラクシヨンを減圧下に濃縮
し、アセトンで粉末化して濾取すると表題の化
合物60mg（収率：55.3％）が得られた。
IR（KBr）cm-1：1755，1665，1530，1535，
1400，1270，1240，1200，1165，1050
実施例 ３
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−メトキシイミノア
セトアミド〕−４−フルオロメチル−２−オキ
ソ−１−アゼチジンスルホン酸カリウム塩
ａ （3S，4R）−（−）−３−Cbz−アミノ−４−
フルオロメチル−２−オキソ−１−アゼチジン
スルホン酸TBA塩700mg（1.2mmol）の
DMF15ml溶液に、10％パラジウム炭素350mgを
加えて１時間水素化した。触媒をセライトを通
して濾過し、DMF2mlで洗つた。濾液と洗液を
一緒にした溶液に１−ヒドロキシベンゾトリア
ゾール（以下、HOBtと略す）178mg
（1.3mmol）と（Ｚ）−２−（２−アミノ−４−
チアゾリル）−２−メトキシイミノ酢酸241mg
（1.2mmol）を加え、氷冷下にＮ，N′−ジシク
ロヘキシルカルボジイミド（以下、DCCと略
す）260mg（1.26mmol）を加え、室温で17時間
攪拌した。沈澱を濾別し、濾液を減圧下に留去
し、残渣を酢酸エチル−アセトン（４：１〜
１：２）を用いたシリカゲルフラツシユカラム
クロマトグラフイに付し、（3S，4R）−（−）−
３−〔（Ｚ）−２−（２−アミノ−４−チアゾリ
ル）−２−（メトキシイミノアセトアミド〕−４
−フルオロメチル−１−アゼチジンスルホン酸
TBA塩524mg（収率：70％）を得た。
IR（KBr）cm-1：1770，1670，1620，1535，
1270，1040
NMR（DMSO−d6）δin ppm：0.95（12H，ｔ，
Ｊ＝７Hz），1.10〜1.80（16H，ｍ），3.00〜
3.50（8H，ｍ），3.70〜4.10（4H，ｍ），4.76
（2H，ｍ），4.82（1H，dd，Ｊ＝7.5＆2.0Hz），
6.76（1H，ｓ），7.21（2H，br ｓ），9.36（1H，
ｄ，Ｊ＝7.5Hz）
ｂ 実施例３−ａで得られた化合物479mg
（0.77mmol）の水20ml溶液を活性炭処理した
後、ダイヤイオン
SK−102（K+）５mlのカラ
ムに通液し、目的物を含むフラクシヨンを凍結
乾燥し、表題の化合物260mg（収率：87.2％）
得た。
［α］20 D−23.5°（ｃ＝１，H2O）
IR（KBr）cm-1：1775，1665，1620，1535，
1380，1270，1245，1050，960，815，720，
650
NMR（D2O）δin ppm：4.03（3H，ｓ），4.15
（1H，ｍ），4.92（2H，ｍ）5.01（1H，ｄ，Ｊ
＝2.5Hz），6.97（1H，ｓ）
実施例 ４
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（１−カルボキシラ
ート−１−メチルエトキシイミノ）アセトアミ
ド〕−４−フルオロメチル−２−オキソ−１−
アゼチジンスルホン酸 ジカリウム塩
ａ （3S，4R）−（−）−３−Cbz−アミノ−４−
フルオロメチル−２−オキソ−１−アゼチジン
スルホン酸TBA塩2.14ｇ（3.73mmol）の
DMF75ml溶液を10％パラジウム炭素640mgと共
に水素化を２時間行つた。触媒を濾別した後、
濾液に２−（２−アミノ−４−チアゾリル）−２
−（１−ジフエニルメトキシカルボニル−１−
メチルエトキシイミノ）酢酸1.64ｇ
（3.73mmol）、HOBt0.55ｇ（4.07mmol）及び
DCC0.77ｇ（3.73mmol）を加えた。室温で20
時間攪拌した後、反応液を減圧下に濃縮して
DMFを除き、残渣にメチレンクロリドを加え
て不溶物を濾過して除き、アセトン−メチレン
クロリド（３：７→６：４）を用いたシリカゲ
ルフラツシユカラムクロマトグラフイに付し、
目的物を含むフラクシヨンを減圧下に濃縮し、
固体を得た。これにアニソール9.4mlを加え、−
15℃に冷却した後、TFA47mlを加え、０℃で
15分間攪拌した。反応液を減圧下に濃縮し、残
渣に酢酸エチルを加えて、不溶物濾取した。不
溶物をメタノール−酢酸エチルで結晶化し、
（3S，4R）−（−）−３−〔２−（２−アミノ−４
−チアゾリル）−２−（１−カルボキシ−１−メ
チルエトキシイミノ）アセトアミド〕−４−フ
ルオロメチル−２−オキソ−１−アゼチジンス
ルホン酸1.20ｇ（収率：70％）を得た。
ｂ 実施例４−ａで得られた化合物720mgを水35
mlに懸濁し、冷却下に0.4N苛性カリ（以下、
KOHと略す）でPH5.5に調整して溶解した。こ
の溶液を凍結乾燥した後、残渣にアセトニトリ
ルを加え、減圧下に溶媒を留去する。（この操
作を３回繰返す。）残渣をエーテルで粉末化し
て濾取し、表題の化合物840mgを得た。
［α］20 D−16.4゜（ｃ＝１，H2O）
IR（KBr）cm-1：3400，1780，1670，1590，
1540，1400，1370，1275，1245，1250，
1160，1050
NMR（DMSO−d6）δin ppm：1.40（3H，ｓ），
1.44（3H，ｓ），3.8〜4.3（1H，ｍ），4.3〜5.2
（3H，ｍ），6.80（1H，ｓ），7.23（2H，br
ｓ）
実施例 ５
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−フエノキシイミノ
アセトアミド〕−４−フルオロメチル−２−オ
キソ−１−アゼチジンスルホン酸カリウム塩
（3S，4R）−（−）−３−Cbz−アミノ−４−フ
ルオロメチル−２−オキソ−１−アゼチジンスル
ホン酸TBA塩574mg（1mmol）のDMF20ml溶液
に、10％パラジウム炭素170mgを加えて、室温で
２時間水素化した。触媒を濾別した後、濾液に
（Ｚ）−２−（２−アミノ−４−チアゾリル）−２−
フエノキシイミノ酢酸263mg（1mmol）、HOBt
148mg（1.1mmol）およびDCC206mg1mmol）を
加えて、室温で18時間攪拌した。反応液を減圧下
に蒸発させ、残渣にメチレンクロリドを加えて不
溶物を濾別し、濾液をアセトン−メチレンクロリ
ド（３：７〜６：４）を用いたシリカゲルフラツ
シユカラムクロマトグラフイに付し、目的物を含
むフラクシヨンを減圧下に濃縮乾固し、残渣を水
に溶かし、ダイヤイオン
SK−102（K+）カラム
に通液して、目的物を含むフラクシヨンを凍結乾
燥し、表題の化合物340mg（収率：70.6％）を白
色粉末として得た。
［α］20 D−16.9゜（ｃ＝１，H2O）
IR（KBr）cm-1：3470，3370，1780，1670，
1620，1595，1540，1490，1280，1250，
1200，1055
NMR（DMSO−d6）δin ppm：3.8〜4.2（1H，
ｍ），4.4〜5.2（3H，ｍ），7.0〜7.5（8H，ｍ），
9.63（1H，ｄ，Ｊ＝８Hz）
実施例 ６
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−エトキシイミノア
セトアミド〕−４−フルオロメチル−２−オキ
ソ−１−アゼチジンスルホン酸カリウム塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−エトキシイミノ酢酸
を用いて、表題の化合物200mg（収率：46.1％）
を得た。
［α］20 D−26゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1775，1660，1620，
1535，1270，1240，1050
NMR（DMSO−d6）δin ppm：1.21（3H，ｔ，
Ｊ＝７Hz），3.8〜4.2（1H，ｍ），4.21（2H，
ｑ，Ｊ＝７Hz），4.3〜5.2（3H，ｍ），6.74
（1H，ｓ），7.20（2H，br ｓ），9.30（1H，
ｄ，Ｊ＝８Hz）
実施例 ７
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−ベンジルオキシイ
ミノアセトアミド〕−４−フルオロメチル−２
−オキソ−１−アゼチジンスルホン酸カリウム
塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−ベンジルオキシイミ
ノ酢酸を用いて、表題の化合物420mg（収率：
84.8％）を得た。
［α］20 D−16゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1775，1670，1620，
1535，1270，1245，1050
NMR（DMSO−d6）δin ppm：3.8〜4.2（1H，
ｍ），4.3〜5.1（3H，ｍ），5.18（2H，ｓ），
6.79（1H，ｓ），7.23（2H，br ｓ），7.39（5H，
ｓ），9.45（1H，ｄ，Ｊ＝８Hz）
実施例 ８
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−ｎ−プロポキシイ
ミノアセトアミド〕−４−フルオロメチル−２
−オキソ−１−アゼチジンスルホン酸カリウム
塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−ｎ−プロポキシイミ
ノ酢酸を用いて、表題の化合物350mg（収率：
78.2％）を得た。
［α］20 D−23゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1775，1665，1620，
1530，1270，1245，1050
NMR（DMSO−d6）δin ppm：0.89（3H，ｔ，
Ｊ＝７Hz），1.62（2H，ｍ），3.7〜4.2（1H，
ｍ），4.02（2H，ｔ，Ｊ＝７Hz），4.3〜5.3
（3H，ｍ），6.73（1H，ｓ），7.2（2H，br
ｓ），9.31（1H，ｄ，Ｊ＝８Hz）
実施例 ９
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（２−プロペニルオ
キシイミノ）アセトアミド〕−４−フルオロメ
チル−２−オキソ−１−アゼチジンスルホン酸
カリウム塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（２−プロペニルオキ
シイミノ）酢酸を用いて、表題の化合物290mg
（収率：65.1％）を得た。
［α］20 D−25.6°（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1770，1660，1620，
1270，1240，1050，1005
NMR（DMSO−d6）δin ppm：3.7〜4.2（1H，
ｍ），4.3〜5.5（7H，ｍ），6.76（1H，ｓ），
7.22（2H，br ｓ），9.36（1H，ｄ，Ｊ＝８Hz）
実施例 10
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−シアノメトキシイ
ミノアセトアミド〕−４−フルオロメチル−２
−オキソ−１−アゼチジンスルホン酸カリウム
塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−シアノメトキシイミ
ノ酢酸を用いて、表題の化合物310mg（収率：
69.7％）を得た。
［α］20 D−25.6゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1770，1660，1620，
1530，1270，1240，1050，1020
NMR（DMSO−d6）δin ppm：3.7〜4.2（1H，
ｍ），4.3〜5.2（3H，ｍ），5.06（2H，ｓ），
6.92（1H，ｓ），7.34（2H，br ｓ），9.60（1H，
ｄ，Ｊ＝８Hz）
実施例 11
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−シクロペンチルオ
キシイミノアセトアミド〕−４−フルオロメチ
ル−２−オキソ−１−アゼチジンスルホン酸カ
リウム塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−シクロペンチルオキ
シイミノ酢酸を用いて、表題の化合物360mg（収
率：76％）を得た。
［α］20 D−15.6゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1775，1660，1620，
1530，1270，1240，1050，990
NMR（DMSO−d6）δin ppm：1.7（8H，ｍ），
3.7〜4.2（1H，ｍ），4.3〜5.2（4H，ｍ），6.73
（1H，ｓ），7.23（2H，br ｓ），9.24（1H，
ｄ，Ｊ＝８Hz）
実施例 12
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−イソプロポキシイ
ミノアセトアミド〕−４−フルオロメチル−２
−オキソ−１−アゼチジンスルホン酸カリウム
塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−イソプロポキシイミ
ノ酢酸を用いて、表題の化合物300mg（収率：
67.1％）を得た。
［α］20 D−22.7゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1775，1660，1620，
1530，1270，1240，1050，985
NMR（DMSO−d6）δin ppm：1.20（6H，ｄ，
Ｊ＝６Hz），3.7〜4.2（1H，ｍ），4.2〜5.2
（4H，ｍ），6.71（1H，ｓ），7.20（2H，br
ｓ），9.22（1H，ｄ，Ｊ＝８Hz）
実施例 13
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（プロピニルオキシ
イミノ）アセトアミド〕−４−フルオロメチル
−２−オキソ−１−アゼチジンスルホン酸カリ
ウム塩
実施例５の方法に準じ、（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−（２−プロピニルオキ
シイミノ）酢酸を用いて、表題の化合物310mg
（収率：69.9％）を得た。
［α］20 D−28.2゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，2120，1770，1660，
1620，1530，1265，1240，1050，1015，1005
NMR（DMSO−d6）δin ppm：3.48（1H，ｔ，
Ｊ＝２Hz），3.7〜4.2（1H，ｍ），4.3〜5.2
（5H，ｍ），6.80（1H，ｓ），7.23（2H，br
ｓ），9.41（1H，ｄ，Ｊ＝８Hz）
実施例 14
（3S，4R）−（−）−３−〔（Ｚ）−２−（２−アミ
ノ−４−チアゾリル）−２−カルボキシラート
メトキシイミノアセトアミド〕−４−フルオロ
メチル−２−オキソ−１−アゼチジンスルホン
酸ジカリウム塩
（3S，4R）−（−）−３−Cbz−アミノ−４−フ
ルオロメチル−２−オキソ−１−アゼチジンスル
ホン酸TBA塩574mg（1mmol）をDMF20mlに溶
解し、10％パラジウム炭素170mgを加え、室温で
２時間水素化する。触媒を濾別し、濾液に（Ｚ）
−２−（２−アミノ−４−チアゾリル）−２−（ジ
フエニルメトキシカルボニルメトキシイミノ）酢
酸411mg（1mmol）、HOBt 148mg（1.1mmol）お
よびDCC 206mg（1mmol）を加え、この溶液を
室温で18時間攪拌した。反応液を減圧下に蒸発さ
せて、残渣にメチレンクロリドを加えて、不溶物
を濾去した。濾液をシリカゲルフラツシユカラム
クロマトグラフイに付し、アセトン−メチレンク
ロリド（３：７〜６：４）を用いて目的物を含む
フラクシシヨンを濃縮乾固した。残渣にアニソー
ル2.9mlを加え、−15℃に冷却した後、冷TFA1.44
mlを加え、０℃以下で15分間攪拌した。減圧下に
TFAを蒸発させて除き、残渣に酢酸エチルを加
えて沈澱を濾取し、それを水20mlに懸濁し、氷冷
攪拌下に0.4N KOHでPH5.0に調整して溶解し、
凍結乾燥して表題の化合物を430mg（収率：92.3
％）を白色粉末として得た。
［α］20 D−19゜（ｃ＝１，H2O）
IR（KBr）cm-1：3450，1770，1660，1610，
1535，1270，1245，1050
NMR（DMSO−d6）δin ppm：3.8〜4.3（1H，
ｍ），4.33（2H，ｓ），4.4〜5.3（3H，ｍ），
6.85（1H，ｓ），7.20（2H，br ｓ），11.6（1H，
ｄ，Ｊ＝８Hz）
参考例 １
（3S，4R）−（−）−３−Boc−アミノ−４−フ
ルオロメチル−２−オキソアゼチジン
ａ γ−フルオロ−Ｌ−トレオニン１ｇ
（7.29mmol）とTEA1.5ml（10.9mmol）を水４
mlに溶解させた。この溶液にBoc−S1.9ｇ
（8.02mmol）をジオキサン４mlに溶かした溶液
を加えて、室温で約20時間攪拌した。この反応
液に水11mlを加え、酢酸エチル15mlで２回洗浄
後、酢酸エチル11mlを積層させて、6N塩酸で
PH２に調整した。酢酸エチル層を分離し、さら
に酢酸エチル６mlで２回抽出した。酢酸エチル
抽出液を合わせて、食塩を飽和させた５％塩酸
７mlで２回洗浄後、無水硫酸ナトリウムで乾燥
し、減圧で蒸発乾固させると油状のＮ−Boc−
γ−フルオロ−Ｌ−トレオニン1.93ｇが得られ
た。
ｂ Ｏ−ベンジルヒドロキシルアミン塩酸塩2.32
ｇ（14.6mmol）を水64mlに溶解させ、6N苛性
ソーダ（以下、NaOHと略す）でPH4.5に調整
した。この溶液に参考例１−ａで得られた化合
物1.93ｇのテトラヒドロフラン（以下、THF
と略す）16mlの溶液を加える。次に6N塩酸で
PH4.5に保ちながらDCC3ｇ（14.6mmol）の
THF 48ml溶液を攪拌しながら滴下した。PHの
変動がなくなるまで攪拌を続けた後、減圧下に
THFを蒸発させ、酢酸エチル80mlを加えた。
不溶のＮ，N′−ジシクロヘキシル尿素を濾過
して除き、酢酸エチル層を分離し、さらに酢酸
エチル40mlで２回抽出した。酢酸エチル抽出液
を合わせ、無水硫酸ナトリウムで脱水し、減圧
下に濃縮し、析出した結晶を濾取し、ジエチル
エーテルで洗つた。N1−ベンジルオキシ−N2
−Boc−γ−フルオロトレオニンアミド1.95ｇ
（γ−フルオロ−Ｌ−トレオニンからの収率：
78.1％）を得た。Mp122〜123℃。
IR（KBr）cm-1：3350，1665，1530，1370，
1310，1250，1170
NMR（DMSO−d6）δin ppm：1.43（9H，ｓ），
3.9〜4.7（4H，ｍ），4.83（2H，ｓ），5.46
（1H，ｄ，Ｊ＝５Hz），6.45（1H，ｄ，Ｊ＝
7.5Hz），7.43（5H，ｓ），11.28（1H，ｓ）
ｃ 参考例１−ｂで得られた化合物1.46ｇ
（4.26mmol）を無水アセトニトリル42mlに溶解
し、そこにトリフエニルホスフイン1.55ｇ
（5.54mmol）、四塩化炭素0.54ml（5.54mmol）
およびTEA0.54ml（6.4mmol）を加え、窒素雰
囲気下、室温で約18時間攪拌した。反応液を減
圧下に濃縮し、シリカゲルフラツシユカラムク
ロマトグラフイに付し、ｎ−ヘキサン−酢酸エ
チル（４：１）を用いて溶離し、目的物を含む
フラクシヨンを濃縮し、残渣をジイソプロピル
エーテル（以下、IPEと略す）から結晶化させ
ると（3S，4R）−（−）−３−Boc−アミノ−１
−ベンジルオキシ−４−フルオロメチル−２−
オキソアゼチジン390mg（収率：28.3％）が得
られた。Mp86〜87℃。
［α］20 D−44.5゜（ｃ＝１，CH3OH）
元素分析値 C16H21FN2O4
計算値：Ｃ，59.25：Ｈ，6.53：Ｎ，8.64
実測値：Ｃ，59.32：Ｈ，6.75：Ｎ，8.70
IR（KBr）cm-1：3330，1760，1710，1540，
1285，1170，995
NMR（DMSO−d6）δin ppm：1.41（9H，ｓ），
3.9〜4.4（2H，ｍ），4.7（2H，dd，Ｊ＝48＆
３Hz），4.99（2H，ｓ），7.48（5H，ｓ）7.67
（1H，ｄ，Ｊ＝７Hz）
ｄ 参考例１−ｃの化合物の製造法の別法
参考例１−ｂで得られた化合物17.15ｇ
（50.1mmol）とトリフエニルホスフイン21ｇ
（65.1mmol）を無水アセトニトリル430ｇに溶解
し、５℃に保ちながらジエチル アゾジカルボキ
シラート9.47ml（65.1mmol）の無水アセトニト
リル20mlの溶液を20分かけて滴下した。反応液を
15℃で４時間攪拌後、減圧下に濃縮し、シリカゲ
ルフラツシユカラムシロマトグラフイに付し、目
的物を含むむフラクシヨンを濃縮し、得られる残
渣をイソプロピルエーテル（以下、IPEと略す）
から結晶化させて、（3S，4R）−（−）−３−Boc
−アミノ−１−ベンジルオキシ−４−フルオロメ
チル−２−オキソアゼチジン6.78ｇ（収率：41.7
％）を得た。本化合物の物理定数は、参考例１−
ｃの化合物と全く一致した。
ｅ 参考例１−ｃまたは参考例１−ｄで得られた
化合物10ｇ（30.8mmol）をメタノール500mlに
溶解し、その溶液に10％パラジウム炭素１ｇを
加え、常圧で２時間水素化した。触媒を濾別
し、濾液を減圧下で蒸発させて（3S，4R）−
（−）−３−Boc−アミノ−４−フルオロメチル
−１−ヒドロキシ−２−オキソアゼチジンを
得、精製することなく次の反応に用いた。
ｆ 参考例１−ｅで得られた化合物の50％メタノ
ール溶液300mlを10％NaOHでPH７に調整し、
この溶液をPH７に保ちながら10℃で20％三塩化
チタン水溶液を２時間かけて滴下し、さらに２
時間攪拌した。反応液のPHを８に調整し、８％
塩化ナトリウム溶液600mlと酢酸エチル1200ml
を加え、不溶物を濾過して除き、有機層を反応
液から分離した。水層をさらに酢酸エチル600
mlで抽出した。抽出液を合わせて、無水硫酸ナ
トリウムで乾燥後、減圧下で濃縮し、残渣を
IPEより結晶化させ、表題の化合物1.82ｇ（前
工程からの収率：27.1％）を得た。Mp189〜
190℃（dec）。
［α］20 D−100.2゜（ｃ＝１，CH3OH）
元素分析値 C9H15FN2O3
計算値：Ｃ，49.54：Ｈ，6.92：Ｎ，12.84
実測値：Ｃ，48.99：Ｈ，7.00：Ｎ，12.56
IR（KBr）cm-1：3270，1760，1750，1685，
1540，1295，1170，1000
NMR（DMSO−d6）δin ppm：1.39（9H，ｓ），
3.3〜4.0（1H，ｍ），4.2〜4.9（3H，ｍ），7.56
（1H，ｄ，Ｊ＝７Hz），8.2（1H，br ｓ）
参考例 ２
（3S，4R）−（−）−３−Cbz−アミノ−４−フ
ルオロメチル−２−オキソ−１−アゼチジンス
ルホン酸TBA塩
ａ 参考例１−ｆで得られた化合物3.0ｇ
（13.7mmol）を０℃に冷却したTFA15mlに溶
解させ、その溶液を同温度で１時間攪拌した。
反応液を減圧下に蒸発させ、残渣にベンゼンを
加えて蒸発させ、さらにこの操作を２回繰返し
た。残渣を酢酸エチル100mlに溶解させ、この
溶液を０℃に冷却し、TEA5mlを加え、次にベ
ンジルクロロホルマート２ml（13.7mmol）を
攪拌下に滴下した。この溶液を２時間攪拌後、
冷水を加え、酢酸エチル層を分取し、無水硫酸
ナトリウムで脱水し、減圧下に濃縮した。残渣
を酢酸エチル−ｎ−ヘキサン（７：３）を用い
たシリカゲルフラツシユカラムクロマトグラフ
イに付し、目的物を含むフラクシヨンを濃縮し
た。残渣をIPEで結晶化させて、（3S，4R）−
（−）−３−Cbz−アミノ−４−フルオロメチル
−２−オキソアゼチジン1.8ｇ（収率：52％）
を得た。Mp98〜100℃。
IR（KBr）cm-1：3280，1760，1745，1690，
1545，1270，1145，1020，1000
NMR（DMSO−d6）δin ppm：3.7〜4.1（1H，
ｍ），4.2〜4.9（3H，ｍ），5.11（2H，ｓ），
5.96（1H，ｄ，Ｊ＝８Hz），6.6（1H，ｓ），
7.36（5H，ｓ）
ｂ 参考例２−ａで得られた化合物1.51ｇ
（6mmol）のDMF20ml溶液にピリジン−無水
硫酸コンプレツクス1.91ｇ（12mmol）を加え
て室温で５日間攪拌した。反応液をPH5.5に調
整した冷0.5M−リン酸カリウム溶液300mlの中
に注ぎ、メチレンクロリド100mlで３回洗浄し、
硫酸水素テトラ−ｎ−ブチルアンモニウム2.04
ｇ（0.6mmol）を加えた。この水溶液をメチレ
ンクロリド100mlで４回抽出し、抽出液を８％
食塩水で洗い、無水硫酸ナトリウムで脱水し、
濃縮し、析出した結晶を酢酸エチルを加えて濾
取し、表題の化合物2.5ｇ（収率：73％）を得
た。Mp113〜115℃。
［α］20 D−12.1゜（ｃ＝１，C2H5OH）
元素分析値 C28H48N3FO6S
計算値：Ｃ，58.61：Ｈ，8.43：Ｎ，7.32
実測値：Ｃ，58.43：Ｈ，8.79：Ｎ，7.40
IR（KBr）cm-1：1765，1720，1530，1280，
1135，1040
NMR（DMSO−d6）δin ppm：0.95（12H，ｔ，
Ｊ＝6.5Hz），1.10〜1.80（16H，ｍ），3.05〜
3.40（8H，ｍ），3.93（1H，ｍ），4.53（1H，
ｄ，Ｊ＝8.7Hz），4.72（2H，dd，Ｊ＝42＆２
Hz），5.08（2H，ｓ），7.40（5H，ｓ），8.05
（1H，ｄ，Ｊ＝8.7Hz）
参考例 ３
（3S，4R）−（−）−３−Cbz−アミノ−４−フ
ルオロメチル−２−オキソ−１−アゼチジンス
ルホン酸TBA塩
ａ γ−フルオロ−Ｌ−トレオニン13.7ｇ
（0.1mol）とTEA20.9ml（0.15mol）の50％
DMF水溶液150mlを冷却し、５〜10℃に保ちな
がら、攪拌下にベンジルクロロホルマート21.6
ml（0.15mol）を滴下し、同温度で１時間攪拌
した。反応液を氷水350mlに注ぎ、酢酸エチル
200mlで洗浄した。水層を6N塩酸でPH2.5に調
整し、酢酸エチルで抽出し、油状のＮ−Cbz−
γ−フルオロ−Ｌ−トレオニン25.7ｇ（収率：
95％）得た。
ｂ 参考例３−ａで得られた化合物27.1ｇ
（0.1mol）とＮ−ヒドロキシスクシンイミド
16.1ｇ（0.11mol）のTHF200ml溶液に氷冷下
にDCC21.6ｇ（0.105mol）を加え、室温で２時
間攪拌した。析出したＮ，N′−ジシクロヘキ
シル尿素を濾別し、濾液を氷冷した7.5Nアン
モニア32mlとTHF32mlの溶液に攪拌下滴下し、
２時間攪拌した。反応液を減圧下に蒸発させ、
残渣を酢酸エチルに溶かし、５％炭酸水素ナト
リウムの飽和食塩水で洗浄し、減圧下に酢酸エ
チルを蒸発させ、析出した結晶を少量の酢酸エ
チルで洗浄してN2−Cbz−γ−フルオロ−Ｌ−
トレオニンアミド23.2ｇ（収率：90％）を得
た。Mp141〜145℃。
［α］20 D9.4゜（ｃ＝１，C2H5OH）
IR（KBr）cm-1：3420，3310，3220，1690，
1640，1535，1420，1300，1250，1060，
1015，870，695
NMR（DMSO−d6）δin ppm：4.0〜4.30（3H，
ｍ），4.60（1H，ｍ），5.08（2H，ｓ），5.40
（1H，ｄ，Ｊ＝５Hz），6.88（1H，ｄ，Ｊ＝
８Hz），7.20（1H，br ｓ），7.30〜7.50（6H，
ｓ）
ｃ 参考例３−ｂで得られた化合物3.36ｇ
（13mmol）を無水ピリジン13mlに溶かし、５
℃以下で攪拌下にメタンスルホニルクロリド
1.2ml（15.3mmol）を滴下し、同温度で２時間
攪拌した。反応液を120ml氷水に注ぎ、30分間
攪拌後、析出した結晶を濾取し、N2−Cbz−Ｏ
−メシル−γ−フルオロ−Ｌ−トレオニンアミ
ド3.79ｇ（収率：83.7％）を得た。
IR（KBr）cm-1：3430，3320，1670，1620，
1535，1350，1250，1185，1070，1050，970，
930，820，750，695
NMR（DMSO−d6）δin ppm：3.16（3H，ｓ），
4.60（1H，dd，Ｊ＝９＆５Hz），4.70（2H，
dd，Ｊ＝５＆3.7Hz），4.9〜5.2（3H，ｍ），
7.35〜7.50（6H，ｍ），7.55〜7.80（2H，ｍ）
ｄ ２−ピコリン8.84mlのメチレンクロリド45ml
溶液に、氷冷下５℃以下に保ち、攪拌下クロル
スルホン酸2.99mlを滴下した。この溶液を参考
例３−ｃで得られた化合物3.79ｇのメチレンク
ロリド60mlの懸濁液に加え、16時間還流煮沸し
た。反応液を冷却し、0.5Mリン酸ナトリウム
溶液（PH4.5）300mlの中に注ぎ、水層を分取し
て、水層に硫酸水素テトラ−ｎ−ブチルアンモ
ニウム5.08ｇを加えて、その溶液をメチレンク
ロリド74mlで２回抽出した。抽出液を減圧下に
蒸発乾固させ、N2−Cbz−O3−メシル−γ−
フルオロ−Ｌ−N1−スルホナート−トレオニ
ンアミドTBA塩5.65ｇ（収率：74％）を泡状
の固体として得た。
NMR（DMSO−d6）δin ppm：0.94（12H，ｔ，
Ｊ＝6.2Hz），1.1〜1.8（16H，ｍ），3.05〜3.50
（11H，ｍ），4.50（1H，ｍ），4.52（2H，dd，
Ｊ＝47.5＆3.7Hz），5.05〜5.30（3H，ｍ），
7.30〜7.50（6H，ｓ），9.96（1H，br ｓ）
ｅ 煮沸還流している炭酸カリウム2.0ｇ、水7.2
mlおよび１，２−ジクロロエタン58mlの混合液
中に参考例３−ｄで得られた化合物3.75ｇ
（5.6mmol）の１，２−ジクロロエタン９ml溶
液を加え、20分間煮沸還流した。反応液を冷却
し、その中にメチレンクロリドを加えて有機層
を分取し、減圧下に蒸発させると油状の残渣を
得た。残渣を酢酸エチル−アセトン（４：１）
を用いたフラツシユシリカゲルカラムクロマト
グラフイに付し、目的物質を含むフラクシヨン
を集め、減圧下に濃縮し、結晶性残渣を少量の
酢酸エチルで洗浄し、表題の化合物0.51ｇ（収
率：15.9％）を得た。
発明の効果
本発明化合物［］は３−アシルアミノ−２−
オキソ−１−アゼチジンスルホン酸の４位にフル
オロメチル基を有する光学活性の新規化合物であ
り、抗菌性物質として有用である。 DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel azetidinone derivative or a pharmaceutically acceptable salt thereof useful as a therapeutic agent for bacterial infections, a method for producing the same, and uses thereof. Prior Art and Problems to be Solved by the Invention Recently, monocyclic β-lactam antibacterial substances with a 2-azetidinone skeleton having an acylamino group at the 3-position and a sulfo group at the 1-position have been developed by A. Imada et al., Nature.
289, 590 (1981), RBSykes et al., Nature,
291, 489 (1981) independently discovered by two groups. Prior art related to chemically modified derivatives of monocyclic β-lactams include JP-A No. 55-164671, JP-A No. 55-164672, JP-A No. 56-125362,
No. 56-133259, No. 133260, No. 56-
Publication No. 135465, Publication No. 56-138169 and Publication No. 56-
Publication No. 139454 is mentioned. The above publications, except for JP-A-56-125362, only describe compounds in which the 4-position of the 2-azetidinone nucleus is unsubstituted. Example of JP-A-56-125362
103 includes a compound [Azthreonam
(aztreonam)] is listed. However, its antibacterial activity is not sufficient, and its stability against β-lactamase is also not satisfactory. None of the publications suggests a (3S,4R)-(-) trans monocyclic β-lactam derivative having a fluoromethyl group at the 4-position of the 2-azetidinone nucleus, which is a feature of the compound of the present invention. do not have. Means for Solving the Problems The present invention is based on the general formula [Wherein, R is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group,
The present invention relates to a compound represented by a cyano C 1-3 alkyl group, a carboxy C 1-3 alkyl group, a benzyl group or a phenyl group, or a pharmaceutically acceptable non-toxic salt thereof, a method for producing the same, and a use thereof. The present inventors added (3S,
We conducted extensive research on compounds having a 4R)-trans-3-acylamino-4-fluoromethyl group,
The present invention was completed based on the discovery that this compound has strong antibacterial activity and is useful as a pharmaceutical. Next, various terms mentioned in this specification will be explained. C 1-3 alkyl group means an alkyl group having 1 to 3 carbon atoms, such as methyl group, ethyl group,
Examples include propyl group and isopropyl group. The C 2-3 alkenyl group means an alkenyl group having 2 to 3 carbon atoms, and includes, for example, a vinyl group and a 2-propenyl group. C 2-3 alkynyl group means an alkynyl group having 2 to 3 carbon atoms, such as ethynyl group, 2
-propynyl group and the like. The C 3-5 cycloalkyl group means a 3- to 5-membered cyclic alkynyl group, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and the like. The cyano C 1-3 alkyl group means the above-mentioned C 1-3 alkyl group substituted with a cyano group, and includes, for example, a cyanomethyl group. Carboxy C 1-3 alkyl group means the above-mentioned C 1-3 alkyl group substituted with a carboxyl group, such as carboxymethyl group, 1-carboxy-1-
Examples include methyl ethyl. Pharmaceutically acceptable non-toxic salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic amine salts such as ammonium salts; trimethylamine salts, triethylamine salts, Organic amine salts such as N,N'-dibenzylethylenediamine salt, procaine salt; hydrochloride, hydrobromide, sulfate,
Inorganic acid salts such as phosphates and nitrates; acetates, lactates,
Organic acid salts such as propionate, maleate, malate, tartrate, citrate, methanesulfonate, isethionate; amino acid salts such as arginine salt, lysine salt, aspartate, glutamate, etc. can be mentioned. Among the compounds of the general formula [] of the present invention, preferred compounds include R being a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-propenyl group, a 2-propynyl group, a carboxymethyl group, a cyanomethyl group, a 1- A compound having a carboxy-1-methylethyl group, a cyclopentyl group, a benzyl group or a phenyl group, and a compound having a 1-carboxy-1-methylethyl group is particularly suitable. Next, a method for producing the compound of the present invention will be explained. The compound of the present invention has the following formula: (a) General formula Compounds represented by [In the formula, R 1 represents a hydrogen atom or a sulfo group] and the general formula [In the formula, R 2 is a hydrogen atom or a protecting group for an amino group, R 3 is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group, a cyano C 1-3 alkyl group, optionally protected carboxy C 1-3 alkyl group, benzyl group or phenyl group] or a reactive derivative thereof; (b) then R 1 When represents a hydrogen atom, the compound obtained in step (a) is sulfonated, (c) if necessary, the protecting group is removed, and (d) if necessary, the compound thus obtained is can be produced by converting it into its pharmaceutically acceptable non-toxic salt. The reaction between the compound of general formula [] and the compound of general formula [] can be carried out using, for example, methylene chloride, chloroform, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N,
The reaction can be carried out in N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof in the presence or absence of a deoxidizing agent. Examples of deoxidizers include sodium carbonate, potassium carbonate,
Metal salts such as calcium carbonate and magnesium carbonate,
or for example triethylamine, N,N-diisopropylethylamine, N-methylmorpholine,
Examples include organic amines such as N,N-dimethylaniline. In the reaction, equimolar moles of the compound of general formula [] are used per mole of the compound of general formula [], and the reaction temperature and reaction time are not particularly limited, but are usually 0 to 40°C for 0.5 to 5 hours. . When R 1 in the general formula [] is a hydrogen atom, after the reaction between the compound of the general formula [] and the compound of the general formula [] is completed, a sulfonation reaction is carried out using an organic amine-sulfuric anhydride complex. In the sulfonation reaction, 1 to 5 mol of the complex is used per 1 mol of the condensate of the compound of general formula [] and the compound of general formula [], and the reaction temperature and reaction time are as follows:
Although not particularly limited, it is usually 5 to 80 hours at 10 to 30°C. Compounds in which R 1 of the general formula [] is a sulfo group are:
The compound was converted into a tetrabutylammonium salt (hereinafter referred to as
It can also be used in this reaction as TBA salt (abbreviated as TBA salt). The amino group and R 3 in the general formula [] may be protected if necessary, and when a protecting group exists, the compound [] of the present invention can be obtained by removing the protecting group. As the protecting group for the carboxyl group and amino group in the above general formula, protecting groups commonly used in the field of β-lactam synthesis can be appropriately selected and used. Examples of protecting groups for amino groups include trityl group, tert-butoxycarbonyl group, and benzyloxycarbonyl group. Examples of the carboxyl protecting group include benzhydryl group and tert-butyl group. Before specifically explaining the present production method, the method for synthesizing the raw material compound of the present invention will be explained. (3S, 4R) is an important intermediate of the compound of the present invention
-(-)-3-tert-butoxycarbonylamino-
The synthesis of 4-fluoromethyl-2-azetidinone (6) is based on γ-fluoro-L-threonine (1) {[α] 20 D −
18゜(c=5, H 2 O)} as a starting material, MJ
Miller et al., J.Am.Chem.Soc., 102 , 7026
(1980). γ-Fluoro-L-threonine (1) in dioxane with 2-tert
Using -butoxycarbonylthio-4,6-dimethylpyrimidine (hereinafter abbreviated as Bos-S),
tert-butoxycarbonyl (hereinafter abbreviated as Boc)
N-Boc-γ-fluorothreonine (2)
get. Next, compound (2) is directly reacted with O-benzylhydroxylamine in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) to form N1 -benzyloxy- N2. -Boc-γ-fluorothreonine amide (3)
can be obtained. Also, compound (3) is compound (2)
and N-hydroxysuccinimide (hereinafter referred to as HOSu
It can also be obtained by reacting 1-hydroxybenzotriazole (hereinafter abbreviated as HOBt) with DCC to obtain an active ester of compound (2), and then reacting it with O-benzylhydroxylamine. Next, compound (3) was added to triphenylphosphine, carbon tetrachloride and triethylamine (hereinafter referred to as TEA).
) or in the presence of diethyl azodicarboxylate (hereinafter abbreviated as DEAD) and triphenylphosphine,
(3S,4R)-(-)-3-Boc-amino-1-benzyloxy-4-fluoromethyl-2-oxoazetidine (4) {[α] 20 D -44.5° (c=1,
CH 3 OH)}. Catalytic reduction of compound (4) in the presence of palladium on carbon yields 1-hydroxyazetidinone (5)
is obtained. When compound (5) is reduced with titanium trichloride, (3S,4R)-(-)-3-Boc-amino-4-
Fluoromethyl-2-oxoazetidine (6) is obtained {[α] 20 D −110.2° (c=1, CH 3 OH)}. Next, the method for producing the compound of the present invention will be specifically explained. The compound of the present invention [ ] can be synthesized using compound (6) as follows. When compound (6) is treated with trifluoroacetic acid (hereinafter abbreviated as TFA), (3S,4R)-3-amino-
Gives 4-fluoromethyl-2-oxoazetidine (7). On the other hand, (Z)-2-(2-tritylamino-4-thiazolyl)-2-substituted oxyiminoacetic acid
(8) is converted to acid chloride by the action of phosphorus pentachloride, and the acid chloride and compound (7) are reacted in the presence of TEA to form (3S,4R)-3-{(Z)- 2-(2
-tritylamino-4-thiazolyl)-2-substituted oxyiminoacetamide}-4-fluoromethyl-2-oxoazetidine (9) is obtained. Compound
(9) with N,N-dimethylformamide (hereinafter referred to as
(3S,4R)-3-[(Z)-
2-(2-tritylamino-4-thiazolyl)-2
-Substituted oxyiminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid (10) is obtained. When compound (10) is treated with water-containing formic acid, TFA, or a mixture thereof, not only the trityl group of the amino protecting group but also the tert-butyl group or benzhydryl group of the carboxyl protecting group are removed, resulting in (3S, 4R) -(-)-3-{(Z)-2-(2
-amino-4-thiazolyl)-2-substituted oxyiminoacetamide}-4-fluoromethyl-2-
An inner salt of oxo-1-azetidinesulfonic acid [ ] can be obtained. This intramolecular salt is neutralized with a suitable caustic alkali or alkali carbonate, etc. and freeze-dried to obtain the potassium salt or sodium salt of the target compound [ ]. The target compound [] can also be synthesized by starting from compound (6), sulfonating the 1-position of the 2-azetidinone nucleus, and then acylating it. Boc of the amino protecting group of compound (6) was removed with TFA to convert it to compound (7), and the amino group was converted to benzyloxycarbonyl (hereinafter abbreviated as Cbz) with benzyl chloroformate to form (3S,4R)- 3-Cbz-amino-4-fluoromethyl-2-oxoazetidine (11) is obtained. Compound (11) is sulfonated with a pyridine-sulfuric anhydride complex or a 2-picoline-sulfuric anhydride complex to form (3S,4R)-(-)-
It can be 3-Cbz-amino-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid. Furthermore, the sulfonic acid can be isolated as TBA salt (12) {[α] 20 D −12.1° (c=1,
C 2 H 5 OH)}. Furthermore, compound (12) was catalytically reduced in the presence of palladium on carbon to obtain (3S,4R)-3-amino-
It is referred to as 4-fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt (13). Compound (13)
and (Z)-2-(2-amino-4-thiazolyl)-
By reacting an active ester of 2-substituted oximinoacetic acid (8), for example compound (8) with the active ester obtained from HOBt in the presence of DCC, (3S,4R)-3
-{(Z)-2-(2-amino-4-thiazolyl)2
-substituted oxyiminoacetamide}-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt (14) is obtained. If substituent R 3 does not contain a protecting group to be removed,
Compound (14) gives the TBA salt of the target compound [ ]. Further, this TBA salt is dissolved in water or water-containing methanol, treated with a potassium salt type of strongly acidic ion exchange resin, such as Diaion SK-102 (K + ), and freeze-dried to obtain the potassium salt []. In addition, when the substituent R 3 contains a carboxyl group protecting group such as a tert-butyl group or a benzhydryl group, it is treated with TFA-anisole and TFA
After distilling off, the inner salt of the target compound [] is obtained by treatment with an organic solvent such as ethyl acetate. Inner salts can be converted to sodium or potassium salts by treatment with a suitable caustic alkali or alkali carbonate, followed by lyophilization. Compound (13) was prepared by DMFloyd et al., J.Org.
Chem., 47 , 176 (1982) from L-threonine to (3S,4R)-3-Cbz-amino-4-methyl-2
It can also be synthesized according to the method for producing -oxo-1-azetidinesulfonic acid TBA salt. γ-Fluoro-L-
Threonine (1) is converted to N-Cbz-γ-fluoro-L-threonine (15) by reacting with benzyl chloroformate, then reacted with HOSu and DCC to form an active ester, and further reacted with ammonia. This gives N 2 -Cbz-γ-fluoro-L-threonine amide (16). Compound (16) is reacted with methanesulfonyl chloride in pyridine,
N 2 -Cbz-O-mesyl-γ-fluoro-L-threonine amide (17) and then sulfonation of the amide using a pyridine-sulfuric anhydride complex or a 2-picoline-sulfuric anhydride complex. and N2 -Cbz-O-mesyl- N1 -sulfonate-γ-fluoro-L-threoninamide
induced by TBA salt (18). Compound (18) is water-
Compound (12) can be obtained by ring closure in 1,2-dichloroethane in the presence of potassium carbonate. The compounds of the present invention [ ] are useful for the treatment and prevention of bacterial infections. The antibacterial activity (MIC) of the following representative examples is shown. Compound A: (3S,4R)-(-)-3-[(Z)-2-
(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-4-fluoromethyl-2-
Oxo-1-azetidinesulfonic acid potassium salt Compound B: (3S,4R)-(-)-3-[(Z)-2-
(2-amino-4-thiazolyl)-2-ethoxyiminoacetamide]-4-fluoromethyl-2-
Oxo-1-azetidinesulfonic acid potassium salt Compound C: (3S,4R)-(-)-3-[(Z)-2-
(2-Amino-4-thiazolyl)-2-carboxylate methoxyiminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid dipotassium salt Compound D: (3S,4R)-(-)-3 - [(Z)-2-
(2-amino-4-thiazolyl)-2-(1-carboxylate-1-methylethoxyimino)acetamide]-4-fluoromethyl-2-oxo-
1-azetidinesulfonic acid dipotassium salt Compound E: (3S,4R)-(-)-3-[(Z)-2-
(2-Amino-4-thiazolyl)-2-benzyloxyiminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid potassium salt [Table] As is clear from the above table, the compounds of the present invention exhibits excellent antibacterial activity, particularly against Gram-negative bacteria. In order to use the compound of the present invention [ ] for the prevention or treatment of bacterial infections, the compound of the present invention or its salt is used alone or in combination with a pharmaceutically acceptable carrier. The drug is administered orally or parenterally in a dosage form suitable for administration. Preparations of the compound of the present invention include, for example, injections, tablets, capsules, granules, fine granules, powders, solutions, suspensions, emulsions, syrups, elixirs,
Examples include lemonade and suppositories. Furthermore, if necessary, the preparation may include a dissolving solution, an adjuvant,
Commonly used additives such as stabilizers, binders, wetting agents, lubricants, and disintegrants may be added. For example, injections usually contain distilled water for injection, physiological saline, and glucose injection. It may be prepared immediately before use with a solution of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or the like, and may contain a stabilizer such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate.
Tablets, granules, granules and capsules typically contain gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, lactose, sucrose,
Corn starch, calcium phosphate, glycine, magnesium stearate, talc, polyethylene glycol, silica, sodium lauryl sulfate, etc. are used. Liquid formulations typically contain sorbitol syrup, methylcellulose, glucose, sucrose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, edible oil, lecithin, sorbitan monooleate, gum arabic,
Customary additives such as tonsil oil, coconut oil, oil esters, propylene glycol, ethyl alcohol, methyl p-hydroxybenzoate, propionic acid, sorbic acid, etc. are used. Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides. The dosage of the compound of the present invention and its pharmaceutically acceptable salts varies depending on the patient's age, symptoms, and administration target, but is generally 1 to 1 kg per 1 kg of patient body weight.
100 mg, preferably 5 to 30 mg, is administered orally or parenterally in 2 to 4 divided doses per day. The compounds of the present invention can be used to treat or prevent bacterial infections, such as mammalian respiratory tract infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, It can be used to treat or prevent surgical infections and the like. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-4-fluoromethyl-2-oxo-1- Azetidinesulfonic acid a (Z)-2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid 610mg
(1.37 mmol) was added to a solution of 315 mg (1.51 mmol) of phosphorus pentachloride in 15 ml of methylene chloride while cooling at -10°C. The reaction solution was stirred at -5°C for 30 minutes, cooled to -10°C, and triethylamine (hereinafter referred to as
0.42 ml (3.02 mmol) (abbreviated as TEA) and 5 ml of water were added, and the mixture was stirred at 0°C for 3 minutes. The organic layer was separated and dried over anhydrous potassium carbonate-sodium sulfate to prepare an acid chloride solution. On the other hand, (3S,
4R)-(-)-3-Boc-amino-4-fluoromethyl-2-oxoazetidine 300mg
(1.37 mmol) of cold trifluoroacetic acid (hereinafter referred to as
After stirring 1.5 ml solution under ice-cooling for 1 hour, evaporate under reduced pressure, and add 5 ml of ethyl acetate.
ml was added and evaporated. Add 20ml of ethyl acetate to the residue.
Add and cool to -10℃, add 0.96ml of TEA
(6.88 mmol) was added, and the prepared acid chloride solution was added dropwise over 10 minutes.
The mixture was stirred for 30 minutes and then for another 30 minutes without the cooling water bath. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was subjected to silica gel flash column chromatography and eluted with chloroform-methanol (97:3) to obtain the desired The fraction containing the compound was concentrated under reduced pressure, ether was added, and the precipitate was collected by filtration to give 600 mg (yield: 80.3%) of (3S,4R)-(-)-3-[(Z)-2-(2 -tritylamino-4-thiazolyl)-2-methoxyiminoacetamide]-4-fluoromethyl-
2-oxoazetidine was obtained. b 600 mg of the compound obtained in Example 1-a
525 mg of pyridine-sulfuric anhydride complex in 10 ml of anhydrous N,N-dimethylformamide (hereinafter abbreviated as DMF) containing (1.1 mmol)
(3.3 mmol) and stirred at room temperature for 3 days,
DMF was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water, and the organic layer was separated. After drying the organic layer with anhydrous sodium sulfate, chloroform-
It was subjected to silica gel flash column chromatography using methanol (97:3), and the fraction containing the target product was concentrated under reduced pressure (3S,
4R)-(-)-3-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid Obtained. c The compound obtained in Example 1-b was dissolved in 10 ml of formic acid and left at 5°C for 2 days. The solvent of the reaction solution was distilled off under reduced pressure, and acetone was added to the residue to form a powder, which was collected by filtration. The obtained powder was subjected to silica gel flash column chromatography using chloroform-methanol (6:4) to obtain 65 mg of the title compound (combined yield of two steps of sulfonation and detritylation: 15.4%). Ta. IR (KBr) cm -1 : 3450, 1770, 1665, 1625,
1530, 1270, 1240, 1050 Example 2 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(1-carboxy-
1-methylethoxyimino)acetamide]-
784 mg (1.37 mmol) of phosphorus pentachloride
It was added to a solution of 315 mg (1.51 mmol) in 15 ml of methylene chloride at -10°C. After stirring the reaction solution at -5°C for 30 minutes, it was cooled to -10°C and mixed with 5 ml of water.
Add 0.42ml (3.02mmol) of TEA and
Stir for a minute. The organic layer was dried over anhydrous potassium carbonate-sodium sulfate to prepare an acid chloride solution. On the other hand, (3S,4R)-(-)-3-Boc-amino-4-fluoromethyl-2-oxoazetidine
A 1.5 ml solution of 300 mg (1.37 mmol) of cold TFA was stirred for 1 hour under ice cooling. Concentrate the reaction solution under reduced pressure,
5 ml of ethyl acetate was added to the residue and further concentrated.
Add 20 ml of ethyl acetate to the residue and incubate at -10℃.
0.96 ml (6.88 mmol) of TEA was added, and the above acid chloride solution was added dropwise over 10 minutes. −10～
After stirring at 0°C for 30 minutes and further at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. Ethyl acetate and water were added to the residue for extraction, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel flash column chromatography using chloroform-methanol (97:3) to obtain (3S,4R)-(-)-3-[(Z)-
2-(2-tritylamino-4-thiazolyl)-
2-(1-Boc-1-methylethoxyimino)
340 mg (yield: 36.8%) of [acetamido]-4-fluoromethyl-2-oxoazetidine was obtained. IR (KBr) cm -1 : 3400, 1770, 1740, 1670,
1590, 1570, 1200, 1190, 1040, 995 b 340 mg of the compound obtained in Example 2-a
(0.51 mmol) in 6 ml of anhydrous DMF, 240 mg (1.5 mmol) of pyridine-anhydrous sulfuric acid complex
was added and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate-water, and the organic layer was separated, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was diluted with chloroform-methanol (95%). 5) as a solvent was subjected to silica gel flash column chromatography to obtain (3S,4R)-(-)-3-[(Z)-2-(2-
Tritylamino-4-thiazolyl)-2-(1-
Boc-1-methylethoxyimino)acetamide]-4-fluoromethyl-2-oxo-1-
Azetidine sulfonic acid 180 mg (yield: 47.3%)
I got it. IR (KBr) cm -1 : 3400, 1755, 1725, 1670,
1590, 1570, 1280, 1245, 1200, 1140, 1045 c 180 mg of the compound obtained in Example 2-b
A solution of (0.24 mmol) in 5 ml of formic acid was left at 5°C for 4 days, concentrated under reduced pressure, acetone was added to the residue, and the powder was collected by filtration. This powder was subjected to silica gel flash column chromatography using chloroform-methanol (7:3), and the fraction containing the target compound was concentrated under reduced pressure, powdered with acetone, and collected by filtration. 60 mg (yield: 55.3%) was obtained. IR (KBr) cm -1 : 1755, 1665, 1530, 1535,
1400, 1270, 1240, 1200, 1165, 1050 Example 3 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]- 4-Fluoromethyl-2-oxo-1-azetidinesulfonic acid potassium salt a (3S,4R)-(-)-3-Cbz-amino-4-
Fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt 700 mg (1.2 mmol)
350 mg of 10% palladium on carbon was added to 15 ml of DMF solution and hydrogenated for 1 hour. The catalyst was filtered through Celite and washed with 2 ml of DMF. Add 178 mg of 1-hydroxybenzotriazole (hereinafter abbreviated as HOBt) to the solution of the filtrate and washing solution.
(1.3 mmol) and (Z)-2-(2-amino-4-
Thiazolyl)-2-methoxyiminoacetic acid 241mg
(1.2 mmol) was added thereto, and 260 mg (1.26 mmol) of N,N'-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. The precipitate was filtered off, the filtrate was distilled off under reduced pressure, and the residue was mixed with ethyl acetate-acetone (4:1~
(3S,4R)-(-)-
3-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyiminoacetamide]-4
-Fluoromethyl-1-azetidinesulfonic acid
524 mg (yield: 70%) of TBA salt was obtained. IR (KBr) cm -1 : 1770, 1670, 1620, 1535,
1270, 1040 NMR (DMSO-d 6 ) δin ppm: 0.95 (12H, t,
J=7Hz), 1.10~1.80 (16H, m), 3.00~
3.50 (8H, m), 3.70-4.10 (4H, m), 4.76
(2H, m), 4.82 (1H, dd, J = 7.5 & 2.0Hz),
6.76 (1H, s), 7.21 (2H, br s), 9.36 (1H,
d, J=7.5Hz) b 479 mg of the compound obtained in Example 3-a
(0.77 mmol) in water was treated with activated carbon, passed through a 5 ml column of Diaion SK-102 ( K %)
Obtained. [α] 20 D −23.5° (c=1, H 2 O) IR (KBr) cm −1 : 1775, 1665, 1620, 1535,
1380, 1270, 1245, 1050, 960, 815, 720,
650 NMR (D 2 O) δin ppm: 4.03 (3H, s), 4.15
(1H, m), 4.92 (2H, m) 5.01 (1H, d, J
=2.5Hz), 6.97 (1H, s) Example 4 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(1-carboxylate -1-methylethoxyimino)acetamide]-4-fluoromethyl-2-oxo-1-
Azetidinesulfonic acid dipotassium salt a (3S,4R)-(-)-3-Cbz-amino-4-
2.14 g (3.73 mmol) of fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt
Hydrogenation of 75 ml of DMF solution with 640 mg of 10% palladium on carbon was carried out for 2 hours. After filtering out the catalyst,
2-(2-amino-4-thiazolyl)-2 in the filtrate
-(1-diphenylmethoxycarbonyl-1-
Methyl ethoxyimino)acetic acid 1.64g
(3.73mmol), HOBt0.55g (4.07mmol) and
0.77 g (3.73 mmol) of DCC was added. 20 at room temperature
After stirring for an hour, the reaction solution was concentrated under reduced pressure.
DMF was removed, methylene chloride was added to the residue, insoluble matters were removed by filtration, and the mixture was subjected to silica gel flash column chromatography using acetone-methylene chloride (3:7 → 6:4).
The fraction containing the target product is concentrated under reduced pressure,
A solid was obtained. Add 9.4ml of anisole to this and -
After cooling to 15℃, add 47ml of TFA and incubate at 0℃.
Stir for 15 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the insoluble matter was filtered. The insoluble matter was crystallized from methanol-ethyl acetate,
(3S,4R)-(-)-3-[2-(2-amino-4
1.20 g (yield: 70%) of -thiazolyl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid was obtained. b 720 mg of the compound obtained in Example 4-a was added to 35 mg of water.
ml, suspended in 0.4N caustic potash (hereinafter referred to as
(abbreviated as KOH) to adjust the pH to 5.5 and dissolve it. After freeze-drying this solution, acetonitrile is added to the residue, and the solvent is distilled off under reduced pressure. (This operation was repeated three times.) The residue was triturated with ether and collected by filtration to obtain 840 mg of the title compound. [α] 20 D −16.4° (c=1, H 2 O) IR (KBr) cm -1 : 3400, 1780, 1670, 1590,
1540, 1400, 1370, 1275, 1245, 1250,
1160, 1050 NMR (DMSO-d 6 ) δin ppm: 1.40 (3H, s),
1.44 (3H, s), 3.8~4.3 (1H, m), 4.3~5.2
(3H, m), 6.80 (1H, s), 7.23 (2H, br
s) Example 5 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-phenoximinoacetamide]-4-fluoromethyl-2- Oxo-1-azetidinesulfonic acid potassium salt (3S,4R)-(-)-3-Cbz-amino-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt 574mg (1mmol) in 20ml DMF 170 mg of 10% palladium on carbon was added thereto, and hydrogenation was carried out at room temperature for 2 hours. After filtering off the catalyst, (Z)-2-(2-amino-4-thiazolyl)-2-
Phenoxyiminoacetic acid 263mg (1mmol), HOBt
148 mg (1.1 mmol) and 206 mg (1 mmol) of DCC were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated under reduced pressure, methylene chloride was added to the residue, insoluble materials were filtered off, and the filtrate was subjected to silica gel flash column chromatography using acetone-methylene chloride (3:7 to 6:4). Then, the fraction containing the target product was concentrated to dryness under reduced pressure, the residue was dissolved in water, the solution was passed through a Diaion SK-102 (K + ) column, and the fraction containing the target product was freeze-dried. 340 mg (yield: 70.6%) of the compound was obtained as a white powder. [α] 20 D −16.9° (c=1, H 2 O) IR (KBr) cm -1 : 3470, 3370, 1780, 1670,
1620, 1595, 1540, 1490, 1280, 1250,
1200, 1055 NMR (DMSO-d 6 ) δin ppm: 3.8-4.2 (1H,
m), 4.4-5.2 (3H, m), 7.0-7.5 (8H, m),
9.63 (1H, d, J = 8Hz) Example 6 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamide]-4 -Fluoromethyl-2-oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, using (Z)-2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid, the title 200mg of compound (yield: 46.1%)
I got it. [α] 20 D −26° (c=1, H 2 O) IR (KBr) cm −1 : 3450, 1775, 1660, 1620,
1535, 1270, 1240, 1050 NMR (DMSO-d 6 ) δin ppm: 1.21 (3H, t,
J=7Hz), 3.8-4.2 (1H, m), 4.21 (2H,
q, J=7Hz), 4.3-5.2 (3H, m), 6.74
(1H, s), 7.20 (2H, br s), 9.30 (1H,
d, J=8Hz) Example 7 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetamide]-4-fluoromethyl -2
-Oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, 420 mg of the title compound ( yield:
84.8%). [α] 20 D −16° (c=1, H 2 O) IR (KBr) cm −1 : 3450, 1775, 1670, 1620,
1535, 1270, 1245, 1050 NMR (DMSO- d6 ) δin ppm: 3.8-4.2 (1H,
m), 4.3-5.1 (3H, m), 5.18 (2H, s),
6.79 (1H, s), 7.23 (2H, br s), 7.39 (5H,
s), 9.45 (1H, d, J = 8Hz) Example 8 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-n-propoxy iminoacetamide]-4-fluoromethyl-2
-oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, 350 mg of the title compound was prepared using (Z)-2-(2-amino-4-thiazolyl)-2-n-propoxyiminoacetic acid. (yield:
78.2%). [α] 20 D −23° (c=1, H 2 O) IR (KBr) cm −1 : 3450, 1775, 1665, 1620,
1530, 1270, 1245, 1050 NMR (DMSO-d 6 ) δin ppm: 0.89 (3H, t,
J=7Hz), 1.62 (2H, m), 3.7~4.2 (1H,
m), 4.02 (2H, t, J=7Hz), 4.3~5.3
(3H, m), 6.73 (1H, s), 7.2 (2H, br
s), 9.31 (1H, d, J = 8Hz) Example 9 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(2- propenyloxyimino)acetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, (Z)-2-(2-amino-4-thiazolyl)-2- 290 mg of the title compound using (2-propenyloxyimino)acetic acid.
(yield: 65.1%). [α] 20 D −25.6° (c=1, H 2 O) IR (KBr) cm −1 : 3450, 1770, 1660, 1620,
1270, 1240, 1050, 1005 NMR (DMSO- d6 ) δin ppm: 3.7-4.2 (1H,
m), 4.3-5.5 (7H, m), 6.76 (1H, s),
7.22 (2H, br s), 9.36 (1H, d, J = 8Hz) Example 10 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)- 2-cyanomethoxyiminoacetamide]-4-fluoromethyl-2
-Oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, 310 mg of the title compound ( yield:
69.7%). [α] 20 D −25.6° (c=1, H 2 O) IR (KBr) cm -1 : 3450, 1770, 1660, 1620,
1530, 1270, 1240, 1050, 1020 NMR (DMSO-d 6 ) δin ppm: 3.7-4.2 (1H,
m), 4.3-5.2 (3H, m), 5.06 (2H, s),
6.92 (1H, s), 7.34 (2H, br s), 9.60 (1H,
d, J=8Hz) Example 11 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-cyclopentyloxyiminoacetamide]-4-fluoromethyl -2-Oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, the title compound was prepared using (Z)-2-(2-amino-4-thiazolyl)-2-cyclopentyloxyiminoacetic acid. 360 mg (yield: 76%) was obtained. [α] 20 D −15.6° (c=1, H 2 O) IR (KBr) cm -1 : 3450, 1775, 1660, 1620,
1530, 1270, 1240, 1050, 990 NMR (DMSO-d 6 ) δin ppm: 1.7 (8H, m),
3.7~4.2 (1H, m), 4.3~5.2 (4H, m), 6.73
(1H, s), 7.23 (2H, br s), 9.24 (1H,
d, J=8Hz) Example 12 (3S,4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamide]-4-fluoromethyl -2
-oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, 300 mg of the title compound ( yield:
67.1%). [α] 20 D −22.7° (c=1, H 2 O) IR (KBr) cm -1 : 3450, 1775, 1660, 1620,
1530, 1270, 1240, 1050, 985 NMR (DMSO-d 6 ) δin ppm: 1.20 (6H, d,
J=6Hz), 3.7~4.2 (1H, m), 4.2~5.2
(4H, m), 6.71 (1H, s), 7.20 (2H, br
s), 9.22 (1H, d, J = 8Hz) Example 13 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-(propynyloxy imino)acetamido]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid potassium salt According to the method of Example 5, (Z)-2-(2-amino-4-thiazolyl)-2-(2 -310 mg of the title compound using propynyloxyimino)acetic acid
(yield: 69.9%). [α] 20 D −28.2° (c=1, H 2 O) IR (KBr) cm -1 : 3450, 2120, 1770, 1660,
1620, 1530, 1265, 1240, 1050, 1015, 1005 NMR (DMSO-d 6 ) δin ppm: 3.48 (1H, t,
J=2Hz), 3.7~4.2 (1H, m), 4.3~5.2
(5H, m), 6.80 (1H, s), 7.23 (2H, br
s), 9.41 (1H, d, J = 8Hz) Example 14 (3S, 4R)-(-)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-carboxylatemethoxy iminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid dipotassium salt (3S,4R)-(-)-3-Cbz-amino-4-fluoromethyl-2-oxo-1-azetidine Dissolve 574 mg (1 mmol) of sulfonic acid TBA salt in 20 ml of DMF, add 170 mg of 10% palladium on carbon, and hydrogenate at room temperature for 2 hours. Filter the catalyst and add to the filtrate (Z)
411 mg (1 mmol) of -2-(2-amino-4-thiazolyl)-2-(diphenylmethoxycarbonylmethoxyimino)acetic acid, 148 mg (1.1 mmol) of HOBt and 206 mg (1 mmol) of DCC were added, and the solution was stirred at room temperature for 18 Stir for hours. The reaction solution was evaporated under reduced pressure, methylene chloride was added to the residue, and insoluble materials were filtered off. The filtrate was subjected to silica gel flash column chromatography, and the fraction containing the target product was concentrated to dryness using acetone-methylene chloride (3:7 to 6:4). Add 2.9 ml of anisole to the residue, cool it to -15°C, and add 1.44 ml of cold TFA.
ml and stirred for 15 minutes at below 0°C. under reduced pressure
TFA was removed by evaporation, ethyl acetate was added to the residue, the precipitate was collected by filtration, suspended in 20 ml of water, and dissolved by adjusting the pH to 5.0 with 0.4N KOH while stirring on ice.
Freeze-dry to obtain 430 mg of the title compound (yield: 92.3
%) was obtained as a white powder. [α] 20 D −19° (c=1, H 2 O) IR (KBr) cm −1 : 3450, 1770, 1660, 1610,
1535, 1270, 1245, 1050 NMR (DMSO-d 6 ) δin ppm: 3.8-4.3 (1H,
m), 4.33 (2H, s), 4.4~5.3 (3H, m),
6.85 (1H, s), 7.20 (2H, br s), 11.6 (1H,
d, J=8Hz) Reference example 1 (3S,4R)-(-)-3-Boc-amino-4-fluoromethyl-2-oxoazetidine a γ-fluoro-L-threonine 1 g
(7.29 mmol) and TEA 1.5 ml (10.9 mmol) in 4 ml of water
ml. 1.9g of Boc-S in this solution
A solution of (8.02 mmol) dissolved in 4 ml of dioxane was added, and the mixture was stirred at room temperature for about 20 hours. Add 11 ml of water to this reaction solution, wash twice with 15 ml of ethyl acetate, layer with 11 ml of ethyl acetate, and add 6N hydrochloric acid.
Adjusted to PH2. The ethyl acetate layer was separated and extracted twice with 6 ml of ethyl acetate. The ethyl acetate extracts were combined, washed twice with 7 ml of 5% hydrochloric acid saturated with common salt, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to form an oily N-Boc-
1.93 g of γ-fluoro-L-threonine was obtained. b O-benzylhydroxylamine hydrochloride 2.32
g (14.6 mmol) was dissolved in 64 ml of water, and the pH was adjusted to 4.5 with 6N caustic soda (hereinafter abbreviated as NaOH). 1.93 g of the compound obtained in Reference Example 1-a was added to this solution in tetrahydrofuran (hereinafter referred to as THF).
) Add 16 ml of solution. Then with 6N hydrochloric acid
DCC3g (14.6mmol) while maintaining pH4.5
A 48 ml THF solution was added dropwise while stirring. Continue stirring until there is no change in pH, then remove under reduced pressure.
The THF was evaporated and 80 ml of ethyl acetate was added.
Insoluble N,N'-dicyclohexylurea was removed by filtration, and the ethyl acetate layer was separated and extracted twice with 40 ml of ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with diethyl ether. N 1 -benzyloxy-N 2
-Boc-γ-fluorothreonine amide 1.95g
(Yield from γ-fluoro-L-threonine:
78.1%). Mp122-123℃. IR (KBr) cm -1 : 3350, 1665, 1530, 1370,
1310, 1250, 1170 NMR (DMSO-d 6 ) δin ppm: 1.43 (9H, s),
3.9-4.7 (4H, m), 4.83 (2H, s), 5.46
(1H, d, J=5Hz), 6.45 (1H, d, J=
7.5Hz), 7.43 (5H, s), 11.28 (1H, s) c 1.46g of the compound obtained in Reference Example 1-b
(4.26 mmol) was dissolved in 42 ml of anhydrous acetonitrile, and 1.55 g of triphenylphosphine was added thereto.
(5.54mmol), carbon tetrachloride 0.54ml (5.54mmol)
and 0.54 ml (6.4 mmol) of TEA were added, and the mixture was stirred at room temperature for about 18 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and subjected to silica gel flash column chromatography, eluted with n-hexane-ethyl acetate (4:1), the fraction containing the target product was concentrated, and the residue was purified with diisopropyl ether. (hereinafter abbreviated as IPE), (3S,4R)-(-)-3-Boc-amino-1
-benzyloxy-4-fluoromethyl-2-
390 mg (yield: 28.3%) of oxoazetidine was obtained. Mp86-87℃. [α] 20 D −44.5° (c=1, CH 3 OH) Elemental analysis value C 16 H 21 FN 2 O 4 Calculated value: C, 59.25: H, 6.53: N, 8.64 Actual value: C, 59.32: H , 6.75: N, 8.70 IR (KBr) cm -1 : 3330, 1760, 1710, 1540,
1285, 1170, 995 NMR (DMSO-d 6 ) δin ppm: 1.41 (9H, s),
3.9~4.4 (2H, m), 4.7 (2H, dd, J=48&
3Hz), 4.99 (2H, s), 7.48 (5H, s) 7.67
(1H, d, J=7Hz) d Alternative method for producing the compound of Reference Example 1-c 17.15 g of the compound obtained in Reference Example 1-b
(50.1 mmol) and triphenylphosphine 21 g
(65.1 mmol) was dissolved in 430 g of anhydrous acetonitrile, and a solution of 9.47 ml (65.1 mmol) of diethyl azodicarboxylate in 20 ml of anhydrous acetonitrile was added dropwise over 20 minutes while keeping the temperature at 5°C. reaction solution
After stirring at 15°C for 4 hours, it was concentrated under reduced pressure, subjected to silica gel flash column chromatography, and the fraction containing the target product was concentrated, and the resulting residue was diluted with isopropyl ether (hereinafter abbreviated as IPE).
(3S,4R)-(-)-3-Boc
-amino-1-benzyloxy-4-fluoromethyl-2-oxoazetidine 6.78 g (yield: 41.7
%) was obtained. The physical constants of this compound are as follows: Reference Example 1-
It completely matched with the compound of c. e 10 g (30.8 mmol) of the compound obtained in Reference Example 1-c or Reference Example 1-d was dissolved in 500 ml of methanol, 1 g of 10% palladium on carbon was added to the solution, and hydrogenated at normal pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to (3S,4R)-
(-)-3-Boc-amino-4-fluoromethyl-1-hydroxy-2-oxoazetidine was obtained and used in the next reaction without purification. f 300 ml of a 50% methanol solution of the compound obtained in Reference Example 1-e was adjusted to pH 7 with 10% NaOH,
A 20% titanium trichloride aqueous solution was added dropwise to this solution over 2 hours at 10°C while keeping the pH at 7, and then
Stir for hours. Adjust the pH of the reaction solution to 8, and add 8%
600ml of sodium chloride solution and 1200ml of ethyl acetate
was added, insoluble materials were removed by filtration, and the organic layer was separated from the reaction solution. Add 600 ml of ethyl acetate to the aqueous layer.
Extracted in ml. The extracts were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was
Crystallization from IPE gave 1.82 g of the title compound (yield from the previous step: 27.1%). Mp189～
190℃ (dec). [α] 20 D −100.2° (c=1, CH 3 OH) Elemental analysis value C 9 H 15 FN 2 O 3 Calculated value: C, 49.54: H, 6.92: N, 12.84 Actual value: C, 48.99: H , 7.00: N, 12.56 IR (KBr) cm -1 : 3270, 1760, 1750, 1685,
1540, 1295, 1170, 1000 NMR (DMSO-d 6 ) δin ppm: 1.39 (9H, s),
3.3~4.0 (1H, m), 4.2~4.9 (3H, m), 7.56
(1H, d, J = 7Hz), 8.2 (1H, br s) Reference example 2 (3S, 4R)-(-)-3-Cbz-amino-4-fluoromethyl-2-oxo-1-azetidine sulfone Acid TBA salt a 3.0 g of the compound obtained in Reference Example 1-f
(13.7 mmol) was dissolved in 15 ml of TFA cooled to 0°C, and the solution was stirred at the same temperature for 1 hour.
The reaction solution was evaporated under reduced pressure, benzene was added to the residue and evaporated, and this operation was repeated twice. The residue was dissolved in 100 ml of ethyl acetate, the solution was cooled to 0° C., 5 ml of TEA was added, and then 2 ml (13.7 mmol) of benzyl chloroformate was added dropwise with stirring. After stirring this solution for 2 hours,
Cold water was added, and the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography using ethyl acetate-n-hexane (7:3), and the fraction containing the target product was concentrated. The residue was crystallized by IPE to obtain (3S,4R)−
(-)-3-Cbz-amino-4-fluoromethyl-2-oxoazetidine 1.8g (yield: 52%)
I got it. Mp98~100℃. IR (KBr) cm -1 : 3280, 1760, 1745, 1690,
1545, 1270, 1145, 1020, 1000 NMR (DMSO-d 6 ) δin ppm: 3.7-4.1 (1H,
m), 4.2-4.9 (3H, m), 5.11 (2H, s),
5.96 (1H, d, J=8Hz), 6.6 (1H, s),
7.36 (5H, s) b 1.51 g of the compound obtained in Reference Example 2-a
(6 mmol) in 20 ml of DMF was added 1.91 g (12 mmol) of pyridine-sulfuric anhydride complex, and the mixture was stirred at room temperature for 5 days. Pour the reaction solution into 300 ml of cold 0.5M potassium phosphate solution adjusted to pH 5.5, wash 3 times with 100 ml of methylene chloride,
Tetra-n-butylammonium hydrogen sulfate 2.04
g (0.6 mmol) was added. This aqueous solution was extracted four times with 100 ml of methylene chloride, and the extract was 8%
Wash with saline, dehydrate with anhydrous sodium sulfate,
After concentration, the precipitated crystals were collected by filtration with the addition of ethyl acetate to obtain 2.5 g (yield: 73%) of the title compound. Mp113~115℃. [α] 20 D −12.1° (c=1, C 2 H 5 OH) Elemental analysis value C 28 H 48 N 3 FO 6 S Calculated value: C, 58.61: H, 8.43: N, 7.32 Actual value: C, 58.43: H, 8.79: N, 7.40 IR (KBr) cm -1 : 1765, 1720, 1530, 1280,
1135, 1040 NMR (DMSO-d 6 ) δin ppm: 0.95 (12H, t,
J=6.5Hz), 1.10~1.80 (16H, m), 3.05~
3.40 (8H, m), 3.93 (1H, m), 4.53 (1H,
d, J = 8.7Hz), 4.72 (2H, dd, J = 42&2
Hz), 5.08 (2H, s), 7.40 (5H, s), 8.05
(1H, d, J = 8.7Hz) Reference example 3 (3S, 4R)-(-)-3-Cbz-amino-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid TBA salt a γ-fluoro -L-threonine 13.7g
(0.1mol) and 50% of TEA20.9ml (0.15mol)
Cool 150 ml of DMF aqueous solution and add benzyl chloroformate 21.6 mL while stirring while keeping at 5-10℃.
ml (0.15 mol) was added dropwise and stirred at the same temperature for 1 hour. Pour the reaction solution into 350ml of ice water and add ethyl acetate.
Washed with 200ml. The aqueous layer was adjusted to PH2.5 with 6N hydrochloric acid, extracted with ethyl acetate, and the oily N-Cbz-
25.7 g of γ-fluoro-L-threonine (yield:
95%) obtained. b 27.1g of the compound obtained in Reference Example 3-a
(0.1mol) and N-hydroxysuccinimide
21.6 g (0.105 mol) of DCC was added to a solution of 16.1 g (0.11 mol) in 200 ml of THF under ice cooling, and the mixture was stirred at room temperature for 2 hours. The precipitated N,N'-dicyclohexylurea was separated by filtration, and the filtrate was added dropwise to an ice-cooled solution of 32 ml of 7.5N ammonia and 32 ml of THF while stirring.
Stirred for 2 hours. The reaction solution was evaporated under reduced pressure,
The residue was dissolved in ethyl acetate, washed with saturated brine containing 5% sodium bicarbonate, ethyl acetate was evaporated under reduced pressure, and the precipitated crystals were washed with a small amount of ethyl acetate to give N 2 -Cbz-γ-fluoro- L-
23.2 g (yield: 90%) of threoninamide was obtained. Mp141~145℃. [α] 20 D 9.4゜ (c=1, C 2 H 5 OH) IR (KBr) cm -1 : 3420, 3310, 3220, 1690,
1640, 1535, 1420, 1300, 1250, 1060,
1015, 870, 695 NMR (DMSO-d 6 ) δin ppm: 4.0-4.30 (3H,
m), 4.60 (1H, m), 5.08 (2H, s), 5.40
(1H, d, J=5Hz), 6.88 (1H, d, J=
8Hz), 7.20 (1H, br s), 7.30~7.50 (6H,
s) c 3.36 g of the compound obtained in Reference Example 3-b
(13 mmol) in 13 ml of anhydrous pyridine,
methanesulfonyl chloride under stirring at below °C.
1.2 ml (15.3 mmol) was added dropwise and stirred at the same temperature for 2 hours. The reaction solution was poured into 120ml of ice water, stirred for 30 minutes, the precipitated crystals were collected by filtration, and N 2 -Cbz-O
3.79 g (yield: 83.7%) of -mesyl-γ-fluoro-L-threonine amide was obtained. IR (KBr) cm -1 : 3430, 3320, 1670, 1620,
1535, 1350, 1250, 1185, 1070, 1050, 970,
930, 820, 750, 695 NMR (DMSO-d 6 ) δin ppm: 3.16 (3H, s),
4.60 (1H, dd, J=9&5Hz), 4.70 (2H,
dd, J = 5 & 3.7Hz), 4.9~5.2 (3H, m),
7.35-7.50 (6H, m), 7.55-7.80 (2H, m) d 2-picoline 8.84ml methylene chloride 45ml
To the solution was added dropwise 2.99 ml of chlorosulfonic acid while stirring and keeping the temperature below 5° C. under ice cooling. This solution was added to a suspension of 3.79 g of the compound obtained in Reference Example 3-c in 60 ml of methylene chloride, and the mixture was boiled under reflux for 16 hours. The reaction solution was cooled and poured into 300ml of 0.5M sodium phosphate solution (PH4.5), the aqueous layer was separated, 5.08g of tetra-n-butylammonium hydrogen sulfate was added to the aqueous layer, and the solution was extracted twice with 74 ml of methylene chloride. The extract was evaporated to dryness under reduced pressure to give N2 -Cbz- O3 -mesyl-γ-
5.65 g (yield: 74%) of fluoro-L- N1 -sulfonate-threoninamide TBA salt was obtained as a foamy solid. NMR (DMSO-d 6 ) δin ppm: 0.94 (12H, t,
J=6.2Hz), 1.1~1.8 (16H, m), 3.05~3.50
(11H, m), 4.50 (1H, m), 4.52 (2H, dd,
J = 47.5 & 3.7Hz), 5.05~5.30 (3H, m),
7.30-7.50 (6H, s), 9.96 (1H, br s) e 2.0g of potassium carbonate, water 7.2 under reflux at boiling
ml and 3.75 g of the compound obtained in Reference Example 3-d in a mixture of 58 ml of 1,2-dichloroethane.
(5.6 mmol) in 9 ml of 1,2-dichloroethane was added, and the mixture was boiled and refluxed for 20 minutes. The reaction solution was cooled, methylene chloride was added thereto, the organic layer was separated and evaporated under reduced pressure to obtain an oily residue. The residue was dissolved in ethyl acetate-acetone (4:1).
Fractions containing the target substance were collected and concentrated under reduced pressure, and the crystalline residue was washed with a small amount of ethyl acetate to obtain 0.51 g of the title compound (yield: 15.9). %) was obtained. Effect of the invention The compound of the present invention [ ] is 3-acylamino-2-
It is a new optically active compound having a fluoromethyl group at the 4-position of oxo-1-azetidine sulfonic acid, and is useful as an antibacterial substance.
Claims (1)
基、C2-3アルキニル基、C3-5シクロアルキル基、
シアノC1-3アルキル基、カルボキシC1-3アルキル
基、ベンジル基またはフエニル基を示す］で表さ
れる化合物またはその医薬上許容される無毒性
塩。 ２ Ｒがメチル基、エチル基、プロピル基、イソ
プロピル基、２−プロペニル基、２−プロピニル
基、カルボキシメチル基、シアノメチル基、１−
カルボキシ−１−メチルエチル基、シクロペンチ
ル基、ベンジル基またはフエニル基である特許請
求の範囲第１項記載の化合物またはその医薬上許
容される無毒性塩。 ３ （3R，4R）−（−）−３−｛（Ｚ）−２−（２−
アミノ−４−チアゾリル）−２−（１−カルボキシ
−１−メチルエトキシイミノ）アセトアミド｝−
４−フルオロメチル−２−オキソ−１−アゼチジ
ンスルホン酸である特許請求の範囲第１項記載の
化合物またはその医薬上許容される無毒性塩。 ４ (イ) 一般式 ［式中、R1は水素原子またはスルホ基を示
す］で表わされる化合物と 一般式 ［式中、R2は水素原子またはアミノ基の保
護基、R3はC1-3アルキル基、C2-3アルケニル
基、C2-3アルキニル基、C3-5シクロアルキル
基、シアノC1-3アルキル基、保護されていても
よいカルボキシC1-3アルキル基、ベンジル基ま
たはフエニル基を示す］で表される化合物また
はその反応性誘導体とを反応させ、 (ロ) 次にR1が水素原子を示す場合は、工程(イ)で
得られた化合物をスルホン化し、 (ハ) 要すれば、保護基を除去し、そして (ニ) 要すれば、このようにして得られた化合物を
その医薬上許容される無毒性の塩に変換するこ
とを特徴とする、 一般式 ［式中、ＲはC1-3アルキル基、C2-3アルケニル
基、C2-3アルキニル基、C3-5シクロアルキル基、
シアノC1-3アルキル基、カルボキシC1-3アルキル
基、ベンジル基またはフエニル基を示す］で表さ
れる化合物またはその医薬上許容される無毒性塩
の製造法。 ５ 一般式 ［式中、ＲはC1-3アルキル基、C2-3アルケニル
基、C2-3アルキニル基、C3-5シクロアルキル基、
シアノC1-3アルキル基、カルボキシC1-3アルキル
基、ベンジル基またはフエニル基を示す］で表さ
れる化合物またはその医薬上許容される無毒性塩
を有効成分とする抗菌剤。[Claims] 1. General formula [Wherein, R is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group,
a cyano C 1-3 alkyl group, a carboxy C 1-3 alkyl group, a benzyl group or a phenyl group] or a pharmaceutically acceptable non-toxic salt thereof. 2 R is a methyl group, ethyl group, propyl group, isopropyl group, 2-propenyl group, 2-propynyl group, carboxymethyl group, cyanomethyl group, 1-
The compound according to claim 1, which is a carboxy-1-methylethyl group, cyclopentyl group, benzyl group or phenyl group, or a pharmaceutically acceptable non-toxic salt thereof. 3 (3R,4R)-(-)-3-{(Z)-2-(2-
Amino-4-thiazolyl)-2-(1-carboxy-1-methylethoxyimino)acetamide}-
The compound according to claim 1, which is 4-fluoromethyl-2-oxo-1-azetidinesulfonic acid, or a pharmaceutically acceptable non-toxic salt thereof. 4 (a) General formula Compounds represented by [In the formula, R 1 represents a hydrogen atom or a sulfo group] and the general formula [In the formula, R 2 is a hydrogen atom or a protecting group for an amino group, R 3 is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group, a cyano C 1-3 alkyl group, optionally protected carboxy C 1-3 alkyl group, benzyl group or phenyl group] or a reactive derivative thereof; (b) then R 1 When represents a hydrogen atom, the compound obtained in step (a) is sulfonated, (c) if necessary, the protecting group is removed, and (d) if necessary, the compound thus obtained is into its pharmaceutically acceptable non-toxic salt, [Wherein, R is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group,
a cyano C 1-3 alkyl group, a carboxy C 1-3 alkyl group, a benzyl group or a phenyl group] or a pharmaceutically acceptable non-toxic salt thereof. 5 General formula [Wherein, R is a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, a C 3-5 cycloalkyl group,
An antibacterial agent containing as an active ingredient a compound represented by a cyano C 1-3 alkyl group, a carboxy C 1-3 alkyl group, a benzyl group or a phenyl group, or a pharmaceutically acceptable non-toxic salt thereof.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57091471A JPS58208288A (en) | 1982-05-31 | 1982-05-31 | 2-oxo-1-azetidinesulfonic acid derivative |
| HU831902A HU189290B (en) | 1982-05-31 | 1983-05-30 | Process for preparing new 2-oxo-1-azetidine-sulphonic acid derivatives and pharmaceutically acceptable salts thereof, further pharmaceutical compositions containing such derivatives as active substances |
| SU833610702A SU1195908A3 (en) | 1982-05-31 | 1983-05-30 | Method of producing 2-oxo-1-azetidinesulfoacid derivatives or their salts with alkali metals |
| KR1019830002380A KR900005112B1 (en) | 1982-05-31 | 1983-05-30 | Process for preparing 2-oxo-1-azetidine sulfonic acid derivatives |
| CA000429133A CA1203806A (en) | 1982-05-31 | 1983-05-30 | 2-oxo-1-azetidinesulfonic acid derivatives, process for production thereof, and use thereof |
| AT83105395T ATE21103T1 (en) | 1982-05-31 | 1983-05-31 | 2-OXO-1-AZETIDINE SULFONIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE. |
| DE8383105395T DE3364927D1 (en) | 1982-05-31 | 1983-05-31 | 2-oxo-1-azetidinesulfonic acid derivatives, process for production thereof, and use thereof |
| EP83105395A EP0095778B1 (en) | 1982-05-31 | 1983-05-31 | 2-oxo-1-azetidinesulfonic acid derivatives, process for production thereof, and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57091471A JPS58208288A (en) | 1982-05-31 | 1982-05-31 | 2-oxo-1-azetidinesulfonic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58208288A JPS58208288A (en) | 1983-12-03 |
| JPH0343272B2 true JPH0343272B2 (en) | 1991-07-01 |
Family
ID=14027302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57091471A Granted JPS58208288A (en) | 1982-05-31 | 1982-05-31 | 2-oxo-1-azetidinesulfonic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58208288A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2515182B1 (en) * | 1981-10-23 | 1986-05-09 | Roussel Uclaf | NOVEL PRODUCTS DERIVED FROM 3-AMINO 2-OXO AZETIDINE 1-SULFAMIC ACID, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58135883A (en) * | 1981-10-23 | 1983-08-12 | ルセル―ユクラフ | Novel compounds of 3-amino-2-oxoazetidine-1- sulfonic acid derivatives, manufacture, use as drug, composition and intermediate product |
-
1982
- 1982-05-31 JP JP57091471A patent/JPS58208288A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58135883A (en) * | 1981-10-23 | 1983-08-12 | ルセル―ユクラフ | Novel compounds of 3-amino-2-oxoazetidine-1- sulfonic acid derivatives, manufacture, use as drug, composition and intermediate product |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58208288A (en) | 1983-12-03 |
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