JPH0240668B2 - - Google Patents
Info
- Publication number
- JPH0240668B2 JPH0240668B2 JP54092035A JP9203579A JPH0240668B2 JP H0240668 B2 JPH0240668 B2 JP H0240668B2 JP 54092035 A JP54092035 A JP 54092035A JP 9203579 A JP9203579 A JP 9203579A JP H0240668 B2 JPH0240668 B2 JP H0240668B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- carboxylic acid
- cis
- solvent
- 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 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- -1 carbacephem compound Chemical class 0.000 description 24
- 238000004519 manufacturing process Methods 0.000 description 23
- 238000000034 method Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 150000008065 acid anhydrides Chemical class 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 150000002148 esters Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- NAYXQZJKFFTWMQ-UHFFFAOYSA-N 2-methyl-8-oxooct-2-enoic acid Chemical compound OC(=O)C(C)=CCCCCC=O NAYXQZJKFFTWMQ-UHFFFAOYSA-N 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 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 4
- 229930186147 Cephalosporin Natural products 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000012156 elution solvent Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001733 carboxylic acid esters Chemical group 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 description 1
- JQEHQELQPPKXRR-LLVKDONJSA-N (2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetic acid Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 JQEHQELQPPKXRR-LLVKDONJSA-N 0.000 description 1
- QNXHTHMVKRGOSJ-RFZPGFLSSA-N (6r,7r)-7-amino-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1CC(Cl)=C(C(O)=O)N2C(=O)[C@H](N)[C@H]21 QNXHTHMVKRGOSJ-RFZPGFLSSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- SUHXTVABLHHRST-UHFFFAOYSA-N 2-azidoacetyl chloride Chemical compound ClC(=O)CN=[N+]=[N-] SUHXTVABLHHRST-UHFFFAOYSA-N 0.000 description 1
- BEORQCVHHFQCJH-UHFFFAOYSA-N 2-methyl-8-oxooctanoic acid Chemical compound OC(=O)C(C)CCCCCC=O BEORQCVHHFQCJH-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- CXUMRMPZDUKHMR-UHFFFAOYSA-N 3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=C(Cl)CCC2CC(=O)N12 CXUMRMPZDUKHMR-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QNXHTHMVKRGOSJ-UHFFFAOYSA-N 7-amino-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1CC(Cl)=C(C(O)=O)N2C(=O)C(N)C21 QNXHTHMVKRGOSJ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- XDOUXYZJAXUPNT-INEUFUBQSA-N N(=[N+]=[N-])[C@@H]1[C@H]2CCC=C(N2C1=O)C(=O)O Chemical compound N(=[N+]=[N-])[C@@H]1[C@H]2CCC=C(N2C1=O)C(=O)O XDOUXYZJAXUPNT-INEUFUBQSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 102100035591 POU domain, class 2, transcription factor 2 Human genes 0.000 description 1
- 101710084411 POU domain, class 2, transcription factor 2 Proteins 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- BZROUKNHRMKRFR-UHFFFAOYSA-N butyl 8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(CCC)OC(=O)C=1N2C(CC2CCC1)=O BZROUKNHRMKRFR-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DIFLXBCYHDZYRY-UHFFFAOYSA-N tert-butyl 2-amino-2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)C(N)C(=O)OC(C)(C)C DIFLXBCYHDZYRY-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は一般式（）
（式中Ｘはアシル基を、Halはハロゲン原子を、
Ｒはカルボン酸またはカルボン酸エステルを表わ
す）で表わされる７―アシルアミノ―３―ハロゲ
ン置換カルバセフエム化合物およびその塩類に関
する。尚カルバセフエムの命名はJ.Am.Chem.
Soc.，96 7584（1974）の記述に従つた。セフア
ロスポリン抗生物質類の骨格の中、硫黄原子が炭
素原子で置き換えられたいわゆるカルバセフエム
類の合成研究の結果、本発明者らは種々の新規骨
格の合成に成功し、それらは特願昭53−34696号
（特開昭54−128591号公報）、同53−76901号（特
開昭55−4337号公報）、同53−122403号（特開昭
55−49376号公報）、同53−133072号（特開昭55−
59186号公報）に開示されている。さらに一般式
（）で表わされる３位にハロゲン原子をもつカ
ルバセフエム骨格の合成にも成功し、それらは特
願昭53−162008号（特開昭55−87791号公報）に
開示されている。
（式中X1はアジド基、アミノ基、置換アミノ基
を、Halはハロゲン原子を、Ｒはカルボン酸また
はカルボン酸エステルを表わす。）
本発明者はX1＝NH2である一般式（―ａ）
で表わされる化合物
（式中Halはハロゲン原子をR1は水素原子または
エステル残基を表わす）に種々のアシル基を導入
した本発明の化合物を合成した結果、それらに高
い抗菌活性を見い出し、本発明を完成した。
本発明をさらに詳しく説明すると、一般式
（）中のHalとしては塩素・臭素・沃素が例示
され、特に塩素原子を有する本発明化合物が有用
である。またアシル基ＸはX2COで表わされ、X2
としては、シアノメチル基または次の５つのグル
ープが例示される。
１ 一般式
（式中Ｂはシクロヘキセニル、シクロヘキサジ
エニル、フエニル基、またはフリル、チエニ
ル、ピロリル、チアゾリル、オキサゾリル、イ
ソチアゾリル、イソオキサゾリル、イミダゾリ
ル、ピラゾリル、トリアゾリル、テトラゾリ
ル、ピリジニル、ピリミジニル、ピラジニル、
ピリダジニル、トリアジニル、５，６―ジヒド
ロ―１，４―ジチン―２―イル基等の５ないし
６員環の複素環グループを、A1はＢ環上の置
換基であり、水素原子、水酸基、C1〜C4のア
ルコキシ基、ハロゲン原子、ニトロ基、アミノ
基、アミノメチル基、メチルスルホンアミド
基、C1〜C4のアルカノイルオキシ基等が例示
され、ｎは０から５の整数を表わし、A2とし
ては水素原子、アミノ基、水酸基、カルボキシ
ル基、スルホ基等が挙げられる。）
で表わされる基
２ 一般式
〔式中A1、Ｂ、ｎは前記と同義であり、A3、
A4は同一もしくは異なる基であり、水素原子
C1〜C4のアルキル基、一般式
The present invention is based on the general formula () (In the formula, X is an acyl group, Hal is a halogen atom,
The present invention relates to a 7-acylamino-3-halogen-substituted carbacephem compound represented by (R represents a carboxylic acid or a carboxylic acid ester) and salts thereof. Carbasechem was named by J.Am.Chem.
Soc., 96 7584 (1974). As a result of research on the synthesis of so-called carbacephems, in which the sulfur atom in the skeleton of cephalosporin antibiotics is replaced with a carbon atom, the present inventors succeeded in synthesizing various new skeletons. No. 54-128591 (Japanese Unexamined Patent Publication No. 54-128591), No. 53-76901 (Japanese Unexamined Patent Application No. 55-4337), No.
Publication No. 55-49376), No. 53-133072 (Japanese Unexamined Patent Publication No. 55-1983)
No. 59186). Furthermore, we succeeded in synthesizing a carbacefem skeleton having a halogen atom at the 3-position represented by the general formula (), and these are disclosed in Japanese Patent Application No. 162008/1983 (Japanese Patent Application Laid-open No. 87791/1983). (In the formula, X 1 represents an azide group, an amino group, or a substituted amino group, Hal represents a halogen atom, and R represents a carboxylic acid or a carboxylic acid ester.) a)
Compound represented by (In the formula, Hal represents a halogen atom and R 1 represents a hydrogen atom or an ester residue.) As a result of synthesizing the compounds of the present invention with various acyl groups introduced therein, they found high antibacterial activity in them, and completed the present invention. . To explain the present invention in more detail, examples of Hal in the general formula () include chlorine, bromine, and iodine, and the compounds of the present invention having a chlorine atom are particularly useful. Furthermore, the acyl group X is represented by X 2 CO, and X 2
Examples include a cyanomethyl group or the following five groups. 1 General formula (In the formula, B is a cyclohexenyl, cyclohexadienyl, phenyl group, or furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
A 5- to 6-membered heterocyclic group such as pyridazinyl, triazinyl, 5,6-dihydro-1,4-dityn-2-yl group, A 1 is a substituent on ring B, a hydrogen atom, a hydroxyl group, Examples include a C1 to C4 alkoxy group, a halogen atom, a nitro group, an amino group, an aminomethyl group, a methylsulfonamide group, a C1 to C4 alkanoyloxy group, and n represents an integer from 0 to 5. , A 2 includes a hydrogen atom, an amino group, a hydroxyl group, a carboxyl group, a sulfo group, and the like. ) Group 2 represented by general formula [In the formula, A 1 , B, and n have the same meanings as above, and A 3 ,
A 4 is the same or different group, hydrogen atom
C1 - C4 alkyl group, general formula
【式】（但 し、A5はC1〜C4のアルキル基を表わす） で表わされる基、または一般式[Formula] (However, A 5 represents a C 1 to C 4 alkyl group) or a group represented by the general formula
【式】
（但し、A6、A7は同一もしくは異なる基であ
り、水素原子、C1〜C4のアルキル基またはア
ルカリ金属を表わす）で表わされる基を示し、
またA3とA4はＮと環をなして式
[Formula] (However, A 6 and A 7 are the same or different groups and represent a hydrogen atom, a C 1 to C 4 alkyl group, or an alkali metal),
Also, A 3 and A 4 form a ring with N, and the formula
【式】（但し、A8、A8′は同一も
しくは異なる基であり、水素原子、C1〜C4の
アルキル基を示す）で表わされる基もしくは一
般式A group represented by [Formula] (where A 8 and A 8 ' are the same or different groups and represent a hydrogen atom or a C 1 to C 4 alkyl group) or a general formula
【式】（但し、A9は水素原子、
C1〜C4のアルキル基、メタンスルホニル基、
またはフルフリリデンイミノ基を、A9′は水素
原子またはC1〜C4アルキル基を示す）で表わ
される基を示す場合もある〕で表わされる基、
３ 一般式
〔但し、式中A1、Ｂ、ｎは前記と同義であり、
A10は置換アリール基または例えば核上置換ま
たは無置換の[Formula] (However, A 9 is a hydrogen atom, a C 1 to C 4 alkyl group, a methanesulfonyl group,
or a furfurylideneimino group, where A 9 ' represents a hydrogen atom or a C 1 to C 4 alkyl group], 3 a group represented by the general formula [However, in the formula, A 1 , B, and n have the same meanings as above,
A 10 is a substituted aryl group or, for example, a nuclear substituted or unsubstituted
【式】【formula】
【式】
のごとき単環、二環または三環性複素環を示
す〕で表わされる基、
４ 一般式
（但し、式中A1、Ｂ、ｎは前記と同義であり
A11は水素原子、C1〜C6の低級アルキル基、C2
〜C6の低級アルケニル基、C2〜C6の低級アル
キニル基、C3〜C6のシクロアルキル基、また
はアリール基を表わし、これらの基はまたカル
ボキシル基、シアノ基、ハロゲン原子、カルバ
モイル基、C1〜C4の低級アルキルオキシカル
ボニル基等で置換されているものも含まれる）
で表わされる基、
５ 一般式
B1―Ｚ―CH2―
〔式中B1はトリフロロメチル基、シアノメチ
ル基、または（A1）o―Ｂ（式中A1、Ｂ、ｎは前
記に同じ）で表わされる基であり、Ｚは酸素原
子または硫黄原子を表わす〕で表わされる基。
また一般式（）中、Ｒで表わされる基はカル
ボキシル基またはCO2R′で表わされる基であり、
R′は一般のペニシリン、セフアロスポリンの化
学で用いられるカルボキシ保護基である。具体的
にはメチル、エチル、ｎ―プロピル、イソプロピ
ル、ｎ―ブチル、イソブチル、Sec―ブチル、ｔ
―ブチル基のC1〜C5のアルキル基、２，２，２
―トリフロロエチル、２，２，２―トリクロルエ
チル基の如きハロゲン基をもつC1〜C5のアルキ
ル基、ベンジル基、ジフエニルメチル基、トリフ
エニルメチル基等のC7〜C20のアリールメチル基
（これらはまたメトキシ、ニトロ基等をフエニル
核上にもつものも含まれる）、トリメチルシリル
基、トリフエニルシリル基等の置換シリル基等が
例示される。R1としてはまた一般式
（式中、R2は水素原子、C1〜C6の低級アルキル
基を示し、R3はC1〜C6の低級アルキル基、C1〜
C6の低級アルコキシ基またはフエニル基を示す）
で表わされるような生体内で酸素的または非酵素
的に脱離が容易な基も例示される。Ｒがカルボキ
シル基の場合、またはアシル基Ｘ中にカルボキシ
ル基、スルホ基等がある場合は、医薬品として許
容される、無機または有機の塩基との塩類をも包
含する。
またアシル基Ｘ中にアミノ基がある場合は医薬
品として許容される、無機または有機の酸との塩
類をも包含する。また一般式（）で示される化
合物としては６位、７位における立体異性体の全
てを含むが、シス配位のものはトランス配位のも
のに比べ抗菌作用が強く、シス異性体がより有用
である。
アシル基中＝NORであらわされる基において
は下図の如きシン異性とアンチ異性が考えられる
が、一般にシン異性体の方が抗菌作用に秀れてお
りより有用である。A group represented by [Formula] representing a monocyclic, bicyclic or tricyclic heterocyclic ring, 4 General formula (However, in the formula, A 1 , B, and n have the same meanings as above.
A 11 is a hydrogen atom, C 1 to C 6 lower alkyl group, C 2
~ Represents a C 6 lower alkenyl group, a C 2 to C 6 lower alkynyl group, a C 3 to C 6 cycloalkyl group, or an aryl group, and these groups can also be a carboxyl group, a cyano group, a halogen atom, a carbamoyl group , including those substituted with C 1 to C 4 lower alkyloxycarbonyl groups, etc.)
A group represented by the general formula 5 , (same), and Z represents an oxygen atom or a sulfur atom. In addition, in the general formula (), the group represented by R is a carboxyl group or a group represented by CO 2 R',
R' is a carboxy protecting group used in the chemistry of common penicillins and cephalosporins. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl, t
-C1 - C5 alkyl group of butyl group, 2,2,2
-C1 to C5 alkyl groups with halogen groups such as trifluoroethyl and 2,2,2-trichloroethyl groups; C7 to C20 arylmethyl groups such as benzyl groups, diphenylmethyl groups, and triphenylmethyl groups; (These also include those having methoxy, nitro groups, etc. on the phenyl nucleus), substituted silyl groups such as trimethylsilyl group, triphenylsilyl group, and the like. R 1 is also the general formula (In the formula, R 2 represents a hydrogen atom, a C 1 to C 6 lower alkyl group, and R 3 represents a C 1 to C 6 lower alkyl group, C 1 to
(represents C6 lower alkoxy group or phenyl group)
Also exemplified are groups that are easily eliminated in vivo oxygenally or non-enzymatically, such as represented by: When R is a carboxyl group, or when the acyl group X has a carboxyl group, a sulfo group, etc., salts with pharmaceutically acceptable inorganic or organic bases are also included. Furthermore, when an amino group is present in the acyl group X, salts with inorganic or organic acids that are acceptable as pharmaceuticals are also included. In addition, the compound represented by the general formula () includes all stereoisomers at the 6- and 7-positions, but the cis-coordinated one has a stronger antibacterial effect than the trans-coordinated one, and the cis isomer is more useful. It is. For the group represented by NOR in the acyl group, syn isomerism and anti-isomerism are considered as shown in the figure below, but in general, the syn isomer has superior antibacterial activity and is more useful.
【式】
アシル基中の２―アミノ―チアゾリル基はその
互変異性体である２―イミノ―チアゾリニル基を
も含むものである。
一般式（）で表わされる化合物は一般式（
―ａ）で表わされる化合物をアシル化することに
より製造することができる。アシル化の方法は一
般のペニシリン、セフアロスポリンの化学におい
て用いられる方法が適用される。即ち、化合物
（―ａ）またはその塩またはそれと等価なもの
（以下７―アミノ化合物と呼称する。）と一般式
（）
X3CO2H （）
（但し、式中X3はX2と同義かまたはX2がアシル
化時に影響をうける官能基を有する場合は、それ
らの官能基を適切な保護基で保護された基X2を
示す）であらわされるカルボン酸またはその反応
性誘導体でアシル化後必要に応じてX3または
CO2R1中の保護基を常法により脱離することによ
り製造される。X2中の保護を要する官能基とし
ては、水酸基、チオール基、アミノ基、カルボキ
シル基、スルホ基が例示され、それらの保護基と
しては一般のペプチド化学で用いられるものが例
示される。具体的にはJ.F.W.McOmie著
Protective Groups in Organic Chemistry
（Plenum Press、1973）等に記載されている。
カルボン酸（）の反応性誘導体としては１）
酸ハライド、２）酸無水物、３）混合酸無水物、
４）活性エステル、５）酸アジド等が挙げられそ
れぞれを用いるアシル化方法は以下の如くであ
る。
１） 酸ハライド法
７―アミノ化合物と酸ハライドを好ましくは
酸補捉体の存在下縮合させる。酸補捉体として
は炭酸ナトリウム、炭酸カリウム、水酸化ナト
リウム等の無機アルカリ、トリエチルアミン、
Ｎ―メチルモルホリン、ピリジン等の有機塩基
が例示される。溶媒は反応に支障をきたさない
不活性溶媒が用いられ、好ましくはテトラヒド
ロフラン、ジメトキシエタン等のエーテル系、
酢酸エチル等のエステル系、塩化メチレン、ク
ロロホルム等のハロゲン化炭化水素系、ジメチ
ルホルムアミド、ジメチルアセタミド、ヘキサ
メチルホスホアミド等のアミド系、ジメチルス
ルホキシド等のスルホキシド系または水、ある
いはそれらの混合系が用いられる。
反応温度は−20〜40℃で行なわれる。
２） 酸無水物法
７―アミノ化合物と酸無水物を不活性溶媒中
縮合することにより行なわれる。反応溶媒、温
度等は酸ハライド法のそれが適用される。典型
的例としてはジシクロヘキシルカルボジイミド
を用いる酸無水物法が挙げられる。
３） 混合酸無水物法
７―アミノ化合物と混合酸無水物を不活性溶
媒中縮合することにより行なわれる。混合酸無
水物は常法に従い、例えば対応するカルボン酸
X3CO2Hとクロル炭酸エステルとを塩基の存在
下縮合することにより製造される。反応溶媒、
温度等は酸無水物法のそれが適用される。
４） 活性エステル法
７―アミノ化合物と活性エステルを不活性溶
媒中縮合することにより行なわれる。活性エス
テルとしては対応するカルボン酸のフエニルエ
ステル、Ｐ―ニトロフエニルエステル、Ｐ―ニ
トルチオフエニルエステル、トリクロロフエニ
ルエステル、シアノメチルエステル、Ｎ―ヒド
ロキシコハク酸イミドエステル等が用いられ
る。適用される溶媒、温度等は上記３つの方法
に準ずる。
５） 酸アジド法
前述の方法での反応条件に準じて７―アミノ
化合物と酸アジド化合物を縮合することにより
行なわれる。酸アジド化合物は一般には対応す
るカルボン酸のヒドラジド体を−20〜０℃で亜
硝酸と反応して合成することができる。
カルボン酸またはその反応性誘導体中にアシル
化に際して影響をうける官能基、例えばアミノ
基、水酸基、チオール基、カルボキシル基、スル
ホ基等が存在する場合はこれらはアシル化に先立
つて以下のような保護基で保護される。
アミノ基の保護基としてはｔ―ブチルオキシカ
ルボニル基、ベンジルオキシカルボニル基、トリ
クロロエチルオキシカルボニル基、トリチル基、
ホルミル基、クロロアセチル基、トリアルキルシ
リル基、プロトン、β―ジケトン、β―ケトエス
テル等が挙げられる。プロトンで保護された代表
例としては[Formula] The 2-amino-thiazolyl group in the acyl group also includes its tautomer, 2-imino-thiazolinyl group. A compound represented by the general formula () is a compound represented by the general formula (
It can be produced by acylating the compound represented by -a). As the acylation method, methods used in the chemistry of general penicillins and cephalosporins are applied. That is, the compound (-a) or its salt or its equivalent (hereinafter referred to as 7-amino compound) and the general formula () X 3 CO 2 H () (wherein X 3 has the same meaning as X 2 or, if X 2 has functional groups that are affected during acylation, those functional groups are acylated with a carboxylic acid represented by (X 2 ) protected with an appropriate protecting group or a reactive derivative thereof. After X 3 or as required
It is produced by removing the protecting group in CO 2 R 1 by a conventional method. Examples of functional groups in X 2 that require protection include a hydroxyl group, a thiol group, an amino group, a carboxyl group, and a sulfo group, and examples of protecting groups thereof include those used in general peptide chemistry. Specifically written by JFW McOmie
Protective Groups in Organic Chemistry
(Plenum Press, 1973) etc. As a reactive derivative of carboxylic acid (), 1)
acid halide, 2) acid anhydride, 3) mixed acid anhydride,
4) active ester, 5) acid azide, etc., and the acylation method using each is as follows. 1) Acid halide method A 7-amino compound and an acid halide are preferably condensed in the presence of an acid scavenger. As acid scavengers, inorganic alkalis such as sodium carbonate, potassium carbonate, and sodium hydroxide, triethylamine,
Examples include organic bases such as N-methylmorpholine and pyridine. The solvent used is an inert solvent that does not interfere with the reaction, preferably an ether type solvent such as tetrahydrofuran or dimethoxyethane,
Ester systems such as ethyl acetate, halogenated hydrocarbon systems such as methylene chloride and chloroform, amide systems such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, sulfoxide systems such as dimethyl sulfoxide, water, or a mixture thereof. is used. The reaction temperature is -20 to 40°C. 2) Acid anhydride method This is carried out by condensing a 7-amino compound and an acid anhydride in an inert solvent. The reaction solvent, temperature, etc. used in the acid halide method are applied. A typical example is an acid anhydride method using dicyclohexylcarbodiimide. 3) Mixed acid anhydride method This is carried out by condensing a 7-amino compound and a mixed acid anhydride in an inert solvent. Mixed acid anhydrides can be prepared using conventional methods such as the corresponding carboxylic acid.
It is produced by condensing X 3 CO 2 H and chlorocarbonate in the presence of a base. reaction solvent,
Regarding temperature, etc., those of the acid anhydride method are applied. 4) Active ester method This is carried out by condensing a 7-amino compound and an active ester in an inert solvent. As the active ester, phenyl ester, P-nitrophenyl ester, P-nitrthiophenyl ester, trichlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, etc. of the corresponding carboxylic acid are used. The solvent, temperature, etc. to be applied are based on the above three methods. 5) Acid azide method This is carried out by condensing a 7-amino compound and an acid azide compound according to the reaction conditions in the above-mentioned method. Acid azide compounds can generally be synthesized by reacting a hydrazide of the corresponding carboxylic acid with nitrous acid at -20 to 0°C. If a carboxylic acid or its reactive derivative contains functional groups that are affected during acylation, such as amino groups, hydroxyl groups, thiol groups, carboxyl groups, and sulfo groups, these should be protected as follows prior to acylation. protected by Protecting groups for amino groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, trichloroethyloxycarbonyl group, trityl group,
Examples include formyl group, chloroacetyl group, trialkylsilyl group, proton, β-diketone, β-ketoester, and the like. A typical example of proton-protected
【式】がまたβ―ケトエステル で保護された代表例としては[Formula] is also β-ketoester A typical example protected by
【式】が例示される。
水酸基の保護基としてはベンジル基、ベンジル
オキシカルボニル基、トリチル基、テトラヒドロ
ピラニル基、ｔ―ブチル基等が挙げられる。
カルボキシル基の保護基としてはｔ―ブチル
基、ベンジル基、ｐ―メトキシベンジル基、ｐ―
ニトロベンジル基、ベンズヒドリル基等が挙げら
れる。
チオール基の保護基としてはベンジル基、トリ
チル基、ベンジルオキシカルボニル基、ｐ―ニト
ロベンジル基等が挙げられる。保護基の導入法お
よびその脱離法については常法が適用でき前述の
成書Protective Group in Organic Chemistry
の記載に準じて行うことができる。
カルボン酸保護基（R1）の脱離方法は一般の
ペニシリン、セフアロスポリンの化学で用いられ
ている方法が適用される。望ましい方法としては
１）接触還元、２）酸分解、３）ルイス酸による
解裂、４）加水分解、５）亜鉛―酢酸等を用いる
接触還元以外の還元、６）エステラーゼを用いる
方法等が例示される。
本発明に用いられる出発原料、式（―ａ）で
表わされる化合物については特願昭53−162008号
（特開昭55−87791号公報）の明細書にその製造法
が開示されているが参考例として後記の如く示
す。一例を参考工程図〔〕に示す。
図中、化合物６，８が本発明化合物製造の出発
原料の１種である。
また、図中、化合物１の製造法は特願昭53−
34696号（特開昭54−128591号公報）に開示して
あるが後記参考例に示す如く製造される。一例を
参考工程図〔〕に示す。
本発明の化合物はグラム陽性菌、グラム陰性菌
に対し強い抗菌作用を有し各種感染症の治療に殺
菌剤としてまた消毒薬の成分として有用なもので
あり、一般のセフアロスポリン剤と同様な各種担
体材料、賦形剤、希釈剤等で製剤化され、それら
剤型に応じて注射薬、経口薬、坐薬として投与さ
れる。
以下に本発明の実施態様を例示するが、本発明
はこれらに限定されるものではない。
実施例 １
（±）―シス―７―（２―フエニル―２―ｔ―
ブチルオキシカルボニルアミノアセトアミド）
―３―クロロ―１―アザビシクロ〔４，２，
０〕オクト―２―エン―８―オン―２―カルボ
ン酸，第三ブチルエステルの製造：
（猶シスとは６位，７位の立体化学に関してのも
のであり以下同様である。）
参考例２に従い合成される（±）―シス―７―
アミノ―３―クロロ―１―アザビシクロ〔４，
２，０〕オクト―２―エン―８―オン―２―カル
ボン酸，第三ブチルエステル150mg（0.55m
mole）を無水塩化メチレン３mlに溶かす。Ｎ―
ｔ―ブチルオキシカルボニル―（Ｒ）―フエニル
グリシン166mg（0.66m mole）を５mlの無水テト
ラヒドロフランに溶かし−15〜−10℃に冷却し、
1N―Ｎ―メチルモルホリンのテトラヒドロフラ
ン溶液0.66mlおよび1Nクロル蟻酸イイブチルの
テトラヒドロフラン溶液0.66mlを滴下し、同温度
で20分間撹拌する。この温度に維持しながら上記
で調製したアミン溶液を滴下した後徐々に室温に
戻し、さらに一夜室温で撹拌した。反応液に塩化
メチレン10mlを加えた後10％クエン酸，飽和重曹
水，飽和食塩水の順で洗い、無水硫酸ナトリウム
で乾燥する。減圧濃縮しシリカゲルクロマトグラ
フイーで精製し（シリカゲル：和光純薬社製 Ｃ
−200，20ｇ，溶媒 酢酸エチル：ｎ―ヘキサン
＝１：５容量比、以下同じ）目的物（ジアステレ
オ異性体混合物）124mg（収率44.6％）を得る。
このものの物性値は以下のとおりである。
IRνKBr nax（cm-1）：1780，1730，1680，1655，1550
NMR（CDCl3）δ：7.34（５／2H，ｓ），7.31
（５／2H，ｓ），6.93（1H，ｍ），5.63（1H，
ｍ），5.30（１／2H，dd，Ｊ＝5.4，6.8Hz），
5.11〜5.22（３／2H，ｍ），3.76〜3.91（1H，
ｍ），2.33〜2.66（2H，ｍ），1.52（9H，ｓ），
1.41（9H，ｓ），0.92〜1.97（2H，ｍ）
実施例 ２
（6R，7S）７―（Ｒ）―フエニルグリシンア
ミド―３―クロロ―１―アザビシクロ〔４，
２，０〕オクト―２―エン―８―オン―２―カ
ルボン酸(A)および（6S，7R）７―（Ｒ）―フ
エニルグリシンアミド―３―クロロ―１―アザ
ビシクロ〔４，２，０〕オクト―２―エン―８
―オン―２―カルボン酸(B)の製造
実施例１と同様の方法に従い合成した（±）―
シス―７―（Ｒ）―（２―フエニル―２―ｔ―ブ
チルオキシカルボニルアミノアセトアミド）―３
―クロロ―１―アザビシクロ〔４，２，０〕オク
ト―２―エン―８―オン―２―カルボン酸，第三
ブチルエステル128.4mg（0.25m mole）に氷冷下
塩化メチレン１mlおよびトリフロロ酢酸１mlを加
え、同温度で1.5時間撹拌する。減圧下に溶媒を
留去し得られる油状物質を高速液体クロマトグラ
フイーに付し〔カラム：マイクロボンダパツクＣ
―18（ウオーターズ社製），溶媒７％メタノール
0.2N KH2PO4〕ジアステレオ異性体を分離す
る。
各々分離した溶出分画を減圧濃縮しHP―10
（三菱化成社製）レジン10ml（溶媒 メタノー
ル：水＝１：１）で脱塩処理し、高極性異性体(B)
9.4mgおよび低極性異性体(A)7.6mg（計収率19.1％）
を得た。
高極性異性体(B)
〔α〕21°
Ｄ：−75.8゜（ｃ＝0.4，H2O）
融点 300℃以上（褐変）
IRνKBr nax（cm-1）：1765，1700，1550
NMR（D2O）δ：7.49（5H，ｓ）、5.16（1H，
ｄ，Ｊ＝4.7Hz），5.05（1H，ｓ），3.78−4.03
（1H，ｍ）、2.53−2.67（2H，ｍ），1.26−2.09
（2H，ｍ）
低極性異性体(A)
〔α〕21°
Ｄ：＋34.0゜（ｃ＝0.35，H2O）
融点 300℃以上（褐変）
IRνKBr nax（cm-1）：1770，1700，1620
NMR（D2O）δ：7.51（5H，ｓ），5.36（1H，
ｄ，Ｊ＝4.6Hz），5.19（1H，ｓ），3.83−4.00
（1H，ｍ），2.41−2.56（2H，ｍ），1.49−1.79
（1H，ｍ），1.14−1.45（1H，ｍ）
後記の如く、低極性異性体(A)に強い抗菌作用が
みれらることからこの異性体(A)の絶対配位を
（6R，7S）と決めた。
実施例 ３
シス―７―〔（Ｒ）―２―フエニル―２―（４
―エチル―２，３―ジオキソピペラジニルカル
ボニルアミノ）―アセトアミド〕―３―クロロ
―１アザビシクロ〔４，２，０〕オクト―２―
エン―８―オン―２―カルボン酸，第三ブチル
エステルの製造：
Ｎ―（４―エチル―２，３―ジオキソピペラジ
ニルカルボニル）―（Ｒ）―フエニルグリシン
351mg（1.1m mole）を無水テトラヒドロフラン
10mlに溶かし、−15℃〜−10℃で1N Ｎ―メチル
モルホリンのテトラヒドロフラン溶液1.2mlおよ
び1Nクロル蟻酸イソブチルのテトラヒドロフラ
ン溶液1.1mlを加え同温度で30分撹拌する。これ
にシス―７―アミノ―３―クロロ―１―アザビシ
クロ〔４，２，０〕オクト―２―エン―８―オン
―２―カルボン酸，第三ブチルエステル・塩酸塩
309mg（1m mole）および1N Ｎ―メチルモルホ
リンのテトラヒドロフラン溶液1.4mlを含む塩化
メチレン溶液10mlを同温度で滴下した。
徐々に室温に戻し、さらに同温度で一夜撹拌す
る。減圧濃縮後酢酸エチルを加え10％クエン酸、
飽和重曹水，飽和食塩水の順で洗い、無水硫酸ナ
トリウムで乾燥する。溶媒を減圧除去し目的物
（ジアステレオ異性体混合物）を273mg（47.6％）
得る。これをシリカゲルクロマトグラフイー（シ
リカゲル30ｇ，溶媒 酢酸エチル：ｎ―ヘキサン
＝３：２）に付し、ジアステレオ異性体の分離を
行い、低極性異性体78.4mg，高極性異性体112mg
を得る。
低極性異性体
〔α〕21°
Ｄ：−4.4゜（ｃ＝0.5，MeOH）
融点 181―183℃（分解）
IRνKBr nax（cm-1）：1790，1730，1700，1685，
1525，
NMR（CDCl3）δ：9.90（1H，ｄ，Ｊ＝6.3Hz），
7.28−7.35（5H，ｍ），7.17（1H，ｄ，Ｊ＝6.8
Hz），5.46（1H，ｄ，Ｊ＝6.3Hz），5.33（1H，
dd，Ｊ＝4.9，6.8Hz），3.66−4.15（3H，ｍ），
3.41−3.62（4H，ｍ），2.41−2.56（2H，ｍ），
1.51（9H，ｓ），0.88−1.76（2H，ｍ），1.21
（3H，ｔ，Ｊ＝7.3Hz）
高極性異性体
〔α〕21°
Ｄ：−53.0゜（ｃ＝0.5，MeCH）
融点：159−170℃（分解）
IRνKBr nax（cm-1）：1785，1725，1700，1685，1525
NMR（CDCl3）δ：9.86（1H，ｄ，Ｊ＝6.3Hz），
7.35（5H，ｓ），7.06（1H，ｄ，Ｊ＝6.4Hz），
5.42（1H，ｄ，Ｊ＝6.3Hz），5.19（1H，dd，
Ｊ＝4.9，6.4Hz），3.75−4.15（3H，ｍ），3.45
−3.66（4H，ｍ），2.50−2.63（2H，ｍ），0.88
−2.44（2H，ｍ），1.51（9H，ｓ），1.22（3H，
ｔ，Ｊ＝7.3Hz）
実施例 ４
（6R，7S）７―〔（Ｒ）―２―フエニル―２―
（４―エチル―２，３―ジオキソピペラジニル
カルボニルアミノ）―アセトアミド〕―３―ク
ロロ―１―アザビシクロ〔４，２，０〕オクト
―２―エン―８―オン―２―カルボン酸の製
造：
実施例３に従い合成した低極性異性体50mgを無
水塩化メチレン2.5mlに溶かし、氷冷下トリフロ
ロ酢酸25mlを添加する。同温度で４時間撹拌後減
圧下に溶媒を留去する。残渣をシリカゲルクロマ
トグラフイー（シリカゲル５ｇ，溶媒 クロロホ
ルム：メタノール＝20：１）で精製して目的物
2.2mg（48.8％）を得た。
〔α〕21°
Ｄ＝−1.2゜（ｃ＝0.5，MeOH）
融点 175−190℃で徐々に分解
IRνKBr nax（cm-1）：1780，1720，1685，1520
NMR（CDCl3―CD3OD）δ：7.31−7.48（5H，
ｍ），5.45（1H，ｓ），5.32（1H，ｄ，Ｊ＝4.9
Hz），3.75−4.29（3H，ｍ），3.44−3.65（4H，
ｍ），2.44−2.53（2H，ｍ），1.15−2.20（2H，
ｍ），1.23（3H，ｔ，Ｊ＝7.3Hz）
実施例 ５
（6S，7R）７―〔（Ｒ）―２―フエニル―２―
（４―エチル―２，３―ジオキソピペラジニル
カルボニルアミノ）―アセトアミド〕―３―ク
ロロ―１―アザビシクロ〔４，２，０〕オクト
―２―エン―８―オン―２―カルボン酸の製
造：
実施例４における低極性異性体に替えて実施例
３に従い合成した高極性異性体50mgを用いる以外
は実施例４と同様に行い目的化合物17.7mg（39.2
％）を得た。
〔α〕21°
Ｄ＝−50.6゜（ｃ＝0.52，MeOH）
融点 175−190℃で徐々に分解
IRνKBr nax（cm-1）：1780，1720，1680，1520
NMR（CDCl3―CD3OD）δ：7.31−7.48（5H，
ｍ），5.37（1H，ｓ），5.21（1H，ｄ，Ｊ＝4.9
Hz），3.79−4.08（3H，ｍ），3.44−3.65（4H，
ｍ），2.61−2.69（2H，ｍ），1.11−2.07（2H，
ｍ），1.23（3H，ｔ，Ｊ＝7.3Hz）
実施例 ６
（±）―シス―７―フエニルアセトアミド―３
―クロロ―１―アザビシクロ〔４，２，０〕オ
クト―２―エン―８―オン―２―カルボン酸の
製造：
参考例３の方法に従い得られる（±）―シス―
７―アミノ―３―クロロ―１―アザビシクロ
〔４，２，０〕オクト―２―エン―８―オン―２
―カルボン酸・トリフロロ酢酸塩150mg（0.45m
mole）を水２mlおよびアセトン２mlの混合溶媒
に懸濁させ、これに重曹134mg（1.5m mole）を
加えて均一溶液とする。これに氷冷下フエニルア
セチルクロリド84.2mg（0.54m mole）を0.5mlの
アセトンにとかして１時間かけて滴下する。さら
に３時間撹拌後、反応液を1N塩酸でPH２とし２
mlの酢酸エチルで５回抽出し、これを減圧濃縮、
乾燥して80mg（55.0％）の目的物を得る。
IRνKBr nax（cm-1）：1790，1705，1630，1560
NMR（CDCl3）δ：7.29（5H，ｓ），5.36（1H，
ｄ，Ｊ＝５Hz），3.79−3.99（1H，ｍ），2.56
−2.75（2H，ｍ），1.17−2.02（2H，ｍ）
実施例 ７
シス―７―〔２―（２―フリル）―２―シン―
メトキシイミノアセトアミド〕―３―クロロ―
１―アザビシクロ〔４，２，０〕オクト―２―
エン―８―オン―２―カルボン酸の製造：
２―（２―フリル）―２―シンメトキシイミノ
酢酸37.9mg（0.244m mole）を無水メタノールに
溶かし、0.65Nナトリウムメチラートのメタノー
ル溶液344μを加え、ナトリウム塩とし減圧下
溶媒を留去する。
残渣はさらに真空乾燥し粉末としこれに無水ベ
ンゼン１ml，無水ジメチルホルムアミド１滴を加
え懸濁状とし、さらに塩化オキザリル29μ
（0.336m mole）を加え、室温で１時間撹拌する。
減圧濃縮し、無水テトラヒドロフラン２mlを加え
て酸クロリドを調整した。一方シス―７―アミノ
―３―クロロ―１―アザビシクロ〔４，２，０〕
オクト―２―エン―８―オン―２―カルボン酸・
トリフロロ酢酸塩57mg（0.172m mole）にテトラ
ヒドロフラン1.6mlおよび水1.6mlを加え、氷冷下
にトリエチルアミン120μ（0.862m mole）を添
加し均一溶液とする。これに先に調製した酸クロ
リド溶液を滴下しさらに氷冷下一時撹拌した。
1N塩酸でPH２とし酢酸エチルで抽出した。飽和
食塩水で洗い、無水硫酸ナトリウムで乾燥後、減
圧濃縮しさらに真空乾燥し、目的物の粗粉末86.8
mgを得た。クロロホルムより再結晶し、白色結晶
29.6mg（46.7％）を得た。
融点：134−137℃（分解）
IRνKBr nax（cm-1）：1780，1720，1655，1620，1545
NMR（CDCl3−CD3OD）δ：7.54（1H，ｄ，Ｊ
＝1.7Hz），6.73（1H，ｄ，Ｊ＝3.7Hz），6.56
（1H，dd，Ｊ＝1.7，3.7Hz），5.47（1H，ｄ，
Ｊ＝4.9Hz），4.01（3H，ｓ），3.90−4.13（1H，
ｍ），2.65−2.79（2H，ｍ），1.70−2.20（2H，
ｍ）
実施例 ８
（±）シス―７―〔２―（２―クロロアセトア
ミドチアゾール―４―イル）―２―syn―メト
キシイミノアセチルアミノ〕―３―クロロ―１
―アジビシクロ〔４，２，０〕オクト―２―エ
ン―８―オン―２―カルボン酸の製造：
２―（２―クロロアセトアミドチアゾール―４
―イル）―２―syn―メトキシイミノ酢酸122.6mg
（0.44m mole）を無水塩化メチレン2.5mlに溶解
し、これにトリエチルアミン68μ（0.49m
mole）を添加して溶かし、氷―食塩で冷却下五
塩化燐92.0mg（0.44m mole）を添加する。同温
度で１時間撹拌した後、ｎ―ヘキサン５mlを添加
し氷冷下さらに15分間撹拌を続ける。遊離した油
状物質をｎ―ヘキサンをデカンテーシヨン除去す
ることにより得、この油状物質をテトラヒドロフ
ラン４mlに溶解し、酸クロリド溶液を調製する。
他方参考例３と同様にして得られる（±）―７―
アミノ―３―クロロ―１―アザビシクロ〔４，
２，０〕オクト―２―エン―８―オン―２―カル
ボン酸・トリフロロ酢酸塩121.7mg（0.37m
mole）を50％含水テトラヒドロフラン５ml、ト
リエチルアミン0.2ml（1.47m mole）にとかした
溶液に、氷冷下、撹拌しながら先に調製した、酸
クロリドのテトラヒドロフラン溶液を加える。さ
らに同温度で１時間撹拌後、1N―塩酸を加えて
PH３とする。これに水を添加し、酢酸エチルで抽
出し飽和食塩水で洗浄後、酢酸エチル層を無水硫
酸ナトリウムで乾燥した。
減圧下溶媒を十分に留去し、目的化合物を粉末
状として53.9mg（30.5％）得る。
IRνKBr nax（cm-1）：1770，1680，1555，1045
NMR（DMSO―d6）δ：9.38（1H，ｄ，Ｊ＝８
Hz），7.37（1H，ｓ），5.45（1H，ｑ，Ｊ＝5.8
Hz），4.35（2H，ｓ）
実施例 ９
（±）シス―７―〔２―（２―アミノチアゾー
ル―４―イル）―２―syn―メトキシイミノア
セトアミド〕―３―クロロ―１―アザビシクロ
〔４，２，０〕オクト―２―エン―８―オン―
２―カルボン酸の製造：
実施例８で得られるクロロアセトアミド体51.2
mg（0.11m mole）をジメチルアセトアミド１ml
に溶かし、チオ尿素16.3mg（0.22m mole）を添
加する。撹拌しつつ室温で14時間反応した後、エ
ーテル７mlを加え、さらに10分間撹拌を続け、遊
離した油状物を、エーテルとデカンテーシヨン除
去することにより得る。残つた化合物を少量のジ
メチルスルホキシドに溶かし、HP―10、10mlの
カラムに吸着させ、スルホキシドに溶かしHP―
10レジン５mlで２回〔溶出液：水―メタノール
（メタノールの量を徐々に増加し、最終的に水：
メタノール＝１：１で溶出）〕処理することによ
り目的物を15.2mg（35.4％）得た。
融点 185.0−188.0℃（分解）
IRνKBr nax（cm-1）：1765，1670，1630，1540，1040
NMR（DMSO―d6）δ：9.28（1H，ｄ，Ｊ＝
8.8Hz），7.17（2H，ｓ），6.75（1H，ｓ），5.44
（1H，ｑ，5.3Hz，8.8Hz），3.84（3H，ｓ），
1.24−2.52（4H，ｍ）
実施例 10
（6R，7S）７―（Ｒ）―ｐ―ヒドロキシフエ
ニルグリシンアミド―３―クロロ―１―アザビ
シクロ〔４，２，０〕オクト―２―エン―８―
オン―２―カルボン酸の製造：
実施例１の製造法に準じて（±）―シス―７―
アミノ―３―クロロ―１―アザビシクロ〔４，
２，０〕オクト―２―エン―８―オン―２―カル
ボン酸、第三ブチルエステルとＮ―ｔ―ブチルオ
キシカルボニ―（Ｒ）―ｐ―ヒドロキシフエニル
グリシンとから合成した（±）シス―７―〔２―
（ｐ―ヒドロキシフエニル）―２―ｔ―ブチルオ
キシカルボニルアミノアセトアミド〕―３―クロ
ロ―１―アザビシクロ〔４，２，０〕オクト―２
―エン―８―オン―２―カルボン酸，第三ブチル
エステル（ジアステレオ異性体混合物）104.3mg
（20m mole）に氷冷下塩化メチレン１mlおよび
トリフロロ酢酸１mlを加え同温度で1.5時間撹拌
する。減圧濃縮して得られる油状物質を高速液体
クロマトグラフイーに付し（カラム：マイクロボ
ンダパツクＣ―18，溶媒 ７％メタノール―
0.2N H2PO4）ジアステレオ異性体を分離する。
低極性異性体の分画を減圧濃縮しHP―10 10
ml（溶媒 メタノール：水＝１：１）で脱塩処理
し、10.5mg（28.7％）の目的物を得る。
〔α〕20゜
Ｄ：＋44゜（ｃ＝0.25，1N燐酸バツフア
ー PH7.0）
IRνKBr nax（cm-1）：1765，1695，1615，1520
NMR（D2O）δ：7.36（2H，ｄ，Ｊ＝8.8Hz），
6.96（2H，ｄ，Ｊ＝8.8Hz），5.36（1H，ｄ，
Ｊ＝4.6Hz），5.11（1H，ｓ），3.81−4.00（1H，
ｍ），2.42−2.58（2H，ｍ），1.59−1.77（1H，
ｍ），1.17−1.48（1H，ｍ）
次表に上記実施例２，４，７，９，10で得られ
た化合物の抗菌活性を示す。測定はHeart
Infusion Agar Dilution法（PH7.2）によつて行
つた。対照としてセフアゾリンとセフアレキシン
を用いた。[Formula] is exemplified. Examples of protecting groups for hydroxyl groups include benzyl group, benzyloxycarbonyl group, trityl group, tetrahydropyranyl group, and t-butyl group. Protecting groups for carboxyl groups include t-butyl group, benzyl group, p-methoxybenzyl group, p-
Examples include nitrobenzyl group and benzhydryl group. Examples of the protecting group for the thiol group include a benzyl group, a trityl group, a benzyloxycarbonyl group, and a p-nitrobenzyl group. Conventional methods can be applied to the introduction and removal of protective groups, as described in the aforementioned book Protective Group in Organic Chemistry.
This can be done according to the description in . As the method for removing the carboxylic acid protecting group (R 1 ), the method used in general chemistry of penicillin and cephalosporin is applied. Preferred methods include 1) catalytic reduction, 2) acid decomposition, 3) cleavage with Lewis acid, 4) hydrolysis, 5) reduction other than catalytic reduction using zinc-acetic acid, etc., 6) method using esterase, etc. be done. Regarding the starting material used in the present invention, the compound represented by the formula (-a), the manufacturing method thereof is disclosed in the specification of Japanese Patent Application No. 162008/1982 (Japanese Patent Application No. 87791/1983), but please refer to it. An example is shown below. An example is shown in the reference process diagram []. In the figure, compounds 6 and 8 are one type of starting materials for producing the compound of the present invention. In addition, in the figure, the manufacturing method of compound 1 is
It is disclosed in No. 34696 (Japanese Unexamined Patent Publication No. 128591/1983), but it is produced as shown in the reference examples below. An example is shown in the reference process diagram []. The compound of the present invention has a strong antibacterial effect against Gram-positive bacteria and Gram-negative bacteria, and is useful as a bactericidal agent and as a component of a disinfectant in the treatment of various infectious diseases. It is formulated with materials, excipients, diluents, etc., and administered as an injection, an oral drug, or a suppository depending on the dosage form. Embodiments of the present invention are illustrated below, but the present invention is not limited thereto. Example 1 (±)-cis-7-(2-phenyl-2-t-
butyloxycarbonylaminoacetamide)
-3-chloro-1-azabicyclo[4,2,
0] Production of oct-2-en-8-one-2-carboxylic acid, tertiary butyl ester: (The term “cis” refers to the stereochemistry of the 6th and 7th positions, and the same applies hereinafter.) (±)-cis-7- synthesized according to Reference Example 2
Amino-3-chloro-1-azabicyclo[4,
2,0] Oct-2-en-8-one-2-carboxylic acid, tert-butyl ester 150mg (0.55m
mole) in 3 ml of anhydrous methylene chloride. N-
166 mg (0.66 mmole) of t-butyloxycarbonyl-(R)-phenylglycine was dissolved in 5 ml of anhydrous tetrahydrofuran and cooled to -15 to -10°C.
0.66 ml of a solution of 1N-N-methylmorpholine in tetrahydrofuran and 0.66 ml of a solution of 1N ibutyl chloroformate in tetrahydrofuran are added dropwise, and the mixture is stirred at the same temperature for 20 minutes. The amine solution prepared above was added dropwise while maintaining this temperature, and then the temperature was gradually returned to room temperature, and the mixture was stirred overnight at room temperature. After adding 10 ml of methylene chloride to the reaction solution, wash with 10% citric acid, saturated sodium bicarbonate solution, and saturated saline in this order, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify with silica gel chromatography (Silica gel: Wako Pure Chemical Industries, Ltd. C
-200, 20 g, solvent ethyl acetate:n-hexane = 1:5 volume ratio, same hereinafter) 124 mg (yield 44.6%) of the target product (diastereoisomer mixture) was obtained. The physical properties of this material are as follows. IRν KBr nax (cm -1 ): 1780, 1730, 1680, 1655, 1550 NMR (CDCl 3 ) δ: 7.34 (5/2H, s), 7.31
(5/2H, s), 6.93 (1H, m), 5.63 (1H,
m), 5.30 (1/2H, dd, J=5.4, 6.8Hz),
5.11~5.22 (3/2H, m), 3.76~3.91 (1H,
m), 2.33-2.66 (2H, m), 1.52 (9H, s),
1.41 (9H, s), 0.92-1.97 (2H, m) Example 2 (6R, 7S) 7-(R)-phenylglycinamide-3-chloro-1-azabicyclo[4,
2,0] Oct-2-en-8-one-2-carboxylic acid (A) and (6S,7R) 7-(R)-phenylglycinamide-3-chloro-1-azabicyclo[4,2, 0] Octo-2-en-8
Production of -one-2-carboxylic acid (B) Synthesized according to the same method as in Example 1 (±) -
Cis-7-(R)-(2-phenyl-2-t-butyloxycarbonylaminoacetamide)-3
-Chloro-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid, tert-butyl ester (128.4 mg (0.25 m mole)) was added with 1 ml of methylene chloride and 1 ml of trifluoroacetic acid under ice cooling. and stir at the same temperature for 1.5 hours. The oily substance obtained by distilling off the solvent under reduced pressure was subjected to high performance liquid chromatography [Column: Micro Bonder Pack C]
-18 (manufactured by Waters), solvent 7% methanol
0.2N KH 2 PO 4 ] Separate diastereoisomers. Each separated eluted fraction was concentrated under reduced pressure to HP-10.
(Manufactured by Mitsubishi Kasei) Desalt with 10ml of resin (solvent methanol:water = 1:1) to obtain highly polar isomer (B).
9.4 mg and 7.6 mg of the less polar isomer (A) (total yield 19.1%)
I got it. Highly polar isomer (B) [α] 21° D: −75.8° (c=0.4, H 2 O) Melting point 300°C or higher (browning) IRν KBr nax (cm -1 ): 1765, 1700, 1550 NMR (D 2 O) δ: 7.49 (5H, s), 5.16 (1H,
d, J=4.7Hz), 5.05 (1H, s), 3.78−4.03
(1H, m), 2.53-2.67 (2H, m), 1.26-2.09
(2H, m) Low polar isomer (A) [α] 21° D: +34.0° (c = 0.35, H 2 O) Melting point 300°C or higher (browning) IRν KBr nax (cm -1 ): 1770, 1700, 1620 NMR (D 2 O) δ: 7.51 (5H, s), 5.36 (1H,
d, J=4.6Hz), 5.19 (1H, s), 3.83−4.00
(1H, m), 2.41-2.56 (2H, m), 1.49-1.79
(1H, m), 1.14-1.45 (1H, m) As mentioned later, since the low polar isomer (A) has a strong antibacterial effect, the absolute coordination of this isomer (A) is (6R, 7S ) was decided. Example 3 Cis-7-[(R)-2-phenyl-2-(4
-ethyl-2,3-dioxopiperazinylcarbonylamino)-acetamide]-3-chloro-1 azabicyclo[4,2,0]oct-2-
Production of ene-8-one-2-carboxylic acid, tertiary butyl ester: N-(4-ethyl-2,3-dioxopiperazinylcarbonyl)-(R)-phenylglycine
351mg (1.1m mole) of anhydrous tetrahydrofuran
Dissolve in 10 ml, add 1.2 ml of a 1N N-methylmorpholine solution in tetrahydrofuran and 1.1 ml of a 1N isobutyl chloroformate solution in tetrahydrofuran at -15°C to -10°C, and stir at the same temperature for 30 minutes. To this, cis-7-amino-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid, tert-butyl ester, hydrochloride
10 ml of a methylene chloride solution containing 309 mg (1 mmole) and 1.4 ml of a 1N N-methylmorpholine solution in tetrahydrofuran was added dropwise at the same temperature. Gradually return to room temperature and stir at the same temperature overnight. After concentration under reduced pressure, add ethyl acetate and add 10% citric acid.
Wash with saturated sodium bicarbonate solution and saturated saline solution in that order, and dry with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 273 mg (47.6%) of the target product (diastereoisomer mixture).
obtain. This was subjected to silica gel chromatography (30 g of silica gel, solvent ethyl acetate: n-hexane = 3:2) to separate diastereoisomers, resulting in 78.4 mg of low polar isomer and 112 mg of high polar isomer.
get. Low polar isomer [α] 21° D: -4.4° (c=0.5, MeOH) Melting point 181-183°C (decomposition) IRν KBr nax (cm -1 ): 1790, 1730, 1700, 1685,
1525, NMR (CDCl 3 ) δ: 9.90 (1H, d, J = 6.3Hz),
7.28−7.35 (5H, m), 7.17 (1H, d, J = 6.8
Hz), 5.46 (1H, d, J = 6.3Hz), 5.33 (1H,
dd, J=4.9, 6.8Hz), 3.66−4.15 (3H, m),
3.41-3.62 (4H, m), 2.41-2.56 (2H, m),
1.51 (9H, s), 0.88-1.76 (2H, m), 1.21
(3H, t, J=7.3Hz) Highly polar isomer [α] 21° D: -53.0° (c=0.5, MeCH) Melting point: 159-170℃ (decomposition) IRν KBr nax (cm -1 ): 1785 , 1725, 1700, 1685, 1525 NMR (CDCl 3 ) δ: 9.86 (1H, d, J = 6.3Hz),
7.35 (5H, s), 7.06 (1H, d, J=6.4Hz),
5.42 (1H, d, J = 6.3Hz), 5.19 (1H, dd,
J=4.9, 6.4Hz), 3.75-4.15 (3H, m), 3.45
−3.66 (4H, m), 2.50−2.63 (2H, m), 0.88
−2.44 (2H, m), 1.51 (9H, s), 1.22 (3H,
t, J=7.3Hz) Example 4 (6R, 7S)7-[(R)-2-phenyl-2-
(4-ethyl-2,3-dioxopiperazinylcarbonylamino)-acetamide]-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid Manufacturing: 50 mg of the low polar isomer synthesized according to Example 3 is dissolved in 2.5 ml of anhydrous methylene chloride, and 25 ml of trifluoroacetic acid is added under ice cooling. After stirring at the same temperature for 4 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (5 g of silica gel, solvent chloroform:methanol = 20:1) to obtain the desired product.
2.2 mg (48.8%) was obtained. [α]21° D=-1.2° (c=0.5, MeOH) Melting point Gradually decomposes at 175-190℃ IRν KBr nax (cm -1 ): 1780, 1720, 1685, 1520 NMR (CDCl 3 - CD 3 OD ) δ: 7.31−7.48 (5H,
m), 5.45 (1H, s), 5.32 (1H, d, J = 4.9
Hz), 3.75-4.29 (3H, m), 3.44-3.65 (4H,
m), 2.44-2.53 (2H, m), 1.15-2.20 (2H,
m), 1.23 (3H, t, J = 7.3Hz) Example 5 (6S, 7R) 7-[(R)-2-phenyl-2-
(4-ethyl-2,3-dioxopiperazinylcarbonylamino)-acetamide]-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid Manufacturing: The procedure of Example 4 was repeated except that 50 mg of the high polar isomer synthesized according to Example 3 was used instead of the low polar isomer in Example 4, and 17.7 mg (39.2 mg) of the target compound was obtained.
%) was obtained. [α] 21° D=-50.6° (c=0.52, MeOH) Melting point Gradually decomposes at 175-190℃ IRν KBr nax (cm -1 ): 1780, 1720, 1680, 1520 NMR (CDCl 3 - CD 3 OD ) δ: 7.31−7.48 (5H,
m), 5.37 (1H, s), 5.21 (1H, d, J = 4.9
Hz), 3.79-4.08 (3H, m), 3.44-3.65 (4H,
m), 2.61-2.69 (2H, m), 1.11-2.07 (2H,
m), 1.23 (3H, t, J = 7.3Hz) Example 6 (±)-cis-7-phenylacetamide-3
-Production of chloro-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid: (±)-cis- obtained according to the method of Reference Example 3
7-amino-3-chloro-1-azabicyclo[4,2,0]oct-2-ene-8-one-2
-Carboxylic acid/trifluoroacetate 150mg (0.45m
mole) is suspended in a mixed solvent of 2 ml of water and 2 ml of acetone, and 134 mg (1.5 mm mole) of sodium bicarbonate is added to this to make a homogeneous solution. To this, 84.2 mg (0.54 mmole) of phenylacetyl chloride was dissolved in 0.5 ml of acetone and added dropwise over 1 hour while cooling on ice. After stirring for an additional 3 hours, the reaction solution was adjusted to pH 2 with 1N hydrochloric acid.
Extracted with 5 ml of ethyl acetate, concentrated under reduced pressure,
Dry to obtain 80 mg (55.0%) of the target product. IRν KBr nax (cm -1 ): 1790, 1705, 1630, 1560 NMR (CDCl 3 ) δ: 7.29 (5H, s), 5.36 (1H,
d, J=5Hz), 3.79-3.99 (1H, m), 2.56
−2.75 (2H, m), 1.17−2.02 (2H, m) Example 7 Cis-7-[2-(2-Frill)-2-Syn-
Methoxyiminoacetamide]-3-chloro-
1-Azabicyclo [4,2,0] Octo-2-
Production of en-8-one-2-carboxylic acid: Dissolve 37.9 mg (0.244 mmole) of 2-(2-furyl)-2-synmethoxyiminoacetic acid in anhydrous methanol, add 344μ of a 0.65N methanol solution of sodium methylate to form the sodium salt, and evaporate the solvent under reduced pressure. The residue was further dried under vacuum to form a powder, and 1 ml of anhydrous benzene and 1 drop of anhydrous dimethylformamide were added to make a suspension, and then 29μ of oxalyl chloride was added.
(0.336 mmole) and stirred at room temperature for 1 hour.
It was concentrated under reduced pressure and 2 ml of anhydrous tetrahydrofuran was added to prepare acid chloride. On the other hand, cis-7-amino-3-chloro-1-azabicyclo[4,2,0]
Oct-2-ene-8-one-2-carboxylic acid
Add 1.6 ml of tetrahydrofuran and 1.6 ml of water to 57 mg (0.172 mmole) of trifluoroacetate, and add 120μ (0.862 mmole) of triethylamine under ice cooling to make a homogeneous solution. The acid chloride solution prepared earlier was added dropwise to this, and the mixture was further stirred for a time under ice cooling.
The pH was adjusted to 2 with 1N hydrochloric acid and extracted with ethyl acetate. Washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and further dried under vacuum to obtain a crude powder of the target product.
I got mg. Recrystallized from chloroform to give white crystals
Obtained 29.6 mg (46.7%). Melting point: 134-137℃ (decomposed) IRν KBr nax (cm -1 ): 1780, 1720, 1655, 1620, 1545 NMR (CDCl 3 - CD 3 OD) δ: 7.54 (1H, d, J
= 1.7Hz), 6.73 (1H, d, J = 3.7Hz), 6.56
(1H, dd, J = 1.7, 3.7Hz), 5.47 (1H, d,
J=4.9Hz), 4.01 (3H, s), 3.90−4.13 (1H,
m), 2.65-2.79 (2H, m), 1.70-2.20 (2H,
m) Example 8 (±)cis-7-[2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetylamino]-3-chloro-1
-Production of azibicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid: 2-(2-chloroacetamidothiazole-4
-yl)-2-syn-methoxyiminoacetic acid 122.6mg
(0.44m mole) was dissolved in 2.5ml of anhydrous methylene chloride, and 68μ of triethylamine (0.49m mole) was dissolved in 2.5ml of anhydrous methylene chloride.
92.0 mg (0.44 m mole) of phosphorus pentachloride is added while cooling with ice and salt. After stirring at the same temperature for 1 hour, 5 ml of n-hexane was added and stirring was continued for an additional 15 minutes under ice cooling. The liberated oil is obtained by decanting the n-hexane and is dissolved in 4 ml of tetrahydrofuran to prepare an acid chloride solution.
On the other hand, (±)-7- obtained in the same manner as Reference Example 3
Amino-3-chloro-1-azabicyclo[4,
2,0] Oct-2-ene-8-one-2-carboxylic acid trifluoroacetate 121.7mg (0.37m
mole) dissolved in 5 ml of 50% aqueous tetrahydrofuran and 0.2 ml (1.47 mmole) of triethylamine, add the previously prepared solution of acid chloride in tetrahydrofuran while stirring under ice cooling. After further stirring at the same temperature for 1 hour, 1N-hydrochloric acid was added.
Set the pH to 3. Water was added thereto, extracted with ethyl acetate, washed with saturated brine, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was thoroughly distilled off under reduced pressure to obtain 53.9 mg (30.5%) of the target compound as a powder. IRν KBr nax (cm -1 ): 1770, 1680, 1555, 1045 NMR (DMSO-d 6 ) δ: 9.38 (1H, d, J = 8
Hz), 7.37 (1H, s), 5.45 (1H, q, J = 5.8
Hz), 4.35 (2H, s) Example 9 (±)cis-7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamide]-3-chloro-1-azabicyclo[ 4,2,0]Oct-2-en-8-on-
Production of 2-carboxylic acid: Chloroacetamide compound 51.2 obtained in Example 8
mg (0.11 mm mole) in 1 ml of dimethylacetamide
and add 16.3 mg (0.22 mmole) of thiourea. After 14 hours of reaction at room temperature with stirring, 7 ml of ether are added, stirring is continued for a further 10 minutes and the liberated oil is obtained by removing the ether and decantation. Dissolve the remaining compound in a small amount of dimethyl sulfoxide, adsorb it on a 10ml column of HP-10, dissolve it in sulfoxide, and absorb it on a 10ml HP-10 column.
10 twice with 5 ml of resin [eluate: water-methanol (gradually increase the amount of methanol, and finally water:
Elution with methanol = 1:1)] yielded 15.2 mg (35.4%) of the desired product. Melting point 185.0-188.0℃ (decomposed) IRν KBr nax (cm -1 ): 1765, 1670, 1630, 1540, 1040 NMR (DMSO-d6) δ: 9.28 (1H, d, J=
8.8Hz), 7.17 (2H, s), 6.75 (1H, s), 5.44
(1H, q, 5.3Hz, 8.8Hz), 3.84 (3H, s),
1.24-2.52 (4H, m) Example 10 (6R,7S)7-(R)-p-hydroxyphenylglycinamide-3-chloro-1-azabicyclo[4,2,0]oct-2-ene- 8-
Production of on-2-carboxylic acid: According to the manufacturing method of Example 1 (±)-cis-7-
Amino-3-chloro-1-azabicyclo [4,
2,0] Oct-2-en-8-one-2-carboxylic acid, synthesized from tertiary butyl ester and Nt-butyloxycarbony(R)-p-hydroxyphenylglycine (±) Sis-7-[2-
(p-hydroxyphenyl)-2-t-butyloxycarbonylaminoacetamide]-3-chloro-1-azabicyclo[4,2,0]oct-2
-en-8-one-2-carboxylic acid, tert-butyl ester (diastereoisomer mixture) 104.3 mg
Add 1 ml of methylene chloride and 1 ml of trifluoroacetic acid to (20 mmole) under ice-cooling, and stir at the same temperature for 1.5 hours. The oily substance obtained by concentration under reduced pressure was subjected to high performance liquid chromatography (column: Microbondapak C-18, solvent: 7% methanol).
0.2NH 2 PO 4 ) to separate diastereoisomers. Concentrate the fraction of low polar isomer under reduced pressure to HP-10 10
ml (solvent methanol:water=1:1) to obtain 10.5 mg (28.7%) of the desired product. [α] 20°D: +44° (c=0.25, 1N phosphoric acid buffer PH7.0) IRν KBr nax (cm -1 ): 1765, 1695, 1615, 1520 NMR (D 2 O) δ: 7.36 (2H, d , J=8.8Hz),
6.96 (2H, d, J = 8.8Hz), 5.36 (1H, d,
J=4.6Hz), 5.11 (1H, s), 3.81−4.00 (1H,
m), 2.42-2.58 (2H, m), 1.59-1.77 (1H,
m), 1.17-1.48 (1H, m) The following table shows the antibacterial activity of the compounds obtained in Examples 2, 4, 7, 9, and 10 above. Measurement is Heart
This was done by the Infusion Agar Dilution method (PH7.2). Cefazolin and cephalexin were used as controls.
【表】
参考例 １
（±）シス―７―アジド―３―クロロ―２―ｔ
―ブチルオキシカルボニル―１―アザビシクロ
〔４，２，０〕オクト―２―エン―８―オンの
製造：
本化合物は以下ａ），ｂ），ｃ），ｄ）の工程を
経て製造される。
ａ） （±）シス―７―アジド―３―フエニルチ
オ―１―アザビシクロ〔４，２，０〕―オクタ
ン―８―オン―２―カルボン酸，第三ブチルエ
ステルの製造：
後記参考例４により製造された（±）シス―
７―アジド―１―アザビシクロ〔４，２，０〕
オクト―２―エン―８―オン―２―カルボン
酸，第三ブチルエステル528mg（2m mole）を
無水ベンゼン15mlに溶解しこれにチオフエノー
ル0.2ml（2m mole）およびピペリジン0.2ml
（2m mole）を添加し、室温で２時間撹拌す
る。
反応後反応液を10％クエン酸、飽和食塩水で
洗浄後無水硫酸ナトリウムで乾燥する。減圧下
溶媒を留去し、得られる油状残渣をシリカゲル
カラムクロマトグラフイー〔30ｇ、溶出溶媒
酢酸エチル―ｎ―ヘキサン（１：４）に付し精
製すると目的化合物を720mg（96.3％）を得る。
融点 77.5−78.0℃
IRνKBr nax（cm-1）：2110，1765，1745
NMR（CDCl3）δ：7.28−7.60（5H，ｍ），
4.78，（1H，ｄ，Ｊ＝５Hz），4.33（1H，ｓ），
3.78−3.98（1H，ｍ），3.81（1H，ｓ），1.50−
2.34（4H，ｍ），1.42（9H，ｓ）
ｂ） （±）シス―７―アジド―３―フエニルス
ルフイニル―１―アザビシクロ〔４，２，０〕
オクタン―８―オン―２―カルボン酸，第三ブ
チルエステルの製造：
前記参考例１―ａ）で得られる３―フエニル
チオ体480mg（1.28m mole）を50mlの無水クロ
ロホルムに溶解し、氷冷下ｍ―クロロ過安息香
酸240mg（1.41m mole）を添加する。撹拌しな
がら氷冷下30分反応後、反応液を飽和重曹水、
飽和食塩水で洗浄し次いで無水硫酸ナトリウム
で乾燥する。減圧下に溶媒を留去すると目的物
500mg（99.9ｇ）が得られる。
融点 95.5−96.5℃
IRνKBr nax（cm-1）：2120，2100，1780，1735，1035
NMR（CDCl3）δ：7.55−7.91（5H，ｍ），4.87
（1H，ｄ，Ｊ＝4.6Hz），4.05（1H，ｓ），3.90
−4.10（1H，ｍ），3.10（1H，ｓ），1.70−2.84
（4H，ｍ），1.30（9H，ｓ）
ｃ） （±）シス―７―アジド―３―クロロ―３
―フエニルスルフイニル―１―アザビシクロ
〔４，２，０〕―オクタン―８―オン―２―カ
ルボン酸，第三ブチルエステルの製造：
前記参考例１―ｂ）で得られるスルホキシド
化合物109mgを無水塩化メチレン１mlに溶解し、
酸化カルシウム23.5mg（0.42m mole）を添加
する。氷冷下塩化スルフイニル27μ（0.34m
mole）を添加する。撹拌しつつ氷冷下１時間
反応後、反応液を10％クエン酸、飽和重曹水、
次いで飽和食塩水で洗浄し、次いで無水硫酸ナ
トリウムで乾燥する。溶媒を減圧留去し、得ら
れる油状残渣をシリカゲルクロマトグラフイー
（シリカゲル５ｇ溶出溶媒 酢酸エチル―ｎ―
ヘキサン＝１：５）に付し精製すると油状目的
物が66.5mg（56.1％）得られる。
IRνCHCl3 nax（cm-1）：2120，1770，1735，1055
NMR（CDCl3）δ：7.53―8.00（5H，ｍ），4.90
（1H，ｄ，Ｊ＝５Hz），4.43（1H，ｓ），4.15
−4.35（1H，ｍ），1.83−2.85（4H，ｍ），1.38
（9H，ｓ）
ｄ） （±）シス―７―アジド―３―クロロ―１
―アザビシクロ〔４，２，０〕オクト―２―エ
ン―８―オン―２―カルボン酸，第三ブチルエ
ステルの製造：
前記参考例１―ｃ）と同様にして得られる３
―クロロ―３―フエニルスルフイニル化合物
1.3ｇ（3.06m mole）を四塩化炭素100ml中で
６時間加熱還流する。反応終了後減圧下溶媒を
留去して得られる残渣をシリカゲルクロマトグ
ラフイー（シリカゲル100ｇ、溶出溶媒：酢酸
エチル：ｎ―ヘキサン＝１：５）に付し精製す
ると目的物が596mg（65.2％）得られる。
融点 96−97℃
IRνKBr nax（cm-1）：2120，1765，1735，1630
PMR（CDCl3）δ：4.93（1H，ｄ，Ｊ＝５Hz），
3.72−3.92（1H，ｍ），2.56−2.70（2H，ｍ），
1.86−2.32（2H，ｍ），1.55（9H，ｓ）
CMR（CDCl3）δ：127.7，125.0
参考例 ２
（±）シス―７―アミノ―３―クロロ―１―ア
ザビシクロ〔４，２，０〕オクト―２―エン―
８―オン―２―カルボン酸，第三ブチルエステ
ルの製造：
参考例１―ｄ）で得られるアジド体350mg
（1.17m mole）をエタノール20mlに溶解し、1N
―塩酸1.2mlおよび10％Pd―C70mgを添加する。
常温常圧で水素ガスを３時間通気後パラジウム炭
素を去し、液を減圧下濃縮し得られる固体を
水に溶解しエーテル洗浄する。水層に重曹を添加
して弱アルカリ性とした後、酢酸エチルで抽出し
た。
酢酸エチル層を飽和食塩水で洗浄後無水硫酸ナ
トリウムで乾燥する。溶媒を十分に減圧留去し目
的物を218.4mg（68.4％）粉末状として得る。
融点 102.5−104.5℃
IRνKBr nax（cm-1）：1770，1720，1620
NMR（CDCl3）δ：4.43（1H，ｄ，Ｊ＝５Hz），
3.52−3.90（1H，ｍ），2.52−2.72（2H，ｍ），
2.22（2H，br），1.87−2.17（2H，ｍ），1.55
（9H，ｓ）
参考例 ３
（±）シス―７―アミノ―３―クロロ―１―ア
ザビシクロ〔４，２，０〕オクト―２―エン―
８―オン―２―カルボン酸・トリフロロ酢酸塩
の製造：
参考例２で得られるアミノ―エステル体102.2
mg（0.31m mole）に氷冷下トリフロロ酢酸１ml
を添加し、室温で30分撹拌する。減圧下溶媒を留
去し得られる油状残渣にエーテルを添加し粉末状
とした後、吸引取する。
更に真空乾燥し目的物を75.5mg（60.9％）得
る。
融点 208−220℃（分解）
IRνKBr nax（cm-1）：1795，1630
参考例 ４
（±）シス―アジド―１―アザビシクロ〔４，
２，０〕オクト―２―エン―８―オン―２―カ
ルボン酸，第三ブチルエステルの製造：
本化合物は、以下の１），２）の工程を経て製
造される。
１） ２―〔４―（３―ブテニル）―３―アジド
―２―オキソアゼチジン―１―イル〕―２―ジ
エチルホスホノ酢酸―ｔ―ブチルエステルの製
造。
ｔ―ブチル―α―アミノジエチルホスホノア
セテート447mg（1.78m mole）を無水エーテル
25mlに溶かし４―ペンテン―１―アール164mg
（1.96m mole）を加え室温で１時間撹拌後、モ
レキユラーシープ（4A）〔和光純薬(株)製、以下
同じものを用いた〕200mgと無水硫酸マグネシ
ウム150mgを加えてさらに１時間撹拌した。
反応液を減圧過し液を減圧濃縮し淡黄色
の油状物を得た。これに無水ベンゼンを加え再
び減圧濃縮して淡黄色の油状物を得た。（この
ものは核磁気共鳴スペクトルでシツフ塩基の生
成を確かめた。）これに12.5mlのシクロヘキサ
ンと12.5mlの無水ベンゼンを加えて溶かし、ト
リエチルアミン0.369ml（2.66m mole）とモレ
キユラーシープを200mg加え、室温撹拌下、ア
ジドアセチルクロリド319mg（2.66m mole）を
12.5mlのシクロヘキサンに溶かした溶液を１時
間30分で滴下し、さらに30分間撹拌した。反応
液に10mlのベンゼンを加えて薄め、５％稀塩
酸、飽和重曹水、脱イオン水、飽和食塩水の順
で洗滌し、芒硝で乾燥し減圧濃縮して褐色の油
状物を得た。このものは目的化合物の粗製品と
同定した。この油状物をシリカゲル45ｇを充填
したカラムにチヤージし、展開溶媒（ｎ―ヘキ
サン：酢酸エチル＝１：２）を用いて溶出し、
２種類の異性体を得た。これらの物性値は以下
に示す通りであるが３位、４位の水素について
のシス異性体（345mg）、およびトランス異性体
（58mg）と同定した。併せて収率54.2％。各物
性値は以下の通り。
シス異性体 IRνCHCl3 nax（cm-1）：2120，1775，
1770（sh），1750，1740（sh），1645。
NMR（CDCl3）δ：6.13〜6.33（1H，ｍ），4.93
〜5.17（2H，ｍ），4.50〜4.93（2H，ｍ），3.80
〜4.40（5H，ｍ），1.93〜2.17（4H，ｍ），1.50
（9H，ｓ），1.33（6H，ｔ）
トランス異性体 IRνCHCl3 nax（cm-1）：2120，1780
，
1755，1750（sh），1650
NMR（CDCl3）δ：5.43〜6.20（1H，ｍ），4.80
〜5.30（2H，ｍ），3.75〜4.75（7H，ｍ），2.0
〜2.50（4H，ｍ），1.50（9H，ｄ），1.17（6H，
ｍ）
２） （±）シス―７―アジド―１―アザビシク
ロ〔４，２，０〕オクト―２―エン―８―オン
―２―カルボン酸，第三ブチルエステルの製
造。
上記１）で得られたシス、２―〔４―（３―
ブテニル）―３―アジド―２―オキソアゼチジ
ン―１―イル〕―２―ジエチルホスホノ酢酸―
ｔ―ブチルエステル298mg（0.716m mole）を
8.5mgのジオキサン、25mlの脱イオン水にとか
し、四酸化オスミウムを30mg加えて30分撹拌し
た。黒色反応液に粉末状の過沃素酸ソーダ4966
mg（2.32m mole）を20分で加え、一時間撹拌
した後、反応液をエーテル50mlで３回抽出し、
合せたエーテル層を飽和食塩水で洗い芒硝で乾
燥し減圧濃縮すると黒褐色の油状物が得られ
た。この油状物をシリカゲル５ｇを充填したカ
ラムにチヤージし、溶出溶媒（ベンゼン：酢酸
エチル＝１：２）を用いて溶出し、2.4―ジニ
トロフエニルヒドラジン反応陽性を示す画分を
集めて濃縮すると235mgの油状物を得た。この
油状物を15mlの無水アセトニトリルに溶かし、
室温で撹拌しながら窒素気流下27.1mg（0.536m
mole）の50％水素化ナトリウムを加える。20
分撹拌後反応液を２％酢酸水（20ml）中に注入
しエーテル50mlで４回抽出し、エーテル層を飽
和食塩水で洗滌、芒硝で乾燥し減圧濃縮すると
180mgの油状物を得た。この油状物をシリカゲ
ル５ｇを充填したカラムにチヤージし、溶出溶
媒（ｎ―ヘキサン：酢酸エチル＝3.5：１）を
用いて溶出し、91mgの目的化合物の白色結晶を
得た。収率51％。
このものの物性値は下記の通り。
融点 64.5〜65.5℃
IRνCHCl3 nax（cm-1）：2130，1790，1730，1640
NMR（CDCl3）δ：6.30（1H，ｔ，Ｊ＝４Hz），
4.93（1H，ｄ，Ｊ＝５Hz），3.80（1H，ｑ），
1.6〜2.6（4H，ｍ），1.52（9H，ｓ）。[Table] Reference example 1 (±)cis-7-azido-3-chloro-2-t
-Production of butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2-en-8-one: This compound is produced through the following steps a), b), c), and d). a) Production of (±)cis-7-azido-3-phenylthio-1-azabicyclo[4,2,0]-octan-8-one-2-carboxylic acid, tert-butyl ester: (±) cis produced according to Reference Example 4 described later
7-azido-1-azabicyclo[4,2,0]
Dissolve 528 mg (2 m mole) of oct-2-en-8-one-2-carboxylic acid, tert-butyl ester in 15 ml of anhydrous benzene and add 0.2 ml (2 m mole) of thiophenol and 0.2 ml of piperidine.
(2 mmole) and stirred at room temperature for 2 hours. After the reaction, the reaction solution was washed with 10% citric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting oily residue was subjected to silica gel column chromatography [30 g, elution solvent
Purification with ethyl acetate-n-hexane (1:4) yields 720 mg (96.3%) of the desired compound. Melting point 77.5-78.0℃ IRν KBr nax (cm -1 ): 2110, 1765, 1745 NMR (CDCl 3 ) δ: 7.28-7.60 (5H, m),
4.78, (1H, d, J=5Hz), 4.33 (1H, s),
3.78−3.98 (1H, m), 3.81 (1H, s), 1.50−
2.34 (4H, m), 1.42 (9H, s) b) (±) cis-7-azido-3-phenylsulfinyl-1-azabicyclo[4,2,0]
Production of octane-8-one-2-carboxylic acid, tertiary butyl ester: 480 mg (1.28 mmole) of the 3-phenylthio compound obtained in Reference Example 1-a) is dissolved in 50 ml of anhydrous chloroform, and 240 mg (1.41 mmole) of m-chloroperbenzoic acid is added under ice cooling. After reacting for 30 minutes under ice-cooling with stirring, the reaction solution was diluted with saturated sodium bicarbonate solution,
Wash with saturated saline and then dry with anhydrous sodium sulfate. When the solvent is distilled off under reduced pressure, the desired product is obtained.
500 mg (99.9 g) is obtained. Melting point 95.5-96.5℃ IRν KBr nax (cm -1 ): 2120, 2100, 1780, 1735, 1035 NMR (CDCl 3 ) δ: 7.55-7.91 (5H, m), 4.87
(1H, d, J=4.6Hz), 4.05 (1H, s), 3.90
−4.10 (1H, m), 3.10 (1H, s), 1.70−2.84
(4H, m), 1.30 (9H, s) c) (±)cis-7-azido-3-chloro-3
-Production of phenylsulfinyl-1-azabicyclo[4,2,0]-octan-8-one-2-carboxylic acid, tert-butyl ester: 109 mg of the sulfoxide compound obtained in Reference Example 1-b) was dissolved in 1 ml of anhydrous methylene chloride,
Add 23.5 mg (0.42 mmole) of calcium oxide. Sulfinyl chloride 27μ (0.34m) under ice cooling
mole). After reacting for 1 hour under ice-cooling with stirring, the reaction solution was mixed with 10% citric acid, saturated sodium bicarbonate solution,
Next, it is washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting oily residue was subjected to silica gel chromatography (5 g of silica gel eluent: ethyl acetate-n-
Purification with hexane (1:5) yields 66.5 mg (56.1%) of the desired oily product. IRν CHCl3 nax (cm -1 ): 2120, 1770, 1735, 1055 NMR (CDCl 3 ) δ: 7.53-8.00 (5H, m), 4.90
(1H, d, J=5Hz), 4.43 (1H, s), 4.15
−4.35 (1H, m), 1.83 −2.85 (4H, m), 1.38
(9H,s) d) (±)cis-7-azido-3-chloro-1
-Production of azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid, tert-butyl ester: 3 obtained in the same manner as Reference Example 1-c) above
-Chloro-3-phenylsulfinyl compound
1.3 g (3.06 mmole) is heated under reflux for 6 hours in 100 ml of carbon tetrachloride. After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel chromatography (100 g of silica gel, elution solvent: ethyl acetate: n-hexane = 1:5) to obtain 596 mg (65.2%) of the target product. can get. Melting point 96-97℃ IRν KBr nax (cm -1 ): 2120, 1765, 1735, 1630 PMR (CDCl 3 ) δ: 4.93 (1H, d, J = 5Hz),
3.72-3.92 (1H, m), 2.56-2.70 (2H, m),
1.86−2.32 (2H, m), 1.55 (9H, s) CMR (CDCl 3 ) δ: 127.7, 125.0 Reference example 2 (±) cis-7-amino-3-chloro-1-azabicyclo[4,2,0 ]Octo-2-en-
Production of 8-one-2-carboxylic acid, tertiary butyl ester: 350 mg of azide compound obtained in Reference Example 1-d)
(1.17m mole) in 20ml of ethanol, 1N
- Add 1.2 ml of hydrochloric acid and 70 mg of 10% Pd-C.
After bubbling hydrogen gas for 3 hours at room temperature and pressure, the palladium on carbon was removed, the liquid was concentrated under reduced pressure, and the resulting solid was dissolved in water and washed with ether. The aqueous layer was made weakly alkaline by adding sodium bicarbonate, and then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was thoroughly distilled off under reduced pressure to obtain 218.4 mg (68.4%) of the desired product in powder form. Melting point 102.5-104.5℃ IRν KBr nax (cm -1 ): 1770, 1720, 1620 NMR (CDCl 3 ) δ: 4.43 (1H, d, J = 5Hz),
3.52-3.90 (1H, m), 2.52-2.72 (2H, m),
2.22 (2H, br), 1.87−2.17 (2H, m), 1.55
(9H,s) Reference example 3 (±)cis-7-amino-3-chloro-1-azabicyclo[4,2,0]oct-2-ene-
Production of 8-one-2-carboxylic acid trifluoroacetate: Amino-ester compound 102.2 obtained in Reference Example 2
mg (0.31m mole) to 1ml of trifluoroacetic acid under ice cooling.
and stir at room temperature for 30 minutes. Ether is added to the oily residue obtained by distilling off the solvent under reduced pressure to form a powder, which is then sucked off. Further vacuum drying yields 75.5 mg (60.9%) of the desired product. Melting point 208-220℃ (decomposition) IRν KBr nax (cm -1 ): 1795, 1630 Reference example 4 (±)cis-azido-1-azabicyclo[4,
2,0] Production of oct-2-en-8-one-2-carboxylic acid, tertiary butyl ester: This compound is produced through the following steps 1) and 2). 1) Production of 2-[4-(3-butenyl)-3-azido-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid-t-butyl ester. 447mg (1.78m mole) of t-butyl-α-aminodiethylphosphonoacetate was dissolved in anhydrous ether.
Dissolve in 25ml 4-pentene-1-A 164mg
(1.96 mmole) was added and stirred at room temperature for 1 hour, then 200 mg of Molecular Sheep (4A) [manufactured by Wako Pure Chemical Industries, Ltd., the same product was used hereinafter] and 150 mg of anhydrous magnesium sulfate were added and stirred for another 1 hour. did. The reaction solution was filtered under reduced pressure and the liquid was concentrated under reduced pressure to obtain a pale yellow oil. Anhydrous benzene was added to this and the mixture was again concentrated under reduced pressure to obtain a pale yellow oil. (The formation of Schiff's base was confirmed by nuclear magnetic resonance spectroscopy.) To this, 12.5 ml of cyclohexane and 12.5 ml of anhydrous benzene were added and dissolved, and 0.369 ml (2.66 mm mole) of triethylamine and 200 mg of molecular sheep were added. Add 319 mg (2.66 mmole) of azidoacetyl chloride under stirring at room temperature.
A solution dissolved in 12.5 ml of cyclohexane was added dropwise over 1 hour and 30 minutes, and the mixture was further stirred for 30 minutes. The reaction solution was diluted with 10 ml of benzene, washed successively with 5% diluted hydrochloric acid, saturated aqueous sodium bicarbonate, deionized water, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. This product was identified as a crude product of the target compound. This oil was charged to a column packed with 45 g of silica gel and eluted using a developing solvent (n-hexane: ethyl acetate = 1:2).
Two types of isomers were obtained. These physical property values are as shown below, and they were identified as a cis isomer (345 mg) and a trans isomer (58 mg) regarding hydrogen at the 3rd and 4th positions. Combined yield is 54.2%. The physical property values are as follows. Cis isomer IRν CHCl3 nax (cm -1 ): 2120, 1775,
1770 (sh), 1750, 1740 (sh), 1645. NMR ( CDCl3 ) δ: 6.13-6.33 (1H, m), 4.93
~5.17 (2H, m), 4.50 ~ 4.93 (2H, m), 3.80
~4.40 (5H, m), 1.93 ~ 2.17 (4H, m), 1.50
(9H, s), 1.33 (6H, t) Trans isomer IRν CHCl3 nax (cm -1 ): 2120, 1780
，
1755, 1750 (sh), 1650 NMR ( CDCl3 ) δ: 5.43-6.20 (1H, m), 4.80
~5.30 (2H, m), 3.75 ~ 4.75 (7H, m), 2.0
~2.50 (4H, m), 1.50 (9H, d), 1.17 (6H,
m) 2) Production of (±)cis-7-azido-1-azabicyclo[4,2,0]oct-2-en-8-one-2-carboxylic acid, tert-butyl ester. Cis obtained in 1) above, 2-[4-(3-
butenyl)-3-azido-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid-
298mg (0.716m mole) of t-butyl ester
8.5 mg of dioxane was dissolved in 25 ml of deionized water, 30 mg of osmium tetroxide was added, and the mixture was stirred for 30 minutes. Powdered sodium periodate 4966 in black reaction solution
mg (2.32 mmole) was added over 20 minutes, and after stirring for 1 hour, the reaction solution was extracted three times with 50 ml of ether.
The combined ether layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a dark brown oil. This oil was charged to a column packed with 5 g of silica gel, eluted using an elution solvent (benzene: ethyl acetate = 1:2), and fractions showing a positive 2.4-dinitrophenylhydrazine reaction were collected and concentrated to yield 235 mg. of oil was obtained. Dissolve this oil in 15 ml of anhydrous acetonitrile,
27.1 mg (0.536 m
Add mole) of 50% sodium hydride. 20
After stirring for several minutes, the reaction solution was poured into 2% aqueous acetic acid (20 ml), extracted four times with 50 ml of ether, and the ether layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
180 mg of oil was obtained. This oily substance was charged to a column packed with 5 g of silica gel and eluted using an elution solvent (n-hexane:ethyl acetate=3.5:1) to obtain 91 mg of the target compound as white crystals. Yield 51%. The physical properties of this product are as follows. Melting point 64.5-65.5℃ IRν CHCl3 nax (cm -1 ): 2130, 1790, 1730, 1640 NMR (CDCl 3 ) δ: 6.30 (1H, t, J = 4Hz),
4.93 (1H, d, J=5Hz), 3.80 (1H, q),
1.6-2.6 (4H, m), 1.52 (9H, s).
Claims (1)
ルホンアミド基を示し、ｎは０から２の整数を表
わし、Halはハロゲン原子を、Ｒはカルボン酸ま
たはカルボン酸エステルを表わす）で表わされる
セフアロスポリン類縁体およびその塩類。 ２ ６位、７位の水素がシスである特許請求の範
囲第１項記載の化合物。 ３ Halが塩素原子である特許請求の範囲第１ま
たは２項記載の化合物。[Claims] 1. General formula (In the formula, A 1 represents a hydroxyl group, an amino group, or a methylsulfonamide group, n represents an integer from 0 to 2, Hal represents a halogen atom, and R represents a carboxylic acid or carboxylic acid ester) Analogs and their salts. 2. The compound according to claim 1, wherein the hydrogens at the 6th and 7th positions are cis. 3. The compound according to claim 1 or 2, wherein Hal is a chlorine atom.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9203579A JPS5616491A (en) | 1979-07-19 | 1979-07-19 | Cephalosporin analog |
| NO800315A NO155548C (en) | 1979-02-10 | 1980-02-06 | PROCEDURE FOR THE PREPARATION OF OPTICALLY ACTIVE CEPHALOSPORIN ANALOGS. |
| CA000345348A CA1171373A (en) | 1979-02-10 | 1980-02-07 | Optically active cephalosporin analogs |
| DK054880A DK170255B1 (en) | 1979-02-10 | 1980-02-08 | Analogous Process for Preparation of Optically Active Cephalosporin Analogs |
| AU55382/80A AU5538280A (en) | 1979-02-10 | 1980-02-08 | 1-azabicyclo (4,2,0) oct-2-em derivatives |
| ES488428A ES8101591A1 (en) | 1979-02-10 | 1980-02-08 | A procedure for the preparation of cefalosporine analogues. (Machine-translation by Google Translate, not legally binding) |
| EP80100666A EP0014476B1 (en) | 1979-02-10 | 1980-02-08 | Optically active acylated cephalosporin analogs, processes for their preparation and pharmaceutical compositions comprising them |
| DE8080100666T DE3064509D1 (en) | 1979-02-10 | 1980-02-08 | Optically active acylated cephalosporin analogs, processes for their preparation and pharmaceutical compositions comprising them |
| ES495037A ES495037A0 (en) | 1979-02-10 | 1980-09-12 | A PROCEDURE FOR THE PRODUCTION OF OPTICALLY ACTIVE COMPOUNDS OF CEPHALOSPORIN ANALOGS |
| NO841499A NO841499L (en) | 1979-02-10 | 1984-04-13 | PROCEDURE FOR THE PREPARATION OF OPTICALLY ACTIVE CEPHALOSPORIN ANALOGUE |
| MX9203636A MX9203636A (en) | 1979-02-10 | 1992-06-26 | ANALOG COMPOUNDS OF CEPHALOSPORIN AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9203579A JPS5616491A (en) | 1979-07-19 | 1979-07-19 | Cephalosporin analog |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5616491A JPS5616491A (en) | 1981-02-17 |
| JPH0240668B2 true JPH0240668B2 (en) | 1990-09-12 |
Family
ID=14043263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9203579A Granted JPS5616491A (en) | 1979-02-10 | 1979-07-19 | Cephalosporin analog |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5616491A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60174787A (en) * | 1984-02-21 | 1985-09-09 | Kyowa Hakko Kogyo Co Ltd | 3-position-substituted carbacephem compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS49133594A (en) * | 1972-11-06 | 1974-12-21 | ||
| JPS5321188A (en) * | 1976-08-09 | 1978-02-27 | Shionogi & Co Ltd | Cephalosporin analogs |
| JPS549296A (en) * | 1977-04-02 | 1979-01-24 | Hoechst Ag | Cephem derivative and its preparation |
-
1979
- 1979-07-19 JP JP9203579A patent/JPS5616491A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS49133594A (en) * | 1972-11-06 | 1974-12-21 | ||
| JPS5321188A (en) * | 1976-08-09 | 1978-02-27 | Shionogi & Co Ltd | Cephalosporin analogs |
| JPS549296A (en) * | 1977-04-02 | 1979-01-24 | Hoechst Ag | Cephem derivative and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5616491A (en) | 1981-02-17 |
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