CN85106733A - Process for the preparation of novel cephalosporin compounds - Google Patents
Process for the preparation of novel cephalosporin compounds Download PDFInfo
- Publication number
- CN85106733A CN85106733A CN85106733.6A CN85106733A CN85106733A CN 85106733 A CN85106733 A CN 85106733A CN 85106733 A CN85106733 A CN 85106733A CN 85106733 A CN85106733 A CN 85106733A
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- -1 cephalosporin compounds Chemical class 0.000 title claims abstract description 118
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 38
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims description 57
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 153
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 44
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 35
- 125000006239 protecting group Chemical group 0.000 claims abstract description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 150000002148 esters Chemical class 0.000 claims abstract description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 10
- 125000002541 furyl group Chemical group 0.000 claims abstract description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 104
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 90
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 72
- 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 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 125000003277 amino group Chemical group 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 28
- 159000000000 sodium salts Chemical class 0.000 claims description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 150000002500 ions Chemical class 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229940074654 diuril Drugs 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 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 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 3
- 125000004436 sodium atom Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- 150000001768 cations Chemical group 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 22
- 239000002585 base Substances 0.000 description 20
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- 238000001035 drying Methods 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 229960001866 silicon dioxide Drugs 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001782 cephems Chemical class 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 210000002700 urine Anatomy 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 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 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 230000002152 alkylating effect Effects 0.000 description 5
- 239000003292 glue Substances 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 235000009518 sodium iodide Nutrition 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001733 carboxylic acid esters Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-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
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QMXZLJNHSDVYNX-CYBMUJFWSA-N C1[C@@H]2N(C1=O)C(=C(CS2)C=CC3=CC=CC=C3)C(=O)O Chemical compound C1[C@@H]2N(C1=O)C(=C(CS2)C=CC3=CC=CC=C3)C(=O)O QMXZLJNHSDVYNX-CYBMUJFWSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002027 dichloromethane extract Substances 0.000 description 3
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- SDEIKNWRVHSKQN-FFFFSGIJSA-N (6R)-7-amino-3-[2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound Cc1ncsc1C=CC1=C(N2[C@H](SC1)C(N)C2=O)C(O)=O SDEIKNWRVHSKQN-FFFFSGIJSA-N 0.000 description 2
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- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- 230000008025 crystallization Effects 0.000 description 2
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- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
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- YKFFACBRWIUUOD-UHFFFAOYSA-N 4-chloro-2,2-dimethylbutanoic acid Chemical compound OC(=O)C(C)(C)CCCl YKFFACBRWIUUOD-UHFFFAOYSA-N 0.000 description 1
- TZCYLJGNWDVJRA-UHFFFAOYSA-N 6-chloro-1-hydroxybenzotriazole Chemical compound C1=C(Cl)C=C2N(O)N=NC2=C1 TZCYLJGNWDVJRA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
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- JDMUIZKDUAEHOM-UHFFFAOYSA-N O(O)O.C(C)N1OC(=CC1)C1=C(C=CC=C1)S(=O)(=O)O Chemical compound O(O)O.C(C)N1OC(=CC1)C1=C(C=CC=C1)S(=O)(=O)O JDMUIZKDUAEHOM-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 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
- 229920000388 Polyphosphate Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000190932 Rhodopseudomonas Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- PAAZCQANMCYGAW-UHFFFAOYSA-N acetic acid;2,2,2-trifluoroacetic acid Chemical compound CC(O)=O.OC(=O)C(F)(F)F PAAZCQANMCYGAW-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000006177 alkyl benzyl group Chemical group 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
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- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AMLOVCZDAFXPKB-UIDYPRJRSA-N benzhydryl (6R)-7-amino-3-[2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)OC(=O)C1=C(CS[C@H]2N1C(C2N)=O)C=CC1=C(N=CS1)C AMLOVCZDAFXPKB-UIDYPRJRSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 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
- 125000001246 bromo group Chemical group Br* 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- QALAKUHQOSUJEU-UHFFFAOYSA-N calcium;magnesium Chemical compound [Mg+2].[Ca+2] QALAKUHQOSUJEU-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- ZEGDXSGIGIQDPG-UHFFFAOYSA-N carbon dioxide;magnesium Chemical compound [Mg].O=C=O ZEGDXSGIGIQDPG-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- HVBMYHDTXIDFKE-UHFFFAOYSA-N diethyl hydrogen phosphate;ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O.CCOP(O)(=O)OCC HVBMYHDTXIDFKE-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-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
- 150000002576 ketones Chemical class 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 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
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- WHIXAQMINGAVQI-UHFFFAOYSA-N n,n-diethyl-4-(iminomethylideneamino)cyclohexan-1-amine Chemical compound CCN(CC)C1CCC(N=C=N)CC1 WHIXAQMINGAVQI-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229950000477 triflutate Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new cephalosporin compound (cis isomer) shown by a general formula (I) and capable of being used as an antibacterial, and a preparation method of salts or esters of the compound (I) which can be used as a medicine. Wherein R is1Is amino or protected amino; r2Is lower alkyl, carboxymethyl or protected carboxymethyl; r3Is a hydrogen atom, a salt-forming cation or a carboxyl protecting group; a is unsubstituted or substituted phenyl, unsubstituted or substituted furyl, unsubstituted or substituted thiazolyl, or unsubstituted or substituted 3-lower alkylthiazolyl.
Description
The salt and the ester that the present invention relates to can be used as the new cephalosporin compound of antibiotic and can make medicine.More specifically, the cephalosporin compound that the present invention relates to (cis-isomeride) has-the 2-(substituted imido 7 of cephem nuclear)-2-(2-aminothiazole base)-the ethanoyl side chain, and have at its 3-beta substitution vinyl side chain.The present invention also relates to the pharmaceutical composition of new cephalosporin compound as effective ingredient.The present invention relates to the method for producing new cephalosporin compound in addition.
As Japanese patent application (early stage open) " Ko Kai " No.12 4790/80, No.212890A pair of No.122383/81 and UK Patent Application (early stage open) and cephalosporin compound of the present invention be more closely-related-and beta-lactam carried out report.Similar in appearance to cephalosporin compound of the present invention, above-mentioned early stage disclosed Japanese patent application is carried, and these known cephalosporin compounds have-the beta substitution vinyl, and it is as the side chain of 3 of cephem nuclears.Yet, new cephalosporin compound of the present invention, the substituent that β-position generated at the beta substitution vinyl groups of 3 of cephem nuclears is different from above-mentioned known cephalosporin compound.
Cynnematin type microbiotic is known to the strong efficiency of various Gram-positives and negative bacterium.The existing commercial applications of different types of half one synthetic cephalosporin compound, and be used for the various transmissible diseases of clinical treatment.But in these half one synthetic cephalosporin compounds, it is effective to the bacterial strain for the treatment of Rhodopseudomonas and proteus that a part is seldom only arranged.These known cephalosporin compounds also can be degraded by β-Beta Alanine enzyme that some anti-strain bacterium produces, they only (see N.E Brunswick " chemistry of cynnematin and penicillin and biology " E.H. fluorine woods chief editor to the very poor activity of clinical treatment index generation that some has infectation of bacteria, university press, New York, the N.Y1972 version, Chapter 11).
We are the present inventor, successful prepared new compound, be the cephalosporin compound shown in the following logical formula I simultaneously we have found that above-mentioned cephalosporin compound demonstrates the anti-microbial activity of wide region, these new compounds are not only effective in cure but also effective to some anti-strain to various gram negative bacteriums.We have finished the present invention.
The present invention at first provides the new cephalosporin compound shown in a kind of logical formula I:
R wherein
1Be an amino or protected amino; R
2Be a low alkyl group, a carboxymethyl or a protected carboxymethyl; R
3Be a hydrogen atom, all one's life salifiable positively charged ion or a carboxy protective group; A is monobasic or unsubstituted phenyl, and one replaces or unsubstituted furyl, the unsubstituted or thiazolyl that replaces or a 3-unsubstituted or that replace be rudimentary-alkyl-and this cephalosporin compound can be used as the salt or the ester of medicine.
Cephalosporin compound shown in the logical formula I of the present invention comprises two kinds of isomer, i.e. (E) isomer (trans-isomer(ide)) and (Z)-isomer (cis-isomeride), this is to be connected to 3 of cephem nuclears, and it is fixed that the substituting group on the ethylene double bond of beta substitution vinyl and the relative position of hydrogen atom come.Therefore cephalosporin compound of the present invention comprises (E)-isomer, (Z)-isomer and composition thereof.(the Z)-isomer of cephalosporin compound of the present invention is that group A and cephem integral part are connected on the vinyl double bond of 3 vinyl groups shown in the logical formula I with " suitable "-position.(the E)-isomer of cephalosporin compound is that group A and cephem integral part are connected on the two keys of ethylene vinyl of 3 of cephem nuclears with " anti--" position.Some nouns that are used in the specification sheets have as giving a definition:
" rudimentary " refers to alkyl or alkoxyl group or alkanoyl, unless otherwise indicated, only has 1 to 6 carbon atom.Amino protecting group, as amino protecting group by R
1The protection of representative amino group in, can comprise that one can be easy to the amido protecting group removed by acidolysis usually, for example, an alkoxycarbonyl group such as uncle's one butoxy carbonyl group; One carboxyl groups is as a formyl radical group and a chloracetyl group; With a trityl group.R
2" protect carboxymethyl group " of representative is; carboxyl in the carboxymethyl group is by being protected with the low-grade alkyl group esterification; these low-grade alkyl groups for example can be; methyl; ethyl; propyl group, just-butyl and the tertiary butyl or an aromatic yl group such as a phenyl or an aromatic alkyl group, as benzyl.
R
3The salifiable positively charged ion of the life of representative is general metallic cation, can be cash metallic cation, alkaline earth metal cation or ammonia.Preferentially select sodium cation for use.R
3The carboxyl-protecting group of representative is the carboxyl-protecting group that generally is used for cynnematin; it can be an aromatic yl group; one low-grade alkyl group, a lower alkoxy methyl group, a lower alkylthio methyl group and a lower alkane acyloxy methyl group and similar group thereof.R
3Group is the unsettled group of a metabolism also, this group hydrolysis at an easy rate in vivo and cracking, it can comprise, for example, one lower alkoxycarbonyl alkyl group, one rudimentary-alkyl-carbonyl oxyalkyl group, monobasic or unsubstituted (2-oxygen-1,3-dioxane pentadiene-4-yl) methyl group and similar group thereof.
The phenyl group of the unsubstituted or replacement of A representative comprises phenyl; Phenyl group with low-grade alkyl substituent, for example, right-tolyl; Fontanel is for phenyl group, as an adjacent phenyl-monofluoride base and a rudimentary alcoxyl phenyl group, as to an anisyl.
The A representative replaces or unsubstituted furan group comprises a 2-furyl group ,-3-furyl group and 5-nitro-2-furyl group.
" replacement or not substituted thiazolyl group " of A representative comprises the thiazol-2-yl group, thiazole-4-base group, thiazole-5-base group, 2-is rudimentary-alkyl thiazole-5-base group, (for example, 2-methylthiazol-5-base group),-4-methylthiazol-5-base group, 4-fontanel-thiazole-5-base group and 2,4-two fontanels thiazole-5-base group
" unsubstituted or replace 3-low alkyl group thiazolyl " of A representative comprises 3,4-dimethyl-5-thiaozolio base group.
First embodiment of preferentially selecting for use according to the present invention, provide general formula (I cephalosporin compound a),
R wherein
1Be an amino group or a protected amino group, R
2Be a low-grade alkyl group, a carboxymethyl group or a protected carboxymethyl group, R
3Be a hydrogen atom, all one's life salifiable positively charged ion or a carboxy protective group, Y is a hydrogen atom, a low-grade alkyl group, a lower alkoxy groups, or the plain atom of a fontanel.
Second embodiment that the present invention preferentially selects for use provides the cephalosporin compound of general formula (I b),
R wherein
1Be the amino group that an amino group or has been protected, R
2Be a low-grade alkyl group, the carboxymethyl group that carboxymethyl group or has protected, R
3Be a hydrogen atom, a salt-forming cation or a carboxy protective group, Z are a hydrogen atom, nitryl group or fontanelle atom.
The 3rd embodiment that the present invention preferentially selects for use provides the cephalosporin compound of general formula (I c),
R wherein
1Be the amino group that an amino group or has been protected, R
2Be a low-grade alkyl group, a carboxymethyl group, or a carboxymethyl group of having protected, R
3Be a hydrogen atom, a salifiable positively charged ion or a carboxy protective group.
The 4th embodiment that the present invention preferentially selects for use provides the cephalosporin compound shown in the general formula (I d),
R wherein
1Be the amino group that an amino group or has been protected, R
2Be a rudimentary (C
1～C
6) alkyl group, the carboxymethyl group that a carboxymethyl group or has been protected, R
3Be hydrogen atom, salt-forming cation or hydroxyl protecting group, and R is a low-grade alkyl group.
The 5th embodiment that the present invention preferentially selects for use provides the cynnematin shown in the general formula (I e)
R wherein
1Be the amino group that an amino group or has been protected, R
2Be a rudimentary (C
1～C
6) alkyl group, the carboxymethyl group that a carboxymethyl group or has been protected, R
3Be hydrogen atom, a salifiable positively charged ion or a carboxy protective group, Y are a hydrogen atom or a fontanelle atom, and n is 1 to 2 integer.
The 6th embodiment that the present invention preferentially selects for use provides the cephalosporin compound shown in the general formula (I f),
R wherein
1Be the amino group that an amino group or has been protected, R
2Be a rudimentary (C
1～C
6) alkyl group, the carboxymethyl group that a carboxymethyl group or has been protected, R
3Be a hydrogen atom, a salifiable positively charged ion or a carboxy protective group.
Logical formula I of the present invention or general formula (I is a) as follows to the embodiment that the new cephalosporin compound shown in (I f) is preferentially selected for use:
(A) 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)-kharophen]-the 3-(2-styryl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer, or cis-isomer, cis-isomeride).
(B) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-the 3-(2-phenyl vinyl)-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide) or cis-isomeride, cis isobutyl body).
(C) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2(ortho-fluorophenyl base) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or cis-isomeride, cis-isomer).
(D) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2(ortho-fluorophenyl base) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or, cis-isomeride, cis-isomer).
(E) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-the 3-[2(2-(2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomer).
(F) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-the 3-[2(2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer, or cis-isomeride, cis-isomeride).
(G) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-(5-nitro 2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomeride).
(H) [2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(5-nitro-2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomer).
(I) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-(thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomer).
(J) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-thiazole-4-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomer).
(K) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer, or cis-isomer, cis-isomer).
(L) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or, or cis-isomer, cis-isomer).
(M) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide) or cis-isomer, cis-isomeride).
(N) kharophen 7-[2-spy-butoxy carbonyl methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or cis-isomer, cis-isomeride).(O) kharophen 7-[2-carboxyl methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide), or cis-isomer, cis-isomer).
(P) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide), or cis-isomer, cis-isomeride).
(Q) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide) or cis-isomer, cis-isomer).
(R) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-(2-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide) or cis-isomer, cis-isomeride).
(S) kharophen 7-[2-methoxyimino-thiazolamine-4-yl)]-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer(ide) or cis-isomer, cis-isomer).
(T) kharophen 7-[2-methoxyimino-2-(2-amino-thiazolyl--4-yl)]-3-[2-(2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or cis-isomer, cis-isomer).
(U) kharophen 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl)]-3-[2-(3, the vinyl of 4-dimethyl-5-thiazolio)]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or cis-isomer, cis-isomer) iodide or trifluoro-acetate.
(V) kharophen 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)]-3-[2-(3, the vinyl of 4-dimethyl-5-thiazolio)]-3-cephem-4-carboxylic acid (cis-isomer, trans-isomer or cis-isomer, cis-isomer) iodide or triflutate.
Each above-mentioned cephem compounds can its carboxylate salt or the form of ester have (carboxylic groups that cephem nuclear is 2), for example, with its sodium salt, methyl esters, ethyl ester, phenylbenzene methyl esters, to a methoxyl group phenyl ester, the form of pivalyl oxygen methyl ester and (5-methyl-2-oxygen-1,3-dioxane pentadiene) methyl esters exists.
One of can following two methods prepare general formula of the present invention
The new compound of (I).
Method 1:
In method 1, the mould alkanoic acid compound of the amino cephalo bacterium of the 7-shown in the molecule formula II
R wherein
3With A as defined above, or the 2-(2-amino-thiazolyl--4-yl shown in the response derivative of molecule formula II compound (in the 7-of molecular formula amine groups reaction) or its salt and the molecule formula III)-2-alkoxyimino acetic acid compound reacts,
R wherein
1And R
2As defined above, or response derivative (in the carboxyl reaction shown in the molecular formula) or its salt of a part formula III idic acid.
The response derivative embodiment of compound (II) amino group comprises the imido derivative of Shiff-alkali, this derivative can be by reacting a compound (II) and a carbonyl compound, alkene ammonia type isomer (tautomer) as aldehydes or ketones or above-mentioned imido-compound makes, can pass through compound (II) and silylation compound, for example two-(trimethyl silyl) ethanamide reaction makes silyl derivatives; Also available compound (II) makes derivative with phosphorus trichloride or phosgene reaction.
The embodiment of compound (II) or (III) comprises its acid salt, for example, and compound (II) or (III) and organic acid such as acetate, toxilic acid, tartrate, Phenylsulfonic acid, the salt that toluenesulphonic acids generates; Compound (II) or (III) and mineral acid, hydrochloric acid for example, Hydrogen bromide, sulfuric acid, the salt that phosphoric acid generates; Compound (II) or (III) and basic metal, as sodium, potassium or and alkaline-earth metal, as calcium, the metal-salt (carboxylate salt) that magnesium generates; The ammonium salt (carboxylate salt) of compound (II) or (III); Compound (II) or (III) and organic amine are as the amine salt of triethylamine and dicyclohexyl amine generation.
The suitable embodiment of compound (III) carboxylic group response derivative comprises the acyl group fontanel of compound (III), acid azide, acid anhydrides, active amide, and active ester; And the particularly chloride of acid or the acid bromide of compound (III); Compound (III) and the sour mixed acid anhydride that forms are for example with the phosphoric acid that replaces, as dialkyl group phosphoric acid; Phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, fontanel is for phosphoric acid, with dialkyl group phosphoric acid, sulfurous acid, thiosulfuric acid, sulfuric acid is with alkyl carbonate such as methyl carbonic, the ethyl carbonate ester is with aliphatic carboxylic acid such as PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid, 2-ethyl acetic acid, Tricholroacetic Acid, or with aromatic carboxylic acid such as phenylformic acid; A kind of symmetric anhydride of compound III; Compound (III) and imidazoles, 4-substituted imidazole, dimethyl pyrazole, triazole, or the reactive amines of tetrazolium generation; The active ester of compound III is as cyano methyl ester, methoxymethyl ester, the dimethylimino methyl ester, vinyl ester, propargyl ester, right-the nitrophenyl ester, 2,4-dinitrophenyl ester, the trichlorophenyl ester, five chlorophenyl ester, methylsulfonyl phenylester, the phenylazo-phenylester, the benzene thioesters, right-the nitrophenylsulfenyl ester, right-toluene sulfenyl ester, carboxymethyl sulfenyl ester, pyranyl ester, pyridyl ester, piperidyl ester, or quinolyl ester, or compound (III) and N-oxy-compound, as N, N-dimethyl hydroxyl amine, the 1-hydroxyl-2-(1H)-pyridone, N-hydroxy-succinamide, the ester that N-hydroxyl phthalimide or 1-hydroxyl-6-chloro-1H-benzotriazole is generated.
According to the character of participating in the compound of reaction III, can suitably select the response derivative of compound ii.
The condensation reaction of compound ii and compound III is general to be adopted and not to participate in the solvent that reacts usually, as water, and acetone ， diox, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), vinyl acetic monomer, N, dinethylformamide, pyridine, or other can not produce the solvent of the opposite effect to reaction.These solvents mix with water, use as mixed solvent.
When the compound III was used with the form of free acid or salt, reaction was preferentially carried out under the condition that condensing agent exists.For example condensing agent can be N, the N-dicyclohexylcarbodiimide; N-cyclohexyl-N-morpholino-ethyl carbodiimide; N, N '-(4-diethylamino cyclohexyl) carbodiimide; N, N '-diethyl carbodiimide; N, N '-DIC; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N '-carbonyl-two-(glyoxal ethyline); Pentylidene ketene-N-U-4527; Diphenylethlene ketone-N-U-4527; Ethoxy acetylene; 1-alkoxyl group-1-vinylchlorid; Trialkylphosphate; The phosphoric acid ethyl ester, the sec.-propyl polyphosphate; Phosphorus oxychloride; Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine; 2-ethyl-7-hydroxy benzo isoxazolium salt; Between 2-ethyl-5-(-sulfophenyl) isoxazole oxyhydroxide (molecule inner salt); 1-(is right-chlorobenzene sulphonyl oxygen)-6-chloro-1-H-benzotriazole; With dimethyl formamide and thionyl chloride, the Vilsmeier reagent of phosgene and phosphorus oxychloride prepared in reaction.
The reaction of method I also can be carried out in the presence of inorganic and organic bases.These inorganic and examples organic bases can be alkali-metal supercarbonates, as sodium bicarbonate, and saleratus, a kind of basic metal hydrochloric acid, as yellow soda ash, salt of wormwood, a kind of alkaline earth metal carbonate, as lime carbonate, a kind of three-(rudimentary)-alkylamine, as Trimethylamine, triethylamine, pyridine, N-(is rudimentary) alkyl morpholine, N, N-two (rudimentary) alkyl benzyl amine.
Can carry out above-mentioned reaction under non-critical temperature, generally be to carry out under cooling or heating.
The compound products of the logical formula I that makes with above-mentioned reaction; if desired; also available general method is removed remaining carboxy protective group and/or remaining amido protecting group; and/or with general method the carboxylic group of compound (I) is transferred to metabolizable, unsettled non-toxic ester (carboxylicesters) group.Can select to remove their method according to the character of the carboxyl-protecting group that will remove and amino protecting group.
Available general deprotection technology is removed the amino protecting group of compound (I); for example; with hydrolysis or reductive method; in the time of need removing as amino protecting group the carboxyl groups of compound; can make compound (I) and an imines one fontanel for reagent react; then with an etherificate imines reagent react, if desired, hydrolysis again.Acidolysis is to remove amino protecting group method commonly used, can be used for removing alkoxycarbonyl group, formyl radical group, trityl group.The acid that can be used as acidolysis has: formic acid, and trifluoracetic acid, right-toluenesulphonic acids, hydrochloric acid, and other organic or inorganic acid, the acid of preferentially selecting for use is formic acid, trifluoracetic acid and hydrochloric acid, they can make reaction mixture be easy to aftertreatment.The character of removing amino protecting group according to need selects to be used for the acid of acidolysis.Hydrolysis reaction can not have solvent to carry out with having in the presence of the solvent, and solvent for use can be a water, a kind of mixture of hydrophilic organic solvent.When using the trifluoracetic acid acidolysis, reaction can be carried out in the presence of anisole.Also available general method is removed carboxyl-protecting group, for example, and hydrolysis or reduction.Acidolysis is the method for using always that removes protection, and it is beneficial to the carboxyl-protecting group of removing as silicomethane and this class of diphenyl methyl group.
Method that can be general changes into the unsettled ester group group of metabolism with carboxyl, and this method comprises the metal-salt of carboxylic acid cpd and alkyl fontanel such as pivalyl oxygen methyl fontanel, reacts in organic solvent as pivalyl oxygen methyl chloride.
Method 2
According to method 2, the cephem compounds of logical formula I, wherein group A representative-3-rudimentary-alkyl thiazolyl group, i.e. following formula (I ') compound:
R wherein
1, R
2, R
3As defined above, R is a low-grade alkyl group, R
4And R
5Can be identical also can be different, respectively be hydrogen atom, low-grade alkyl group, or fontanelle atom can be by leading to the compound of formula I as the chlorine atom process preparation of aforesaid method 1 (its can);
R wherein
1, R
2, R
3, R
4And R
5As defined above,
Make with the alkylating reagent reaction, this alkylating reagent is selected from the alkyl fontanel that molecular formula is RX, and wherein R is a low-grade alkyl group, and as methyl, ethyl, X are fontanelle atoms, as chlorine, and bromine, iodine; One single or two-rudimentary-alkyl-sulphate; Low alkyl group lower alkane sulfonated hydrocarbon, the thiazolyl 3-nitrogen-atoms of alkylated compound (I).Alkyl fontanel as alkylating reagent RX can be a monobromethane, methyl iodide, monobromethane, iodoethane.Dan Shuanyi low alkyl group vitriol as alkylating reagent can be single methyl or two monomethyl vitriol and single ethyl or two sulfovinate.The rudimentary alkane sulfonate of low alkyl group can be a methylmethane sulfonate.The alkylated reaction of the 3-nitrogen-atoms of compound (I) thiazolyl can carry out with general known organonitrogen atom alkyl method.When with the lower alkyl esters of sulfuric acid or sulfonic acid as alkylating reagent (RX) when carrying out alkylated reaction, anti-used solvent such as benzene, toluene, ethylene dichloride can be carried out in solvent generally, methylene dichloride, chloroform, water, acetone, tetrahydrofuran (THF), ethanol, the ether dimethyl formamide, or can not carry out reacting in the reactive solvent at other.
The reaction of method 2 can preferentially be reacted in the presence of organic or inorganic alkali as the mode that method 1 is introduced.Above-mentioned alkylated reaction can carry out under any non-critical temperature condition, and alkylated reaction generally carries out below the used solvent boiling point in this reaction, can adopt the method for cooling or heating.
If desired; the compound (I) for preparing in above-mentioned alkylation mode; can further remove remaining carboxyl one protecting group group and/or amino protecting group group with general method; and/or further the carboxyl of compound (I ') is changed into the unsettled non-toxic ester of metabolism (carboxylicesters) group, (usefulness method 1 described method).
Second aspect of the present invention provides a kind of method for preparing logical formula I cephalosporin compound,
R wherein
1Be amino group or the amino group protected, R
2Be a low-grade alkyl group, a carboxymethyl group, or a carboxymethyl group of having protected, R
3It is a hydrogen atom; an one salifiable positively charged ion or a carboxy protective group; A is a phenyl group that has not replaced or replace; the one furyl group that has not replaced or replaced; an or thiazolyl group that has not replaced or replaced; or one the 3-that has not replaced or replaced rudimentary-alkyl thiazolyl group, it is characterized in that this method comprises the mould alkanoic acid of the amino cynnematin of 7-of logical formula II
R wherein
3With A as defined above, or the group identical (comprising the response derivative of amino group of molecule formula II compound and the salt of logical formula II compound) with its function, with logical formula III-2-(2-aminothiazole-4-yl)-2-alkoxyimino acetic acid reaction
R in the logical formula III
1And R
2As defined above, or the identical group (the acid-respons derivative that comprises logical formula III compound) of a function is reflected in the nullvalent solvent and carries out, temperature of reaction is no more than the boiling point of solvent for use, generate the compound of logical formula I, then if desired, when the compound of the logical formula I that is generated is that following general formula (during a kind of compound shown in the II "), can prepare the compound of general formula (I " ')
At formula I " in, R
1, R
2And R
3As defined above,
R
4, R
5Be identical or different, it is respectively hydrogen atom, low-grade alkyl group or fontanelle atom such as chlorine atom, general formula (alkylation of the 3-nitrogen-atoms of the thiazolyl of I ") compound is, by with molecular formula be that the alkyl fontanel reaction of Rx is finished, the R among the Rx is a low-grade alkyl group; X is a fontanelle atom; as chlorine atom or bromine atoms, single or two-rudimentary-alkyl-sulphate or low alkyl group lower alkane sulfonate
R in general formula (I " ')
1, R
2, R
3, R
4And R
5As defined above; R and used fontanel are for the low-grade alkyl group of alkane; single or two-low alkyl group vitriol or low alkyl group lower alkane sulfonated hydrocarbon are consistent; in addition; if desired; can from the compound of the logical formula I that generates and general formula (I " '), remove remaining amino protecting group and carboxyl-protecting group.
The method of second aspect of the present invention can comprise a further reaction, the compound shown in the promptly logical formula I; Wherein R is-hydrogen atom, with-alkali metal hydroxide, alkali metal hydrocarbonate or-alkaline carbonate or alcohol as lower alkyl alcohol reaction, generate the compound that leads to formula I; Wherein R be-alkali metal cation or-generate the group of ester, as-low-grade alkyl group.The available currently known methods of reaction that carboxylic acid is converted to corresponding alkali metal carboxylate salt or carboxylicesters carries out.Equally, the compound of the logical formula I that exists with free carboxy acid's form can change into the form of alkali metal carboxylate or carboxylicesters.
The example that logical formula I can be used as the salt of medicine acceptance comprises general non-toxic salt, and for example an alkali metal salt (carboxylate salt) is as sodium salt or sylvite; Alkaline earth salt such as calcium; Magnesium; Ammonium salt, compound (I) and organic bases, as Trimethylamine, triethylamine, pyridine, skin Courlene, dicyclohexylamine .N, the base addition salt of N '-dibenzyl-ethylenediamin; Compound (I) and organic acid such as acetic acid, trifluoroacetic acid, toxilic acid, tartrate, methylsulphonic acid, Phenylsulfonic acid, formic acid, the acid salt of toluenesulphonic acids is with mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, the acid salt of phosphoric acid; With amino acid such as arginine, aspartic acid, the acid salt of L-glutamic acid.
The example that the logical formula I compound of the present invention can be used as the ester of medicine comprises, 2-carboxylic group and lower alkane acyl-oxygen methyl group by logical formula I compound, as pivalyl oxygen methyl group, lower alkylcarbonyl oxyalkyl group, lower alkoxycarbonyl oxyalkyl group, or-esterification of (2-oxygen-1,3-dioxane pentadiene-4-yl) methyl group or similar compound and the ester that makes.
Compound of the present invention all is new compound.Table 1 shows with agar dilution and measures the minimum inhibitory concentration (MIC, mcg/ml) of some new compound to bacterial growth.Can find out that from table 1 under test conditions of the present invention, whole compound exhibits has gone out high anti-microbial activity, and antibacterial range is very wide, this explanation The compounds of this invention is useful as antibiotic.
Compound shown in the last table, as follows through identifying:
Embodiment 10, compound:
7-(2-methyl-imino-2-(2-aminothiazole-4-) basic acetylaminohydroxyphenylarsonic acid 3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, trans-isomer(ide))
Embodiment 11 compounds:
7-(2-methyl-imino-2-(2-aminothiazole-4-yl) kharophen)-the 3-(2-phenyl vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, trans-isomer(ide))
Embodiment 12 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2-furyl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, trans-isomer(ide))
Embodiment 13 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(5-nitro-2-furyl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, trans-isomer(ide)).
Embodiment 14, compound:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(ortho-fluorophenyl base) vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, suitable, trans isomer mixture).
Embodiment 15 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(3, the vinyl of 4-dimethyl-5-thiazolio))-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride).
Embodiment 16 compounds:
7-(2-carboxyl methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, trans-isomer(ide)).
Embodiment 18 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, trans-isomer(ide)).
Embodiment 21 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-diuril azoles-5-yl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis isomerism, cis-isomeride).
Embodiment 30 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, trans-isomer(ide)).
Embodiment 31 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid trifluoroacetate (cis-isomeride, cis-isomeride).
Embodiment 32 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(thiazole-4-yl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, cis-isomeride).
Embodiment 33 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(thiazole-5-yl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, cis-isomeride).
Embodiment 34 compounds:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2,4-dichloro thiazole-5-yl) vinyl)-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, cis-isomeride).
The logical formula I of the present invention or (I is a) to the new compound of (I f) formula, or it can be used as the salt or the ester of medicine, pay the time spent to the people being used for the treatment of bacterial infectious disease, can by with pharmacology on acceptable solid or liquid vehicle or excipient be mixed and made into pharmaceutical composition.
The invention provides in addition-the medicine antibacterial composition, it comprises that (I is a) to (I f) compound as the above-mentioned logical formula I of the significant quantity of active constituent or general formula, or acceptable salt or ester on its pharmacology, and acceptable carrier on the pharmacology as activeconstituents.
With active compound mutually on the blended pharmacology acceptable carrier can be general solid or liquid vehicle, also can select the carrier of organic or inorganic, specifically according to the type of service of the formula of medicine of being prepared, promptly oral also right and wrong oral or be used for outward fixed.Pharmaceutical composition of the present invention can be general formulation forms, as capsule, tablet, coated tablet, ointment, suppository, solution, suspension and emulsion.Other additive commonly used, comprise that conditioning agent, stablizer, wetting agent, emulsifying agent and damping fluid also all can add in the pharmaceutical composition of the present invention; And this medicine contains the compound (I) as activeconstituents.
New cephalosporin compound of the present invention is as oral preparation, can be absorbed by the intestines of animal at an easy rate, before from animal urine, excreting, the anti-microbial activity that keeps its actual amount in animal body, this can observe by the cephalosporin compound of measuring residual content, promptly reclaim urine, observe the compound in live body that reality is not recovered to.
We have done some tests, and after being about to cephalosporin compound and taking to mouse with oral form, appraisal is as antibacterial active compounds, the amount of the cephalosporin compound of the present invention that can reclaim from urine.
Test 1
Make ICR kind mouse (male, 4 weeks, triad) oral administration of compound under following test conditions, promptly every mouse is taken 0.5 milligram of compound.Test compound with the form of suspension in the aqueous solution of 0.2% carboxymethyl cellulose.Take compound after 4 hours, collect whole urine that mouse excretes, use e. coli k-12 8236,, measure the total amount of cephalosporin compound of the present invention in the urine with the paper disc test method(s) as testing line.
The compound that is used for this test is the compound of embodiment 22, that is: 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-diuril azoles-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis isomerism, cis-isomeride) pivalyl oxygen methyl ester; With embodiment 38 compounds, i.e. 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(thiazole-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) pivalyl oxygen methyl ester.
Mole number according to the oral cephalosporin compound recently calculates the recovery ratio of cephalosporin compound in the urine with cephalosporin compound (with free carboxy acid's form) the mole number percentage that reclaims.
Following table 2 has provided test-results (in the mean value of 3 mouse)
Table 2
The recovery ratio % of experimental compound in the test compound urine
The compound 24 of embodiment 22
The compound 20 of embodiment 38
In above-mentioned experiment, after oral cephalosporin compound was absorbed in animal body, it was converted into corresponding free carboxy acid's form in vivo, and process is simple division is generated ester by compound 4-hydroxy-acid group a pivalyl oxygen methyl group.Form with the free carboxy acid excretes experimental compound from urine, measure the antibacterial efficacy of compound with biological test method.
With reference to following example explanation the present invention.Embodiment 1 to 39 explanation the present invention prepares the method for new cephalo bacterium compound, and reference example 1 to 8 has illustrated the preparation method of preparation The compounds of this invention raw material.
Reference example 1
Preparation 7-(benzene oxygen kharophen)-vinyl of 3-[2-(4-methyl-thiazole-5-yl)]-3-cephem-4-carboxylic acid benzhydryl ester
(1) with diphenyl-methyl 7-(benzene oxygen kharophen)-3-(phenyl-phosphine-dimethyl (diylmethyl)-3-cephem-4-carboxylate salt (1.55 gram) and 4-methylthiazol base-5-carbonyl aldehyde (0.305 restrains) is dissolved in the methylene dichloride (20 milliliters), adds 20 milliliters of saturated sodium bicarbonate aqueous solutions at ambient temperature.At ambient temperature the mixture that generates was stirred 17 hours.Standing mixt, until water phase separated and organic solvent mutually.Remove water, and, washings (in methylene dichloride) and isolated organic phase are merged with methylene dichloride (20 milliliters) washing.Solution with anhydrous magnesium sulfate drying has merged is concentrated into driedly then under reduced pressure.The solid residue of purifying and obtaining with silica gel column chromatography (wako silica gel C-300,40 gram).Make developping agent with benzene-vinyl acetic monomer (5: 1).Obtain title compound, 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.741 gram).
NMR，δ（CDCl
3）：2.34（3H，s），3.24（1H，d，J＝18Hz），3.48（1H，d，J＝18Hz），4.55（2H，s），5.12（1H，d，J＝5Hz），5.95（1H，dd，J＝5Hz，9Hz），6.25（1H，d，J＝12Hz），6.49（1H，d，J＝12Hz），6.8-7.5（16H，m），8.56（1H，s）.
(2) with diphenyl-methyl 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylate salt (0.725 gram) is dissolved in the anisole (2 milliliters), adds 7 milliliters of trifluoracetic acids under ice-cooled condition.Under ice-cooled condition, this mixture was stirred 1 hour.Under reduced pressure reaction mixture is concentrated into pulpous state, makes its curing by in it, adding isopropyl ether then.Resulting solid is ground, add the isopropyl ether washing, filtering mixt is to reclaim decorating film, drying under reduced pressure then.Obtain 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (0.512 gram).
NMR，δ（CDCl
3）：2.38（3H，s），3.19（1H，d，J＝18Hz），3.46（1H，d，J＝18Hz），4.55（2H，s），5.09（1H，d，J＝5Hz），5.91（1H，d，J＝5Hz），6.44（1H，d，J＝12Hz），6.57（1H，d，J＝12Hz），6.8-7.6（6H，m），8.79（1H，s）.
(3) with 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (0.490 gram) is dissolved in 5 milliliters of vinyl acetic monomers, adds 0.300 gram 2 ethyl hexanoic acid sodium.The mixture that is generated was stirred 30 minutes, remove by filter the precipitation of generation, mixed solution washing with vinyl acetic monomer and isopropyl ether (1: 1), solid product (sodium salt) is dissolved in the dimethyl formamide under ice-cooled condition, adds the iodomethyl Pivalate for preparing with chloromethyl Pivalate (0.45 gram) and sodium iodide (0.450 gram) (in dimethyl formamide 3 milliliters).Under ice-cooled condition, stirred the mixture 1 hour.In reaction mixture, add vinyl acetic monomer (50 milliliters), use the frozen water purging compound then three times (each 30 milliliters).From mixture, isolate the organic solvent phase,, under reduced pressure be concentrated into dried with anhydrous magnesium sulfate drying.With the solid residue that silica gel column chromatography (Wako silica gel C-300,20 grams) is purified and obtained, be spread agent (5: 1) with benzene-vinyl acetic monomer.Obtain 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid pivalyl oxygen methyl ester (0.405 gram).
NMR，δ（CDCl
3）：1.15（9H，s），2.45（3H，s），3.17（1H，d，J＝18Hz），3.50（1H，d，J＝18Hz），4.57（2H，s），5.12（1H，d，J＝5Hz），5.77（1H，d，J＝5Hz），5.84（1H，d，J＝5Hz），5.95（1H，dd，J＝5Hz，9Hz），6.35（1H，d，J＝12Hz），6.64（1H，d，J＝12Hz），6.8-7.5（6H，m），8.62（1H，s）.
(4) with 7-(benzene oxygen kharophen)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid valeryl oxygen ester (0.303 gram) is dissolved in (3 milliliters) in the methylene dichloride.With the solution impouring one that obtains contain phosphorus pentachloride (0.331 gram) and pyridine (0.43 restrains) in-30 ℃ dichloromethane solution.Under ice-cooled condition,, be cooled to-30 ℃, be poured in the methyl alcohol (20 milliliters), then restir 30 minutes at ambient temperature the solution stirring that generates 3 hours.Under ice-cooled condition, the reaction solution that obtains is poured in the mixed aqueous solution of a saturated sodium-chloride (50 milliliters) and methylene dichloride (50 milliliters), under ice-cooled condition, stirred 1 hour then.Isolate organic phase from aqueous phase, extract water with methylene dichloride (20 milliliters).Extracting solution (in methylene dichloride) and organic phase are merged, with the mixture of saturated sodium bicarbonate aqueous solution washing generation.Use the anhydrous magnesium sulfate drying organic phase, under reduced pressure, it is concentrated into 5 milliliters.Obtain 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid valeryl oxygen methyl ester (in methylene dichloride).
Embodiment 1
Preparation 7-(2-methoxyimino)-and 2-(2-(trityl amino-thiazolyl--4-yl) kharophen] 3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride) pivalyl oxygen methyl ester
Will be with the 7-amino of the method for above-mentioned reference example 1 preparation)-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid pivalyl oxygen methyl ester (0.229 gram) is dissolved in (5 milliliters) in the methylene dichloride.With solution and the 2-(2-trityl aminothiazole-4-yl that generates)-2-methoxyimino acetate (cis-isomeride, 0.235 gram) and methylene dichloride (5 milliliters) mixing.In mixture, add pyridine (0.07 milliliter), and drip phosphinylidyne oxygen (0.07 milliliter) at-20 ℃.Stirred the mixture 10 minutes at 0 ℃, then it is poured in the mixed solution of frozen water and vinyl acetic monomer (50 milliliters).After the stirring, go out organic phase, with the frozen water washing, again with ice-cold saturated sodium bicarbonate aqueous solution washing from aqueous phase separation.Use the anhydrous magnesium sulfate drying organic phase, under reduced pressure, concentrate.Is developping agent with the silica gel column chromatography residuum (Wako silica gel C-300,20 gram) of purifying with benzene-vinyl acetic monomer (5: 1).Obtain 7-(2-methoxyimino-2-(2-trityl amino-thiazolyl--4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis) pivalyl oxygen methyl ester (0.184 gram).
NMR，δ（CDCl
3）：1.13（9H，s），2.43（3H，s），3.26（1H，d，J＝18Hz），3.57（1H，d，J＝18Hz），4.04（3H，s），5.13（1H，d，J＝5Hz），5.76（1H，d，J＝5Hz），5.82（1H，d，J＝5Hz），5.95（1H，dd，J＝5Hz，9Hz），6.34（1H，d，J＝12Hz），6.64（1H，d，J＝12Hz），6.70（1H，s），6.90（1H，d，J＝9Hz），7.00（1H，broad s），7.1-7.5（25H，m），8.59（1H，s）.
Embodiment 2
Preparation 7-(2-methoxyimino)-and 2-(2-aminothiazole-4-yl) kharophen]-3-[2-4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis) pivalyl oxygen methyl ester.
With the 7-(2-methoxyimino)-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) pivalyl oxygen methyl ester (0.160 gram) is dissolved in anisole (0.5 milliliter).Under ice-cooled condition, the solution that is generated is mixed with trifluoracetic acid (1.5 milliliters), and then under ice-cooled condition, stirred 30 minutes.Reaction mixture is mixed with isopropyl ether (30 milliliters), be settled out meal, filtered and recycled is washed with isopropyl ether.Resulting decorating film is dissolved in vinyl acetic monomer (20 milliliters), with ice-cold saturated sodium bicarbonate aqueous solution washing.Isolate organic phase from aqueous phase, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Obtain the 7-[2-methoxyimino)-2-(2-(aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) pivalyl oxygen methyl ester (0.083 gram).
NMR，δ（CDCl
3）：1.14（9H，s），2.44（3H，s），3.30（1H，d，J＝18Hz），3.47（1H，d，J＝18Hz），4.04（3H，s），5.17（1H，d，J＝5Hz），5.27（2H，b），5.77（1H，d，J＝5Hz），5.82（1H，d，J＝5Hz），6.03（1H，dd，J＝5Hz，9Hz），6.35（1H，d，J＝12Hz），6.64（1H，d，J＝12Hz），6.88（1H，s），7.35（1H，d，J＝9Hz），8.59（1H，s）.
Embodiment 3
7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.223 gram) and 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetate (0.252 gram) reaction, with method processing reaction product, obtain 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl similar in appearance to embodiment 1) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (0.215 gram).
NMR，δ（CDCl
3）：2.35（3H，s），3.25（1H，d，J＝18Hz），3.45（1H，d，J＝18Hz），4.05（3H，s），5.14（1H，d，J＝5Hz），5.98（1H，dd，J＝5Hz，9Hz），6.27（1H，d，J＝12Hz），6.45（1H，d，J＝12Hz），6.72（1H，s），6.88（1H，s），6.99（1H，broad s），7.10-7.5（26H，m），8.54（1H，s）.
Embodiment 4-8
Be prepared as follows compound with the method that is same as embodiment 1:
Embodiment 4
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-the 3-(2-phenyl vinyl)-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (productive rate 68%).
NMR，δ（CDCl
3）：3.25（2H，broad s），4.04（3H，s），5.05（1H，d，J＝5Hz），5.91（1H，d，J＝5Hz），6.48（1H，d，J＝12Hz），6.60（1H，d，J＝12Hz），6.74（1H，s），6.95（1H，s），7.0-7.5（32H，m）.
Embodiment 5
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-the 3-[2-(2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (productive rate 62%).
NMR，δ（CDCl
3）：3.50（2H，broad s），4.07（3H，s），5.11（（1H，d，J＝5Hz），5.91（1H，dd，J＝5Hz，9Hz），6.1-6.4（4H，m），6.76（1H，s），6.88（1H，s），7.00（1H，broad s），7.1-7.6（27H，m）.
Embodiment 6
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(5-nitro-2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (productive rate 75%).
NMR，δ（CDCl
3）：3.40（1H，d，J＝18Hz），3.63（1H，d，J＝18Hz），4.10（3H，s），5.32（1H，d，J＝5Hz），6.05（1H，dd，J＝5Hz，9Hz），6.19（1H，d，J＝12Hz），6.31（1H，d，J＝4Hz），6.53（1H，d，J＝12Hz），6.78（1H，s），6.86（1H，s），7.00（1H，broad s），7.13（1H，d，J＝4Hz），7.15-7.5（26H，m）.
Embodiment 7
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(ortho-fluorophenyl base vinyl]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (productive rate 71%).
NMR，δ（CDCl
3）：3.23（2H，broad s），4.02（3H，s），5.03（1H，d，J＝5Hz），5.91（1H，dd，J＝5Hz，9Hz），6.57（1H，d，J＝12Hz），6.63（1H，d，J＝12Hz），6.72（1H，s），
Embodiment 8
Uncle 7-[2--butoxy carbonyl methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester (productive rate 81%).
NMR，δ（CDCl
3）：1.43（9H，s），2.36（3H，s），3.25（1H，d，J＝18Hz），3.55（1H，d，J＝18Hz），4.75（2H，s），5.14（1H，d，J＝5Hz），5.94（1H，dd，J＝5Hz，9Hz），6.27（1H，d，J＝12Hz），6.45（1H，d，J＝12Hz），6.80（1H，s），6.86（1H，s），6.99（1H，broad s），7.1-7.5（25H，m），8.53（1H，s），8.56（1H，d，J＝9Hz）.
Embodiment 9
Preparation 7-[2-methoxyimino-2-(2-trityl amino-thiazolyl--4-yl) kharophen]-3-[2-3, the vinyl of 4-dimethyl-5-thiazolio)]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester iodide.
With 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.164 milligram) is dissolved in 5 milliliters of benzene, adds methyl iodide (1 milliliter).With this solution stirring seven days, generate precipitation.Remove by filter throw out, wash with benzene, drying under reduced pressure obtains 7-[2-methoxyimino-2-(2-trityl amino-thiazolyl--4-yl) kharophen]-3-[2-(3, the vinyl of 4-dimethyl-5-thiazolio)]-3-cephem-4-carboxylic acid (cis-isomer) benzhydryl ester iodide
(0.122 milligram).
NMR，δ（CDCl
3）：2.30（3H，s），3.32（1H，d，J＝18Hz），3.65（1H，d，J＝18Hz），4.02（3H，s），4.06（3H，s），5.42（1H，d，J＝5Hz），5.92（1H，dd，J＝5Hz，9Hz），6.29（1H，d，J＝12Hz），6.56（1H，d，J＝12Hz），6.64（1H，s），6.89（1H，s），7.0-7.5（27H，m），10.19（1H，s）.
Embodiment 10
Preparation 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer, cis-isomeride) trifluoroacetate.
With 7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.11 gram) is dissolved in (0.33 milligram) in the anisole, adds trifluoracetic acid (1.1 milliliters) under ice-cooled condition.Under ice-cooled condition,, add isopropyl ether (30 milliliters) to generate precipitation with resulting solution stirring 1 hour.The filtered and recycled throw out is with isopropyl ether washing, drying under reduced pressure.Obtain 7-[2-methoxyimino-2-(2-aminothiazole-4-yl)-kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomer) trifluoroacetate (0.067 gram).
NMR，δ（CD
3SOCD
3）：2.44（3H，s），3.39（1H，d，J＝18Hz），3.46（1H，d，J＝18Hz），3.84（3H，s），5.22（1H，d，J＝5Hz），5.80（1H，dd，J＝5Hz，9Hz），6.36（1H，d，J＝12Hz），6.67（1H，d，J＝12Hz），6.76（1H，s），8.90（1H，s），9.63（1H，d，J＝9Hz）.
Embodiment 11 to 16
Prepare following compound with the method that is same as embodiment 10.
Give birth to the sodium salt of the compound of stating embodiment 12 and 13 next life corresponding to the trifluoroacetate of embodiment 10 by preparation, promptly dissolve above-mentioned three fluorate in the sodium bicarbonate aqueous solution of one 2 molconcentration, with-Diaion HP20 column chromatography the solution that (100 times volumes) generated of purifying, with water and 20% aqueous acetone solution is eluent, and lyophilize contains the eluate of required compound.
Embodiment 11
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-the 3-(2-phenyl vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) trifluoroacetate (productive rate 79%)
NMR，δ（CD
3SOCD
3）：3.17（1H，d，J＝18Hz），3.42（1H，d，J＝18Hz），3.82（3H，s），5.20（1H，d，J＝5Hz），5.76（1H，dd，J＝5Hz，9Hz），6.52（1H，d，J＝12Hz），6.58（1H，d，J＝12Hz），6.73（1H，s），7.1-7.5（5H，m），
Embodiment 12
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-the 3-[2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt (productive rate 13%)
NMR，δ（D
2O）：3.51（1H，d，J＝18Hz），3.72（1H，d，J＝18Hz），4.03（3H，s），5.39（1H，d，J＝5Hz），5.86（1H，d，J＝5Hz），6.22（1H，d，J＝12Hz），6.44（1H，d，J＝12Hz），6.4-6.6（2H，m），7.07（1H，s），7.54（1H，d，J＝2Hz）.
Embodiment 13
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(5-nitro-2-furyl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) sodium salt (productive rate 53%)
NMR，δ（D
2O）：3.57（1H，d，J＝18Hz），3.82（1H，d，J＝18Hz），4.03（3H，s），5.34（1H，d，J＝5Hz），5.88（1H，d，J＝5Hz），6.76（1H，d，J＝15Hz），6.79（1H，d，J＝4Hz），7.05（1H，s），7.46（1H，d，J＝15Hz），7.60（1H，d，J＝4Hz）.
Embodiment 14
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(ortho-fluorophenyl base) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-trans-isomer mixture) trifluoroacetate (productive rate 84%)
NMR，δ（CD
3SOCD
3）：3.12（1H，d，J＝18Hz），3.33（1H，d，J＝18Hz），3.77（3H，s），5.07（1H，d，J＝5Hz），5.65（1H，dd，J＝5Hz，9Hz），6.47（2H，s），6.63（1H，s），6.9-7.5（4H，m），9.42（1H，d，J＝9Hz）.
Embodiment 15
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(3,4, the vinyl of-dimethyl-5-Thiazolio)]-3-cephem-4-carboxylic acid (cis-isomeride) two-trifluoroacetate (productive rate 73%).
NMR，δ（CD
3SOCD
3）：2.42（3H，s），3.37（1H，d，J＝18Hz），3.52（1H，d，J＝18Hz），3.82（3H，s），4.04（3H，s），5.24（d，J＝5Hz），5.80（1H，dd，J＝5Hz，9Hz），6.72（3H，s），9.56（1H，d，J＝9Hz），10.25（1H，s）.
Embodiment 16
7-[2-carboxylic methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) trifluoroacetate (productive rate 58%).
Reference example 2
Preparation 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (trans-isomer(ide)) is right-the methoxy-benzyl ester
(1) with right-methoxy-benzyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl-3-cephem-3-carboxylate salt (10.00 gram, 20.52 mmole) and triphenylphosphine (5.65 gram 21.5 mmoles) be dissolved in the acetone (200 milliliters), add sodium iodide (3.23 grams, 21.5 mmoles) at ambient temperature.The mixture that generates was stirred 2 hours, under reduced pressure be concentrated into dried.In solid residue, one after the other add methylene dichloride (100 milliliters), 4-methylthiazol-5-base-carbonyl aldehyde
(26.07 gram, 20.5 mmoles) and saturated sodium bicarbonate aqueous solution (100 milliliters) stir the mixture 16 hours of generation then in envrionment temperature.The mixture that generates is left standstill, make it be divided into water and organic phase.Isolate organic phase from aqueous phase,, use saturated sodium-chloride water solution (250 milliliters) washing then, with the washed organic phase of anhydrous magnesium sulfate drying, concentrating under reduced pressure with 10% aqueous solution of sodium bisulfite (250 milliliters) washing.Add methyl alcohol (200 milliliters) to residue, filter out the precipitation of generation, use methanol wash, drying under reduced pressure.Obtain 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (trans-isomer(ide)) is right-pale yellow powder (productive rate 10%, 1.2 gram) of methoxybenzyl ester.
NMR，δ（CDCl
3）：2.40（3H，s），3.60（2H，broad s），3.62（2H，s），3.78（3H，s），4.93（1H，d，J＝5Hz），5.20（2H，s），5.79（dd，J＝5Hz，9Hz），6.6-6.9（4H，m），7.0-7.4（8H，m），8.51（1H，s）.
(2) with right-p-methoxy-phenyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylate salt (trans-isomer(ide)) (0.720 gram, 1.28 mmoles) is dissolved in (3 milliliters) in the methylene dichloride.The solution that generates is poured into one at-30 ℃, in phosphorus pentachloride in methylene dichloride (0.800 gram, 3.84 mmoles) and pyridine (1.04 milliliters, 12, the 8 mmoles) solution.Under ice-cooled condition,, it is poured in advance in the methyl alcohol (20 milliliters) that is chilled to-30 ℃, stirred at ambient temperature 1 hour the solution stirring that generates 3 hours.In the mixed solution with resulting reaction solution impouring one saturated sodium-chloride water solution (20 milliliters) and methylene dichloride (20 milliliters), the mixed solution that generates was stirred 1 hour.Mixture left standstill make it be separated into water and organic solvent mutually.Water with methylene dichloride (20 milliliters) extracting and separating goes out merges dichloromethane extract and above-mentioned organic phase.With the organic phase after the saturated sodium bicarbonate aqueous solution washing merging, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.With the remnant of silica gel (Wako silica gel C-300,20 grams) column chromatography purification gained, be developping agent with benzene-vinyl acetic monomer (3: 1).Obtain title compound 7-amino-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (trans-isomer(ide)) is to methoxy-benzyl ester (0.443 gram, 78%).
NMR，δ（CDCl
3）：1.83（1H，broad s），2.46（1H，s），3.63（1H，d，J＝18Hz），3.71（1H，d，J＝18Hz），3.77（3H，s），4.72（1H，d，J＝5Hz），4.94（1H，d，J＝5Hz），5.23（2H，s），6.85（1H，d，J＝16Hz），6.8-6.9（2H，m），7.22（1H，d，J＝16Hz），7.3-7.4（2H，m），8.52（1H，s）.
Embodiment 17
Preparation 7-[2-methoxyimino-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl)-vinyl]-3-cephem-4-carboxylic acid is right-methoxy-benzyl ester (cis-isomeride, trans-isomer(ide))
Will-methoxybenzyl 7-amino-3-[2-(4-methylthiazol-5-yl right with the compound of above-mentioned reference example 2 preparations) vinyl]-3-cephem-4-carboxylate salt (trans-isomer(ide)) and 2-(trityl-aminothiazole-4-yl)-2-methoxyimino acetate (cis-isomeride) reaction, to be same as the method processing reaction product of embodiment 1, obtain title compound, productive rate 72%.
NMR，δ（CDCl
3）：2.42（3H，s），3.57（1H，d，J＝18Hz），3.67（1H，d，J＝18Hz），3.73（3H，s），4.02（3H，s），5.01（1H，d，J＝5Hz），5.17（2H，s），5.84（1H，dd，J＝5Hz，9Hz），6.63（1H，s），6.83（1H，d，J＝16Hz），6.8-7.5（20H，m），8.49（1H，s）.
Embodiment 18
Preparation 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-(2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, trans-isomer(ide))
Right-methoxybenzyl 7-[2-methoxyimino-2-(2-trityl-aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylate salt (cis-isomeride, trans-isomer(ide)) with the trifluoracetic acid reaction, handle with the method that is same as embodiment 10, obtain the trifluoroacetate (acetic acid) of title compound.The trifluoroacetate that obtains is dissolved in the saturated sodium bicarbonate aqueous solution neutralizes, carry out chromatogram with Diaion HP20 post then and purify, (100 times of volumes) is with water and 20% aqueous acetone solution wash-out.The eluate lyophilize is obtained title compound, productive rate 82%.
NMR，δ（D
2O）：2.50（3H，s），3.86（2H，broad s），4.06（3H，s），5.34（1H，d，J＝5Hz），5.87（1H，d，J＝5Hz），6.97（1H，d，J＝16Hz），7.06（1H，d，J＝16Hz），7.08（1H，s），8.77（1H，s）.
Embodiment 19
Preparation 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid pivalyl oxygen methyl ester (cis-isomeride, trans-isomer(ide))
With 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid sodium salt (cis-isomeride, trans-isomer(ide)) (0.03 gram, 0.06 mmole) is dissolved in (3 milliliters) in the dimethyl formamide.Under ice-cooled condition, in the solution that is generated, be added in iodomethyl Pivalate in the dimethyl formamide (1 milliliter) (with iodomethyl Pivalate in acetone (0.09 gram, 0.60 mmole) and sodium iodide
(0.09 gram 0.6 mmole reaction makes) stirred the mixture that generated 10 minutes then.Arrive in the resulting reaction solution with frozen water (20 milliliters) and vinyl acetic monomer (20 milliliters), fully stirring and making its standing demix is water and organic phase.Isolate organic phase from aqueous phase, use saturated sodium-chloride water solution (10 milliliters) washing again after washing (10 milliliters) twice with water.With the washed organic phase of anhydrous magnesium sulfate drying, concentrating under reduced pressure then.Carrying out chromatogram with silicagel column (Wako-glue C-300,5 grams) and purify, is developping agent with the vinyl acetic monomer.Obtain title compound (productive rate 67%, 0.025 gram).
NMR，δ（CDCl
3）：1.21（9H，s），2.48（3H，s），3.68（1H，d，J＝18Hz），3.78（1H，d，J＝18Hz），4.04（3H，s），5.12（1H，d，J＝5Hz），5.89（2H，s），5.97（1H，dd，J＝5Hz，9Hz），6.86（1H，s），6.98（1H，d，J＝16Hz），7.33（1H，d，J＝16Hz），7.52（1H，d，J＝9Hz），8.57（1H，s）.
Reference example 3
The preparation molecular formula is
4-chloro-thiazole-5-base-carbonyl aldehyde
Under ice-cooled condition, phosphoryl chloride (122.7 gram) is added drop-wise in the dimethyl formamide (73.1 gram), resulting mixture is stirred 30 minutes (preparation Vilsmeier reagent).With mixture and thiazoline-2, the 4-diketone (
) (23.4 gram) mixing, then 100 ℃ of heating 3 hours.Reaction soln is cooled to envrionment temperature, and incline and place on ice (200 gram) adds sodium-acetate and neutralizes, and uses 200 milliliters every part dichloromethane extraction four times then.With the extract in a spot of saturated sodium bicarbonate aqueous solution washing methylene dichloride, use anhydrous magnesium sulfate drying, under reduced pressure, concentrate.With silicagel column residue being carried out chromatogram and purify, is eluent with benzene-vinyl acetic monomer (10: 1).Obtain flaxen title compound crystallization (1.10 gram).
NMR，δ（CDCl
3）：8.93（1H，d，J＝1Hz），10.03（1H，d，J＝1Hz）.
MS（m/e）：148（M
++1）
Reference example 4
The preparation general formula is
2,4-two chloro-thiazole-5-base-carbonyl aldehyde
Under ice-cooled condition, phosphoryl chloride (122.7 gram) is added drop-wise in the dimethyl formamide solution in the Ethylene Dichloride, stirred then 30 minutes.(preparation Vilsmeier reagent).With solution and the thiazole 2 that is generated, 4-diketone (23.4 gram) mixes, and heating is 1 hour in backflow.The gained reaction soln is cooled to envrionment temperature, and incline and place on ice (200 gram) adds the sodium-acetate neutralization, with 200 milliliters every part dichloromethane extraction 3 times.With the extract in a spot of saturated sodium bicarbonate aqueous solution washing methylene dichloride, use anhydrous magnesium sulfate drying, under reduced pressure, concentrate.Carrying out chromatogram with silica gel column chromatography and purify, is eluent with benzene-vinyl acetic monomer (10: 1).Prepare 4-chloro-thiazole-5-base carbonyl aldehyde (0.34 gram), also obtain faint yellow crystallization title compound (2.05 gram) simultaneously.
NMR，δ（CDCl
3）：9.90（1H，s）
MS（m/e）：182（M
++1）
Reference example 5
Preparation 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride) is right-the methoxybenzyl ester
Right-methoxybenzyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl-3-cephem-4-carboxylate salt (3.265 grams, 6.71 mmoles) and triphenylphosphine (1.859 grams, 7.05 mmoles) are dissolved in (20 milliliters) in the dimethyl formamide.To generate solution and sodium iodide (1.056 grams, 7.05 mmoles) at ambient temperature and mix, stir 2 hours.Under reduced pressure resulting reaction solution is concentrated into driedly, residue is dissolved in (10 milliliters) in the methylene dichloride.4-chloro-thiazole-5-base-carbonyl aldehyde (1.100 grams make with the method for aforementioned reference example 3) and saturated sodium bicarbonate aqueous solution are added in the dichloromethane solution that is generated.At ambient temperature the gained mixture was stirred 6 hours, leave standstill then, until being divided into organic phase and water.With the isolated water of dichloromethane extraction.Dichloromethane extract and organic phase are merged, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.With silica gel (Wako-glue C-300) post the gained residue is carried out Flash Type-column chromatography and purify, carry out wash-out with benzene-vinyl acetic monomer (5: 1).Obtain title compound (productive rate 74%2.891 grams).
NMR，δ（CDCl
3）：3.15（1H，d，J＝18Hz），3.42（1H，d＝18Hz），3.61（2H，s），3.74（3H，s），5.00（1H，d，J＝5Hz），5.06（2H，s），5.84（1H，dd，J＝5Hz，9Hz），6.14（1H，d，J＝9Hz），6.27（1H，d，J＝12Hz），6.56（1H，d，J＝12Hz），6.7-6.75（2H，m），7.05-7.4（7H，m），8.50（1H，s）.
Reference example 6
Preparation 7-amino-3[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride) is right-the methoxybenzyl ester
Right-methoxybenzyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(4-diuril azoles-5-the yl that will make with above-mentioned reference example 5) vinyl]-3-cephem-4-carboxylate salt (cis-isomeride) (2.452 grams, 4.21 mmoles) is dissolved in the methylene dichloride (10 milliliters).Under ice-cooled condition,, gained solution is poured in methylene dichloride (40 milliliters) solution that is dissolved with phosphorus pentachloride (2.630 grams, 12.63 mmoles) and pyridine (3.4 milliliters, 42 mmoles) at-30 ℃.Under ice-cooled condition, the gained reaction solution was stirred 3 hours, be poured in advance then in the methyl alcohol (40 milliliters) that is chilled to-30 ℃, stirred at ambient temperature 1 hour.Mixture is added in the mixed solution of saturated sodium-chloride (100 milliliters) aqueous solution and methylene dichloride (100 milliliters), stirred 1 hour.Leave standstill resulting mixture, make it be divided into water and organic solvent mutually.Isolate water and use methylene dichloride (50 milliliters) to extract.Dichloromethane extract is added in the above-mentioned organic phase, with the saturated aqueous sodium carbonate washing, uses anhydrous magnesium sulfate drying, concentrating under reduced pressure then.With silicagel column (Wako-glue C-300) residue being carried out Flash Type-column chromatography and purify, is developping agent with benzene-vinyl acetic monomer (3: 1), carries out wash-out.Obtain title compound (productive rate 79%, 1.543 gram).
NMR，δ（CDCl
3）：1.75（2H，broad s），3.20（1H，d，J＝18Hz），3.44（1H，d，J＝18Hz），3.75（3H，s），4.77（1H，d，J＝5Hz），4.97（1H，d，J＝5Hz），5.08（2H，s），6.31（1H，d，J＝12Hz），6.53（1H，d，J＝12Hz），6.7-6.85（2H，m），7.1-7.25（2H，m），8.50（1H，s）.
Reference example 7
Preparation 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(2,4-two chloro-thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride) is to the methoxybenzyl ester
With right-methoxybenzyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-chloromethyl-3-cephem-4-carboxylate salt and 2,4-two chloro-thiazole-5-base-carbonyl aldehyde (, in embodiment 4, obtaining) reaction with method similar in appearance to reference implementation 5.Obtain title compound, productive rate 78%.
NMR，δ（CDCl
3）：3.19（1H，d，J＝18Hz），3.40（1H，d，J＝18Hz），5.01（1H，d，J＝5Hz），5.09（2H，s），5.88（1H，dd，J＝5Hz，9Hz），6.10（1H，d，J＝9Hz），6.22（1H，d，J＝12Hz），6.46（1H，d，J＝12Hz），7.7-7.85（2H，m），7.1-7.45（7H，m）.
Reference example 8
Preparation 7-amino-3-[2-(2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride) is right-the methoxybenzyl ester
To be same as the method for reference example 6, with right-methoxybenzyl 7-phenyl acetylaminohydroxyphenylarsonic acid 3-[2-(2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylate salt (cis-isomeride) and phosphorus pentachloride and pyridine reaction, obtain title compound, productive rate 73%.
NMR，δ（CDCl
3）：1.80（2H，broad s），3.20（1H，d，J＝18Hz），3.42（1H，d，J＝18Hz），3.75（3H，s），4.79（1H，d，J＝5Hz），4.98（1H，d，J＝5Hz），5.10（2H，s），6.26（1H，d，J＝12Hz），6.44（1H，d，J＝12Hz），7.7-7.85（2H，m），7.1-7.4（7H，m）.
Embodiment 20
Preparation 7-[2-methoxyimino-2-(2-trityl amino-thiazolyl--4-yl) kharophen]-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) is right-the methoxybenzyl ester
With right-methoxybenzyl 7-amino-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylate salt (cis-isomeride) (1.205 grams, 2.6 mmole) and 2-(2-trityl aminothiazole base)-2-methoxyimino acetic acid (cis-isomeride) (1.153 gram 2.60 mmoles) is dissolved in the methylene dichloride (30 milliliters), in it, add (0.84 milliliter of pyridine, 10.4 mmole), under-20 ℃ of cooling conditionss, add phosphoryl chloride (0.33 milliliter, 3.64 mmoles) then.0 ℃ of stirring reaction liquid 20 minutes, be poured in the mixed solution of a frozen water (100 milliliters) and vinyl acetic monomer (100 milliliters), stir then.Leave standstill mixed solution, make it be divided into water and organic phase.Tell organic phase from aqueous phase,,, under reduced pressure concentrate then with Carbon Dioxide magnesium drying with the saturated sodium bicarbonate aqueous solution washing.(Wako-glue, C-300) (50 gram) post is purified with flash distillation one column chromatography, is that developping agent (5: 1) carries out wash-out with benzene-vinyl acetic monomer with silica gel.Obtain title compound (productive rate 72%, 1.665 gram).
NMR，δ（CDCl
3）：3.20（1H，d，J＝18Hz），3.44（1H，d，J＝18Hz），3.76（3H，s），4.03（3H，s），5.07（2H，s），5.08（1H，d，J＝5Hz），5.94（1H，dd，J＝5Hz，9Hz），6.33（1H，d，J＝12Hz），6.59（1H，d，J＝12Hz），6.7-7.4（22H，m），8.50（1H，s）.
Embodiment 21
Preparation 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt.
With right-methoxybenzyl 7-[2-methoxyimino-2-(2-trityl amino-thiazolyl--4-yl) kharophen]-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylate salt (cis-isomeride, cis-isomeride) (0.856 gram, 0.962 mmole) be dissolved in (2 milliliters) in the anisole, under ice-cooled condition, be added dropwise to trifluoracetic acid (8 milliliters).Under ice-cooled condition, the gained mixture was stirred 1 hour, mix with isopropyl ether then, generate precipitation.Remove by filter precipitation, with isopropyl ether washing, drying under reduced pressure.Obtain title compound (carboxylic acid) (i.e. the additive salt that generates with trifluoracetic acid) with the form of trifluoroacetate (0.586 gram).The gained compound is mixed with water (3 milliliters) and sodium bicarbonate (0.242 gram), with Diaion HP-20 post the solution that is generated is carried out chromatogram and purify, at first water is used 30% aqueous acetone solution wash-out then.Collection contains the wash-out part of required compound, concentrating under reduced pressure, lyophilize then.Obtain title compound (productive rate 82%, 0.433 gram
NMR，δ（D
2O）：3.43（1H，d，J＝18Hz），3.70（1H，d，J＝18Hz），4.03（3H，s），5.42（1H，d，J＝5Hz），5.90（1H，d，J＝5Hz），6.48（1H，d，J＝12Hz），6.71（1H，d，J＝12Hz），7.06（1H，s），8.87（1H，s）.
Embodiment 22
Preparation 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-4-diuril azoles-5-base vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) pivalyl oxygen methyl ester
With 7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(4-diuril azoles-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt (0.104 gram, 0.188 mmole) is dissolved in (3 milliliters) in the dimethyl formamide.Down solution and the iodomethyl Pivalate in dimethyl formamide (1 milliliter) (in acetone, chloromethyl PIVALIC ACID CRUDE (25) (0.141 gram) makes with sodium iodide (0.282 gram) reaction) that is generated mixed ice-cooled, mixture was stirred 10 minutes.In reaction solution, add frozen water (20 milliliters) and vinyl acetic monomer (20 milliliters).After stirring the compound that is generated it is left standstill, be separated into water and organic phase.Isolate organic phase from aqueous phase,, use anhydrous magnesium sulfate drying, concentrating under reduced pressure with the saturated sodium-chloride water solution washing secondary of 10 milliliters every part water and 10 milliliters.With flash distillation column chromatography purification residue, is eluent with the vinyl acetic monomer with silicagel column (Wako-glue C-300,10 grams).Obtain title compound, productive rate 78%, 0.940 gram.
NMR，δ（CDCl
3）：1.13（9H，s），3.30（1H，d，J＝18Hz），3.51（1H，d，J＝18Hz），5.17（1H，d，J＝5Hz），5.43（2H，broad s），5.75（1H，d，J＝6Hz），5.80（1H，d，J＝6Hz），6.06（1H，dd，J＝5Hz，9Hz），6.40（1H，d，J＝12Hz），6.66（1H，d，J＝12Hz），6.78（1H，s），7.65（1H，d，J＝9Hz），8.54（1H，s）.
Embodiment 23～28
Be prepared as follows compound with the method that is same as embodiment 20.
Embodiment 23
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-the 3-[2-(thiazol-2-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) benzhydryl ester (productive rate 72%).
NMR，δ（CDCl
3）：3.45（1H，d，J＝18Hz），3.67（1H，d，J＝18Hz），4.04（3H，s），5.16（1H，d，J＝5Hz），5.97（1H，dd，J＝5Hz，9Hz），6.58（1H，s），6.73（1H，s），6.85（1H，s），6.9-7.5（29H，m），7.74（1H，d，J＝3Hz）.
Embodiment 24
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(2-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) benzhydryl ester (productive rate 68%).
NMR，δ（CDCl
3）：2.63（3H，s），3.56（2H，broad s），4.04（3H，s），5.06（1H，d，J＝5Hz），5.88（1H，dd，J＝5Hz，9Hz），6.73（1H，s），6.82（1H，d，J＝16Hz），6.98（1H，s），7.0-7.5（H29，m）.
Embodiment 25
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-methylthiazol-5-base vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) benzhydryl ester (productive rate 76%).
NMR，δ（CDCl
3）：2.60（3H，s），3.27（1H，d，J＝18Hz），3.48（1H，d，J＝18Hz），4.04（3H，s），5.16（1H，d，J＝5Hz），5.97（1H，dd，J＝5Hz，9Hz），6.13（1H，d，J＝12Hz），6.41（1H，d，J＝12Hz），6.71（1H，s），6.85（1H，s），6.9-7.5（28H，m）.
Embodiment 26
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(thiazole-4-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) is right-methoxybenzyl ester (productive rate 75%).
NMR，δ（CDCl
3）：3.40（1H，d，J＝18Hz），3.62（1H，d，J＝18Hz），3.77（3H，s），4.04（3H，s），5.10（1H，d，J＝5Hz），5.11（2H，s），5.89（1H，dd，J＝5Hz，9Hz），6.53（2H，s），6.7-7.5（23H，m），8.66（1H，d，J＝2Hz）.
Embodiment 27
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) benzhydryl ester (productive rate 69%)
NMR，δ（CDCl
3）：3.27（1H，d，J＝18Hz），3.46（1H，d，J＝18Hz），4.04（1H，d，J＝5Hz），5.96（1H，dd，J＝5Hz，9Hz），6.23（1H，d，J＝12Hz），6.50（1H，d，J＝12Hz），6.71（1H，s），6.83（1H，s），6.9-7.5（27H，m），7.61（1H，s），8.57（1H，s）.
Embodiment 28
7-[2-methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen]-3-[2-(2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) is right-methoxybenzyl ester (productive rate 81%).
NMR，δ（CDCl
3）：3.21（1H，d，J＝18Hz），3.42（1H，d，J＝18Hz），3.76（3H，s），4.04（3H，s），5.09（1H，d，J＝5Hz），5.11（2H，s），5.95（1H，dd，J＝5Hz，9Hz），6.25（1H，d，J＝12Hz），6.47（1H，d，J＝12Hz），6.7-7.4（22H，m）.
Embodiment 29～34
Prepare the following compound that exists with sodium salt or trifluoracetic acid salt form with method similar in appearance to embodiment 21.
Embodiment 29
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-the 3-[2-(thiazol-2-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) sodium salt (productive rate 82%).
NMR，δ（D
2O）：3.82（2H，broad s），4.02（3H，s），5.32（1H，d，J＝5Hz），5.85（1H，d，J＝5Hz），6.99（1H，d，J＝16Hz），7.03（1H，s），7.46（1H，d，J＝16Hz），7.49（1H，d，J＝3Hz），7.76（1H，d，J＝3Hz）.
Embodiment 30
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-vinyl of 3-[2-(2-methylthiazol-5-)]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) trifluoroacetate (productive rate 88%).
NMR，δ（CD
3SOCD
3）：2.62（3H，s），3.75（2H，broad s），3.83（3H，s），5.18（1H，d，J＝5Hz），5.75（1H，dd，J＝5Hz，9Hz），6.75（1H，s），7.13（2H，s），7.60（1H，s），9.58（1H，d，J＝9Hz）.
Embodiment 31
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-vinyl of 3-[2-(2-methylthiazol-5-)]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) trifluoroacetate (productive rate 78%).
NMR，δ（CD
3SOCD
3）：2.59（3H，s），3.41（1H，d，J＝18Hz），3.53（1H，d，J＝18Hz），3.84（3H，s），5.28（1H，d，J＝5Hz），5.82（1H，dd，J＝5Hz，J＝9Hz），6.22（1H，d，J＝12Hz），6.63（1H，d，J＝12Hz），6.73（1H，s），7.57（1H，s），9.60（1H，d，J＝9Hz）.
Embodiment 32
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(thiazole-4-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt (productive rate 74%).
NMR，δ（D
2O）：3.45（1H，d，J＝18Hz），3.58（1H，d，J＝18Hz），4.03（3H，s），5.33（1H，d，J＝5Hz），5.84（1H，d，J＝5Hz），6.56（1H，d，J＝12Hz），6.71（1H，d，J＝12Hz），7.06（1H，s），7.51（1H，d，J＝2Hz），8.99（1H，d，J＝2Hz）.
Embodiment 33
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt (productive rate 78%).
NMR，δ（D
2O）：3.48（1H，d，J＝18Hz），3.70（1H，d，J＝18Hz），4.05（1H，s），5.45（1H，d，2J＝5Hz），5.90（1H，d，J＝5Hz），6.39（1H，d，J＝12Hz），6.81（1H，d，J＝12Hz），7.08（1H，s），7.86（1H，s），8.90（1H，s）.
Embodiment 34
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) ethanoyl]-3-[2-(2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt (productive rate 78%).
NMR，δ（D
2O）：3.46（1H，d，J＝18Hz），3.67（1H，d，J＝18Hz），4.04（3H，s），5.43（1H，d，J＝5Hz），5.91（1H，d，J＝5Hz），6.45（1H，d，J＝12Hz），6.64（1H，d，J＝12Hz），7.08（1H，s）.
Embodiment 35～39
Be prepared as follows compound with the method that is same as embodiment 22.
Embodiment 35
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(2-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide)) (5-methyl-2-oxygen-1, the luxuriant alkene of 3-Er Evil-4-yl) methyl esters (productive rate 62%).
NMR，δ（CDCl
3）：2.21（3H，s），2.69（3H，s），3.65（1H，d，J＝18Hz），3.75（1H，d，J＝18Hz），4.04（3H，s），4.93（1H，d，J＝16Hz），5.12（1H，J＝5Hz），5.14（1H，d，J＝16Hz），5.4（2H，broad），5.99（1H，dd，J＝5Hz，J＝9Hz），6.81（1H，s），6.92（1H，d，J＝16Hz），7.24（1H，d，J＝16Hz），7.53（1H，s），7.64（1H，d，J＝9Hz）.
Embodiment 36
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[2-(2-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) (5-methyl-2-oxygen-1, the luxuriant alkene of 3-Er Evil-4-yl) methyl esters (productive rate 69%).
NMR，δ（CDCl
3）：2.08（3H，s），2.64（3H，s），3.45（1H，d，J＝18Hz），3.54（1H，d，J＝18Hz），4.04（3H，s），4.80（1H，d，J＝16Hz），4.99（1H，d，J＝16Hz），5.22（1H，d，J＝5Hz），5.4（2H，broad），6.10（dd，J＝5Hz，9Hz），6.17（1H，d，J＝12Hz），6.60（1H，d，J＝12Hz），6.78（1H，s），7.46（1H，s），7.72（1H，d，J＝9Hz）
Embodiment 37
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[(2-thiazole-4-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) pivalyl oxygen methyl esters (productive rate 72%).
NMR，δ（CDCl
3）：1.16（9H，s），3.48（1H，d，J＝18Hz），3.68（1H，d，J＝18Hz），4.04（3H，s），5.16（1H，d，J＝5Hz），5.75（1H，d，J＝6Hz），5.86（1H，d，J＝6Hz），5.94（1H，dd，J＝5Hz，9Hz），6.51（1H，d，J＝12Hz），6.58（1H，d，J＝12Hz），6.88（1H，s），7.19（1H，d，J＝2Hz），8.66（1H，d，J＝2Hz）.
Embodiment 38
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[(2-thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) pivalyl oxygen methyl esters (productive rate 76%).
NMR，δ（CDCl
3）：1.13（9H，s），3.32（1H，d，J＝18Hz），3.50（1H，d，J＝18Hz），4.04（3H，s），5.19（1H，d，J＝5Hz），5.74（1H，d，J＝6Hz），5.81（1H，d，J＝6Hz），6.02（1H，dd，J＝5Hz，9Hz），6.35（1H，d，J＝12Hz），6.68（1H，d，J＝12Hz），6.88（1H，s），7.41（1H，d，J＝9Hz），7.75（1H，s），8.66（1H，s）.
Embodiment 39
7-[2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen]-3-[(2-2,4-dichloro thiazole-5-yl) vinyl]-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) pivalyl oxygen methyl esters (productive rate 71%).
NMR，δ（CDCl
3）：1.16（9H，s），3.30（1H，d，J＝18Hz），3.52（1H，d，J＝18Hz），4.05（3H，s），5.16（1H，d，J＝6Hz），5.78（1H，d，J＝6Hz），5.81（1H，d，J＝6Hz），6.05（1H，dd，J＝5Hz，9Hz），6.38（1H，d，J＝12Hz），6.58（1H，d，J＝12Hz），6.91（1H，s）.
Revisal 85106733
After the preceding revisal of the capable revisal of file name page or leaf
Specification sheets 14 from the 4th the row " the present invention also relates to ... " to the 6th row
" ... the method for compound ", leave out.
Claims (16)
1, a kind of method for preparing logical formula I cephalosporin compound and salt or ester,
Wherein R ' is amino group or protected amino group, R
2Be low-grade alkyl group, carboxymethyl group, or protected carboxymethyl group, R
3It is hydrogen atom; salifiable positively charged ion; or carboxy protective group; A is the phenyl group that has not replaced or replace; the furyl group that has not replaced or replaced or the thiazolyl group that has not replaced or replaced or 3-unsubstituted or that replaced be rudimentary-alkyl-thiazolio base group; it is characterized in that this method comprises the mould alkanoic acid compound of the amino cynnematin of 7-of logical formula II
R wherein
3With A as defined above, or 2-(thiazolamine-4-the yl)-2-alkoxyimino-acetic acid reaction of the compound identical (comprising the response derivative of logical formula II compound amino group and the salt of logical formula II compound) and logical formula III with its function,
R wherein
1And R
2As defined above, or identical this reaction of compound (comprising logical formula III compound and sour response derivative) of a function is to carry out in a nonreactive solvent, temperature of reaction is not higher than the boiling point of solvent for use, the reaction back generates the compound of logical formula I, then, and if desired, can be with generate a kind of of logical formula I compound, as general formula (compound shown in the I "), alkylation, promptly by with molecular formula be RX's
(at formula I " in R
1, R
2And R
3R as defined above
4And R
5Can be identical also can be inequality, respectively be hydrogen atom, low-grade alkyl group, or halogen atom)
The alkylogen reaction, make the 3-nitrogen-atoms alkylation of general formula (I ") compound thiazolyl prepare general formula (I ' ") compound, R is a low-grade alkyl group in molecular formula RX, X be halogen atom or single or a two-rudimentary-alkyl-sulphate or rudimentary-alkyl rudimentary-sulfonated alkane
R in formula (I " ')
1, R
2, R
3, R
4And R
5As defined above; the low-grade alkyl group of R and used alkylogen or single or two-low alkyl group vitriol or low alkyl group be rudimentary-and sulfonated alkane is consistent; in addition, if desired, can be from logical formula I or (I ' ") compound remove amino protecting group and carboxyl-protecting group group.
2, according to the method for claim 1, it is characterized in that its be general formula (compound that I a) is represented, wherein
R
1Be amino group or protected amino group, R
2Be low-grade alkyl group, carboxymethyl group or the carboxymethyl group of having protected, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group, Y are hydrogen atoms, low-grade alkyl group, lower alkoxy groups or halogen atom.
3, according to the method for claim 1, it is characterized in that it is the compound of general formula (I b) expression,
Wherein, R
1Be amino group or protected amino group, R
2Be low-grade alkyl group, carboxymethyl group or protected carboxymethyl group, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group, Z are hydrogen atoms, nitryl group or halogen atom.
4, according to the method for claim 1, it is characterized in that it is the compound of general formula (I c) expression,
Wherein, R
1Be amino group or protected amino group, R
2Be low-grade alkyl group, carboxymethyl group or protected carboxymethyl group, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group.
5, according to the method for claim 1, it is characterized in that it is the compound of general formula (I d) expression,
Wherein, R
1Be amino group or protected amino group, R
2Be rudimentary C
1-C
5Alkyl group, carboxymethyl group or protected carboxymethyl group, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group, R are low-grade alkyl groups.
Method is described during 6, according to claim 1, it is characterized in that it is the compound of general formula (I e) expression,
Wherein, R
1Be amino group or protected amino group, R
2Be rudimentary (C
1-C
5) alkyl group, carboxymethyl group or protected carboxymethyl group, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group, y are hydrogen atom or halogen atom, and n is 1 or 2.
7, according to the method for claim 1, it is characterized in that it is the compound of general formula (I f) expression,
Wherein, R
1Be amino group or protected amino group, R
2Be rudimentary (C
1-C
5) alkyl group, carboxymethyl group or protected carboxymethyl group, R
3Be hydrogen atom, salifiable positively charged ion or carboxy protective group.
8, according to the method for claim 1 to 7, it is characterized in that wherein R
1Be amino group, R
2Be methyl or carboxymethyl, R
3Be sodium atom, the diphenyl-methyl group, right-the methoxybenzyl group, valeryl-oxygen-methyl group or (5-methyl-2-oxygen-1,3-two dislikes luxuriant alkene-4-yl)-methyl group.
9, according to the method for claim 1, it is characterized in that a compound wherein can select from following compound: 3-(2-styryl 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen))-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its trifluoroacetate; And 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(ortho-fluorophenyl base) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its trifluoroacetate.
10, according to the method for claim 1, it is characterized in that a compound wherein can select from following compound:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2-furyl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its sodium salt; With
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(5-nitro-2-furyl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its sodium salt.
11, according to the method for claim 1, it is characterized in that a compound wherein can select from following compound:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(thiazol-2-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans structure body, or cis-isomeride, cis-isomeride);
7-(2-methoxyimino-2-(2-aminothiazole-4-yl)-kharophen)-3-(2-thiazole-4-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) and its sodium salt and valeryl-oxygen-methyl ester thereof; With
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(thiazole-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) and its sodium salt and valeryl-oxygen-methyl ester thereof.
12, according to the method for claim 1, it is characterized in that a compound wherein can select from following compound:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its sodium salt, its trifluoroacetate, its valeryl-oxygen-methyl ester, its (5-methyl-2-oxo-1,3-two dislikes luxuriant alkene-4-yl)-methyl ester;
7-(2-carboxylic methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its trifluoroacetate;
7-(2-spy-butoxy carbonyl methoxyimino-2-(2-trityl aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide) or cis-isomeride, cis-isomeride); With
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) and its sodium salt, its trifluoroacetate, its (5-methyl-2-oxo-1,3-two dislikes luxuriant alkene-4-yl)-methyl ester.
13, according to the method for claim 1, it is characterized in that a compound wherein selects from following compound:
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-diuril azoles-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride), its sodium salt, its valeryl-oxygen-methyl ester; With
7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(2,4-dichloro thiazole-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) and its sodium salt, its valeryl-oxygen-methyl ester.
14, according to the method for claim 1, it is characterized in that a compound wherein is 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(3, the vinyl of 4-dimethyl-5-thiazolio))-3-cephem-4-carboxylic acid (cis-isomeride, trans-isomer(ide), or cis-isomeride, cis-isomeride) iodide or two-trifluoroacetate.
15, according to the method for claim 1, it is characterized in that a compound wherein is 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) sodium salt.
16, according to the method for claim 1; it is characterized in that a compound wherein is 7-(2-methoxyimino-2-(2-aminothiazole-4-yl) kharophen)-3-(2-(4-methylthiazol-5-yl) vinyl)-3-cephem-4-carboxylic acid (cis-isomeride, cis-isomeride) valeryl-oxygen methyl ester.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP157005/85 | 1985-07-18 | ||
| JP60157005A JPS6219593A (en) | 1985-07-18 | 1985-07-18 | Novel cephem compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85106733A true CN85106733A (en) | 1987-01-14 |
| CN1034940C CN1034940C (en) | 1997-05-21 |
Family
ID=15640094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85106733A Expired - Lifetime CN1034940C (en) | 1985-07-18 | 1985-09-06 | Preparation process for new cephalosporin compound |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS6219593A (en) |
| CN (1) | CN1034940C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382125A (en) * | 2011-07-29 | 2012-03-21 | 成都市考恩斯科技有限责任公司 | Cefditoren water-soluble composite, preparation method and corresponding pharmaceutical preparation thereof |
| CN102725297A (en) * | 2010-01-27 | 2012-10-10 | 日本化学工业株式会社 | Process for preparation of cephalosporin derivative |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62205088A (en) * | 1986-03-03 | 1987-09-09 | Meiji Seika Kaisha Ltd | Novel cephem compound |
| HU228767B1 (en) * | 1997-06-24 | 2013-05-28 | Meiji Seika Pharma Co | Process for the selective preparation of z-isomers of 3-(2-substituted vinyl)cephalosporins |
| JP4064948B2 (en) * | 2004-06-04 | 2008-03-19 | 明治製菓株式会社 | 3-Alkenylcephem compound and production method |
| CN101245077B (en) * | 2007-02-14 | 2010-06-02 | 山东轩竹医药科技有限公司 | Novel cephalosporin derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0364503A (en) * | 1989-07-28 | 1991-03-19 | Teijin Ltd | Dust-proof cloth |
-
1985
- 1985-07-18 JP JP60157005A patent/JPS6219593A/en active Pending
- 1985-09-06 CN CN85106733A patent/CN1034940C/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102725297A (en) * | 2010-01-27 | 2012-10-10 | 日本化学工业株式会社 | Process for preparation of cephalosporin derivative |
| CN102382125A (en) * | 2011-07-29 | 2012-03-21 | 成都市考恩斯科技有限责任公司 | Cefditoren water-soluble composite, preparation method and corresponding pharmaceutical preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6219593A (en) | 1987-01-28 |
| CN1034940C (en) | 1997-05-21 |
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