CN1315849C - Derivant of cephalosporin alkene, and preparation method - Google Patents
Derivant of cephalosporin alkene, and preparation method Download PDFInfo
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- CN1315849C CN1315849C CNB2004100509018A CN200410050901A CN1315849C CN 1315849 C CN1315849 C CN 1315849C CN B2004100509018 A CNB2004100509018 A CN B2004100509018A CN 200410050901 A CN200410050901 A CN 200410050901A CN 1315849 C CN1315849 C CN 1315849C
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- acid
- compound
- preparation
- salt
- cephem derivative
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- -1 cephalosporin alkene Chemical class 0.000 title abstract description 18
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 9
- 229940124587 cephalosporin Drugs 0.000 title abstract description 9
- 241001597008 Nomeidae Species 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 5
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- JYXACOFERDBGGQ-RHSMWYFYSA-N cefathiamidine Chemical compound S1CC(COC(C)=O)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(NC(C)C)=NC(C)C)[C@H]21 JYXACOFERDBGGQ-RHSMWYFYSA-N 0.000 claims description 22
- 229950005040 cefathiamidine Drugs 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- 150000001782 cephems Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical group CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract description 10
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- 208000015181 infectious disease Diseases 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 241001465754 Metazoa Species 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 28
- 238000003756 stirring Methods 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001035 drying Methods 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 150000003952 β-lactams Chemical class 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002932 luster Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 244000000010 microbial pathogen Species 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- MJGJPHUUDJCUEC-UHFFFAOYSA-N OC(=O)C[Ca] Chemical compound OC(=O)C[Ca] MJGJPHUUDJCUEC-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
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- 229930188189 sulfomycin Natural products 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to derivant of cephalosporin alkene, and the preparation method thereof, which discloses cephalosporin ester amidine having antimicrobial activity, namely acceptable chemical salt with the first characteristic on cephalosporin alkene compound and medicine thereof. The cephalosporin alkene compound makes the cephalosporin ester amidine dissolve in proper solvent to be carried out with catalyzing hydrolysis and condensation by acid, and then the reaction is accomplished through one step. The compound and the salt thereof have stable properties, high purity and good antibacterial activity. The present invention also provides medical compound using the cephalosporin alkene compound as active components and the application in disease infection therapy of human being and animals.
Description
Technical field
The present invention relates to have the cephem compounds and the pharmaceutically acceptable salt thereof of antimicrobial acivity; Relate to have the cynnematin and the pharmaceutically acceptable salt thereof of sulphur amidine acetyl side chain specifically.
Background technology
(β-lactams) means a big class microbiotic that has beta-lactam nucleus in the chemical structure to β-Nei Xiananleikangshengsu, comprise clinical the most frequently used penicillin and cynnematin, and other atypia β-Nei Xiananleikangshengsus such as cephamycin-type of new development, sulfomycin class, monobactams.This type of microbiotic has that fungicidal activity is strong, toxicity is low, indication extensively reaches the good advantage of clinical efficacy.Modify by chemical structure this compounds, promptly by modification to three, four and seven of beta-lactam parent nucleus, obtained acting on the multiple β-Nei Xiananleikangshengsu that characteristics are respectively arranged, formed the microbiotic of many different antimicrobial spectrums and anti-microbial effect and various clinical pharmacology characteristics.
Cefathiamidine is a first generation cephalosporin, has has a broad antifungal spectrum, anti-microbial effect strong (particularly to faecalis, streptococcus aureus), and the Plasma Concentration height, tissue distribution is wide, and clinical efficacy is good, characteristics such as few side effects.Although in clinical use, cefathiamidine is a kind of good first-generation cephem microbiotic, is using and is transporting in the storage process, finds cefathiamidine character instability, and in the put procedure, color and luster is deepened and the content reduction easily.
Tracing it to its cause, at first is because three bit strips of cefathiamidine have an ethanoyl, is hydrolyzed destruction easily; In addition, cefathiamidine also has a quite active carboxyl at four, be subjected to the influence of extraneous various factors easily, cause the variation of this body structure of cefathiamidine, make cefathiamidine generation polymerization or degraded, cause color and luster intensification, content decline and the impurity of product to increase, have influence on the curative effect of cefathiamidine.Cefathiamidine itself is an inner salt in addition, possesses good water-solublely, only is suitable for being prepared into injection and uses, and is also comparatively single aspect administration form.
We have carried out structural modification at the deficiency of cefathiamidine, discovery is by after modifying three, four of the beta-lactam parent nucleus of cefathiamidine, obtain a kind of new cephalosporanic olefinic compound I, Compound I is compared with cefathiamidine, and its structural notable feature is that three and four on the cephem parent nucleus form a stable lactonic ring.Three and four of the relative cefathiamidine of this lactonic ring structure is very stable.
Cephalosporanic olefinic compound I that this is new and salt thereof and their synthetic method are not seen open.The present invention has successfully synthesized Compound I, and has observed its anti-microbial activity and antimicrobial spectrum, finds that Compound I has anti-microbial effect preferably to various bacteriums.
Summary of the invention
An object of the present invention is to provide cephem compounds and pharmaceutically acceptable salt thereof with antimicrobial high activity.
Another object of the present invention provides the preparation method of this cephem compounds and pharmaceutically acceptable salt thereof.
Further aim of the present invention provides a drug regimen, comprising with this cephem compounds and pharmaceutically acceptable salt thereof as activeconstituents.
A further object of the invention provides this cephem compounds and the application of pharmaceutically acceptable salt in the disease infection that treatment causes owing to pathogenic micro-organism thereof.
Technical scheme of the present invention is as follows:
The invention provides a kind of cephem compounds, can represent with following structural formula:
The available following parameter characterization of Compound I (cephalo ester amidine):
1HNMR(DMSO-d
6，500Hz)：
1.23(m，12H，
)，3.29(s，3H，
)，3.83，4.25(d，2H，J＝13.0Hz，C
2-H)，5.05(s，2H，
)，5.14(d，1H，J＝5.0Hz，C
6-H)，5.85(d，1H，J＝4.5Hz，C
7-H)，9.40(d，1H，J＝3.0Hz，
13CNMR(DMSO-d
6，100Hz)：
35.1(t，C-2)，142.9(s，C-3)，122.9(s，C-4)，60.2(d，C-6)，57.0(d，C-7)，163.4(s，C-8)，168.6(s，
)，71.7(t，
)166.8(s，
)，22.7(t，
)，163.4(s，
)，49.7(d，
)，21.4(q，
)，46.6(d，
)，22.3(q，
IR(KBr，cm
-1)：3427、3293、3233、2977，1774，1746，1670，1652，1623，1589，1553，1419，1319，1147，1020，983，677，526。
ESIMS(m/e)：413.3[M+H]
+
FABMS(m/e)：413[M+H]
+
The X-powder diffraction spectrum is indicated as crystal form
X-diffracting spectrum data:
2θ d I/I0
9.46 9.34 1.00
13.00 6.80 0.21
18.98 4.67 0.39
21.00 4.23 0.28
22.20 4.00 0.37
Solvability: this compound is molten in water, methyl alcohol part omitted, and is insoluble in dehydrated alcohol, acetone, methylene dichloride and ether.
Have basic group on the Compound I structure, by with sour salify after can obtain the salt of water miscible Compound I again, the salt of Compound I can be prepared into injection and is used for the treatment of infection like this.
Therefore, the preparation method of the salt of The compounds of this invention obtains for Compound I is added the acid that is fit to.
Compound I can be a salt compatible on the physiology or on the pharmacology, as inorganic acid addition salt and organic acid addition salt class.The salt of above Compound I includes within the scope of the invention.The inorganic acid addition salt class example hydrochloric acid salt of compound, hydrobromate, vitriol, lactic acid salt, Citrate trianion.Nitrate or phosphoric acid salt; Preferably salt hydrochlorate, vitriol, lactic acid salt or Citrate trianion.
The salt of Compound I is example with the vitriol of Compound I, and the X-powder diffraction spectrum shows that it is a crystal form.Its X-diffracting spectrum data are as follows:
2θ d I/I
0
7.78 11.35 0.38
9.26 9.54 1.00
13.42 6.59 0.17
15.62 5.67 0.19
17.98 4.9 0.21
18.60 4.77 0.67
21.82 4.07 0.26
23.52 3.78 0.35
Organic acid addition salt such as tosilate, mesylate, formate, trifluoroacetate or maleate.
Because three and four in the carbon of the beta-lactam nucleus of Compound I has formed a stable lactonic ring; structurally do not have outside active carboxyl of character and ethanoyl be exposed to; so Compound I to ph stability, particularly shows under highly acid condition than cefathiamidine stable properties more.We know that the gastric juice of human body is highly acid, are stable by the Compound I that obtains behind the structural modification in the gastric juice of human body.
The relative cefathiamidine of Compound I in addition, cefathiamidine is water miscible, and Compound I is water-insoluble, and very stable to strong acid, this shows that Compound I can be used for oral administration because the disease infection that pathogenic micro-organism causes;
The preparation method of Cephem Derivative of the present invention is that cefathiamidine formula II is dissolved in the appropriate solvent, with acid-catalyzed hydrolysis and condensation, one step of reaction is finished.
In preparation process, mainly be that the acyl group by three of hydrolysis compound II obtains methylol, methylol obtains lactonic ring with four carboxyl condensation again.This process is not to obtain easily.Because two-step reaction is finished in an individual system, hydrolysis and esterification process are very slow, grope and regulate experimental program by experiment, and we successfully synthesize the high-quality measured Compound I of purity.Because cefathiamidine is extremely unstable under the strong acid and strong base condition, particularly the mother nucleus structure of cefathiamidine itself is destroyed easily down for comparatively high temps (greater than 20 degree), causes the reaction solution color and luster to deepen, and produces a large amount of impurity; If carry out but be reflected under the too low temperature, our needed hydrolysis and esterification process are not easy to obtain.By experiment, discovery can be undertaken by the reaction lucifuge under comparatively high temps, and then reactant is easy to finish, and raw material difficult degraded and polymerization in reaction process, good product quality, and impurity is few, the yield height.
The above-mentioned reaction times is 1 hour to 72 hours, is preferably 12 to 48 hours.
Above-mentioned temperature of reaction is-20 ℃ to 60 ℃, is preferably 0-40 ℃.
The used acid of the present invention comprises organic acid, preferable formic acid, acetate, propionic acid, trichoroacetic acid(TCA), trifluoroacetic acid etc.;
Or mineral acid, preferred hydrochloric acid, bromine hydracid, sulfuric acid, hydrogenchloride, hydrogen bromide etc.;
Or lewis acid, preferred trichoroacetic acid(TCA), trifluoroacetic acid etc.
The present invention is preferably in when reacting with lewis acid under the existence of positively charged ion trapping agent and carries out, and used positively charged ion trapping agent is excellent to be methyl-phenoxide, phenol.
The present invention does not get rid of with suitable alkali as catalyzer, comprise mineral alkali and organic bases: as the carbonate of basic metal (as potassium, sodium etc.), alkaline-earth metal (as calcium, magnesium etc.) or supercarbonate, organic bases is trialkylamine such as Trimethylamine 99, triethylamine, picoline or the like.
Hydrolysis of the present invention and condensation reaction are carried out in the presence of the solvent that reaction is had no adverse effects commonly used exists or be solvent-free usually.Concerning reaction, any solvent of this reaction that do not hinder all can use, as ethers, and ester class, halogenated hydrocarbon, hydro carbons, amides, ketone, nitrile, mixture arbitrarily among alcohols and water or they.
Described solvent is preferably water or comprises amides, ketone, nitrile, alcohols, or the admixture solvent of water and organic solvent with organic solvent that water dissolves each other.
Above-mentioned solvent is methyl alcohol, ethanol, Virahol, acetone, acetonitrile, DMF.
In addition, if the acid, alkali that are used as reaction among the present invention during for liquid, itself also can be used as solvent.
For the purposes of compound 1 is described, the experimental data of the MIC of compound of the present invention (minimum inhibitory concentration) is represented below.
Test method: take conventional extracorporeal bacteria inhibitor test method
Testing data:
Bacteria name minimum inhibitory concentration MIC (mg/L)
Golden staphylococci≤2
Staphylococcus epidermidis≤2
Faecalis 16-128
Streptococcus pneumoniae 0.25-8
Hemophilus influenzae 4-256
Hemolytic streptococcus≤2
Salmonella 8-64
By above substantial evidence, can know that Compound I has bacteriostatic activity preferably to gram-positive microorganism, resistance faecalis and Salmonella there are certain bacteriostatic activity.
The present invention also provides a kind of antibacterial combination, comprises that described Cephem Derivative is as activeconstituents and pharmaceutically acceptable vehicle or carrier.
Above-mentioned antibacterial combination is characterized in that oral preparations or injection formulations.
The compounds of this invention I can be oral as capsule, tablet or granule; Or non-oral as injection, use as known penicillin and cephalosporin preparation.The carrier of injection can be given an example as distilled water or physiological saline.When using as capsule, pulvis, granule or tablet, compatible vehicle (for example, starch, maltose on the pharmacology of Compound I and routine, sucrose, lime carbonate or calcium phosphate), tackiness agent (starch for example, gum arabic, carboxymethyl cellulose, hydroxypropylcellulose or crystalline cellulose), lubricant (for example Magnesium Stearate or talcum powder) and decomposition agent (for example, carboxymethyl calcium or talcum powder) mix mutually.
The pharmaceutical composition that contains Compound I prepares with currently known methods.Said composition is normally produced like this, is about at least a Compound I or its salt and mixes mutually with above-mentioned carrier or vehicle.The ratio that Compound I accounts for whole composition is generally 5-10% (W/W), and to solids composition such as capsule, tablet and granule serve as better with 20-100% (W/W), to liquid composition such as injection etc., serve as better with 5-30% (W/W).
Beneficial effect of the present invention is Compound I from anti-microbial activity, and it has the activity of the resisting gram-positive bacteria of broad; From its physico-chemical property, Compound I has fat-soluble, can consider oral administration, has reduced the treatment cost, and medication is convenient; The salt of Compound I has water-solublely in addition, can consider to be prepared into injection, embodies the rapid-action characteristics of injection.On route of administration, compare with cefathiamidine like this, cefathiamidine can only be used for injection, and route of administration is single, and the route of administration of Compound I is more wide, so Compound I and salt thereof possess unique treatment characteristics in the field of anti-infective therapy.
Compound I stable in properties in addition, the purity height is suitable for storage and transportation, and is not easy to cause that color and luster is deepened, content reduces, and this has guaranteed to have preserved in the actual use of Compound I its good germ resistance from another point of view.
Be embodiment below, embodiments of the invention are not limited to these embodiment.
The preparation of Compound I (cephalo ester amidine)
Embodiment one
Under 30-40 ℃, add 5 gram cefathiamidines in the reactor, add the dissolving of 8ml water and 20ml acetonitrile, filter, add 2.5ml12N hydrochloric acid in the filtrate, insulated and stirred is after 12 hours, between 2-4, stir 3 hours after-filtration with 5% aqueous sodium hydroxide solution regulator solution acidity, the acetonitrile washed twice is drained, drying under reduced pressure, obtain Compound I 3.15 grams, be white or off-white color crystallization, decompose more than 220 ℃ that purity (HPLC normalization method) is 98.1%.
1HNMR(DMSO-d
6，500Hz)：1.23(m，12H，
)，3.29(s，3H，
)，3.83，4.25(d，2H，J＝13.0Hz，C
2-H)，5.05(s，2H，
)，5.14(d，1H，J＝5.0Hz，C
6-H)，5.85(d，1H，J＝4.5Hz，C
7-H)，9.40(d，1H，J＝3.0Hz，
IR(KBr，cm
-1)：
3427，3293，3233，2977，1774，1746，1670，1652，1623，1589，1553，1419，1319，1147，1020，983，677，526。
X-diffracting spectrum data:
2θ d I/I
0
9.46 9.34 1.00
13.00 6.80 0.21
18.98 4.67 0.39
21.00 4.23 0.28
22.20 4.00 0.37
Embodiment two
Under 10-20 ℃, add 5 gram cefathiamidines in the reactor, add 10ml water and 15ml dissolve with methanol, filter, add 3ml12N hydrochloric acid in the filtrate, stir after 30 hours, between 2-4, stir 4 hours after-filtration with 10% ammonia soln regulator solution acidity, twice of washing with alcohol, drain, drying under reduced pressure obtains Compound I 3.05 grams.
The IR of the compound of compound and example one (KBr, cm
-1) and
1HNMR (DMSO-d
6, 500Hz) identical
Embodiment three
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add 8ml water and 20ml acetone and 5ml acetic acid ethyl dissolution, filter, add 5ml phosphoric acid in the filtrate, 35-40 ℃ is stirred after 20 hours, between 2-4, stirs 3 hours after-filtration with 5% aqueous sodium hydroxide solution regulator solution acidity, twice of washing with acetone, drain, drying under reduced pressure obtains Compound I 2.8 grams.
Embodiment four
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add the dissolving of 10ml water and 15ml Virahol alcohol, filter, add 4ml30% sulfuric acid in the filtrate, after lucifuge leaves standstill 48 hours, to 2-4, stir 4 hours after-filtration with 8% ammonia soln regulator solution acidity, twice of washed with isopropyl alcohol, drain, drying under reduced pressure obtains Compound I 3.1 grams.
Embodiment five
Under 0-10 ℃, add 5 gram cefathiamidines in the reactor, add 8ml water and 20ml dissolve with methanol, add 20ml formic acid, stir after 3 hours, the lucifuge room temperature was placed 72 hours, used 8% ammoniacal liquor regulator solution acidity then between 2-4, stirred 3 hours after-filtration, twice of washing with alcohol, drain, drying under reduced pressure obtains Compound I 2.7 grams.
Embodiment six
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add 7ml water and 20ml acetone solution, add 4ml trifluoracetic acid and 1ml methyl-phenoxide, stir after 10 minutes, placed 12 hours, and between 2-4, stirred 2 hours after-filtration for lucifuge 15-20 ℃ with 5% aqueous sodium hydroxide solution regulator solution acidity, twice of washing with acetone, drain, drying under reduced pressure obtains Compound I 2.95 grams.
Embodiment seven
5-10 ℃, add 5 gram cefathiamidines in the reactor, add 10ml water and 20ml dissolve with ethanol, add 3ml12N hydrochloric acid, be warming up to after room temperature leaves standstill 48 hours, with 5% aqueous sodium hydroxide solution regulator solution acidity between 2-4, stir 2 hours after-filtration, absolute ethanol washing twice is drained, drying under reduced pressure obtains Compound I 3.1 grams.
Embodiment eight
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add 10ml water and 20ml dissolve with ethanol, filter, add 3ml12N hydrochloric acid in the filtrate, after lucifuge leaves standstill 24 hours, with 5% aqueous sodium hydroxide solution regulator solution acidity to 2-4, stir 3 hours after-filtration, absolute ethanol washing twice is drained, drying under reduced pressure, obtain Compound I 2.95 grams
Embodiment nine
Under 25-30 ℃, add 5 gram cefathiamidines in the reactor, add 10ml water and 15ml dissolve with ethanol, filter, add 5ml methyl-phenoxide and 5ml trifluoroacetic acid in the filtrate, stirred 5 hours, and between 2-4, stirred 2 hours after-filtration with 5% aqueous sodium hydroxide solution regulator solution acidity, twice of absolute ethanol washing, drain, drying under reduced pressure obtains Compound I 2.4 grams.
The preparation of the salt of Compound I
Embodiment ten
Example one obtains Compound I 5 grams at normal temperatures, add in the reactor, add 6ml water and 12ml ethanol stirring suspension again, the sulfuric acid dissolution solid of dropping 20% in the solution filters, and drips dehydrated alcohol in the filtrate to the solution muddiness, stir growing the grain after 30 minutes, add dehydrated alcohol again, 80ml, normal temperature growing the grain 1 hour, filter, absolute ethanol washing twice is drained, drying under reduced pressure, obtain Compound I vitriol 4.3 grams, be white or off-white color crystallization, purity (HPLC normalization method) is to decompose more than 96.9%, 206 ℃.
X-diffracting spectrum data
2θ d I/I
0
7.78 11.35 0.38
9.26 9.54 1.00
13.42 6.59 0.17
15.62 5.67 0.19
17.98 4.9 0.21
18.60 4.77 0.67
21.82 4.07 0.26
23.52 3.78 0.35
Embodiment 11
Example one obtains Compound I 5 grams at normal temperatures, adds in the reactor, adds 8ml water and 10ml acetone stirring suspension again, drip 3N dissolving with hydrochloric acid solid in the solution, filter, drip acetone in the filtrate to the solution muddiness, stir growing the grain after 30 minutes, add acetone 50ml again, normal temperature growing the grain 1 hour filters, twice of absolute ethanol washing, drain, drying under reduced pressure obtains Compound I hydrochloride 4.1 grams.
Embodiment 12
Example one obtains Compound I 5 grams under 0-5 ℃, adds in the reactor, adds 10ml water and 10ml Virahol stirring suspension again, the sulfuric acid dissolution solid of dropping 20% in the solution filters, and drips Virahol in the filtrate to the solution muddiness, stir growing the grain after 1 hour, add Virahol 80ml again, insulation growing the grain 2 hours filters, twice of washed with isopropyl alcohol, drain, drying under reduced pressure obtains Compound I vitriol 4.2 grams.
Embodiment 13
Example one obtains Compound I 5 grams under 35-45 ℃, adds in the reactor, adds 30ml water stirring suspension again, add 2.6 gram citric acids in the solution, the stirring and dissolving solid filters, drip acetone in the filtrate to the solution muddiness, stir growing the grain after 30 minutes, add acetone 300ml again, cooled to 10-15 ℃ of growing the grain 3 hours, filter, washing with acetone twice is drained, drying under reduced pressure obtains Compound I Citrate trianion 3.1 grams.
Embodiment 14
Under the normal temperature, add example one in the reactor and obtain Compound I 5 grams and lactic acid 2 grams, add 35ml water again, stirring reaction 2 hours, solid dissolving, filter, with 5ml water washing reactor and strainer, merging filtrate, drip Virahol under the room temperature in the solution to the solution muddiness, growing the grain drips Virahol 200ml after 2 hours again, lower the temperature 5-10 ℃ and arrive growing the grain 5 hours, filter twice of washed with isopropyl alcohol, drain, drying under reduced pressure obtains Compound I lactic acid salt 2.7 grams.
Embodiment 15
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add 10ml water and 15ml dissolve with ethanol, filter, add 5ml12N hydrochloric acid in the filtrate, after lucifuge leaves standstill 30 hours, be cooled to 0-5 ℃, drip dehydrated alcohol 150ml, separate out a large amount of solids, stir 3 hours after-filtration, absolute ethanol washing three times, drain
Drying under reduced pressure, the hydrochloride 3.8 that obtains Compound I restrains.
Embodiment 16
Under the normal temperature, add 5 gram cefathiamidines in the reactor, add 10ml water and 15ml one, acetone solution filters, and adds 8ml30% hydrochloric acid in the filtrate, after lucifuge leaves standstill 24 hours, be cooled to 0-5 ℃, drip acetone 100ml, separate out a large amount of solids, stir 4 hours after-filtration, washing with acetone twice is drained, drying under reduced pressure, the vitriol 3.5 that obtains Compound I restrains.
Claims (12)
1, compatible salt on Cephem Derivative shown in the structural formula I and the physiology thereof or on the pharmacology:
2, the described Cephem Derivative of claim 1 is characterized by inorganic acid addition salt or organic acid addition salt class.
3, the described Cephem Derivative of claim 2, wherein inorganic acid addition salt class preferably salt hydrochlorate, vitriol, lactic acid salt or Citrate trianion.
4, the preparation method of the described Cephem Derivative of one of claim 1-3 is characterized in that cefathiamidine is dissolved in the appropriate solvent, with acid-catalyzed hydrolysis and condensation, one step of reaction is finished.
5, the preparation method of the described Cephem Derivative of one of claim 2-3 is characterized in that by Compound I is added the salt that the acid that is fit to obtains Compound I.
6, the preparation method of the described Cephem Derivative of claim 4 is characterized in that the temperature range of reacting is 0 ℃ to 40 ℃, and the reaction times is 12 hours to 48 hours.
7, the preparation method of claim 4 or 5 described Cephem Derivatives is characterized in that described acid is organic acid, mineral acid or lewis acid.
8, the preparation method of the described Cephem Derivative of claim 7 is characterized in that:
Organic acid is formic acid, acetate, propionic acid, trichoroacetic acid(TCA), trifluoroacetic acid etc.;
Mineral acid is hydrochloric acid, bromine hydracid, sulfuric acid, hydrogenchloride, hydrogen bromide etc.;
Lewis acid is trichoroacetic acid(TCA), trifluoroacetic acid etc., uses the positively charged ion trapping agent when reacting with lewis acid, and the positively charged ion trapping agent is methyl-phenoxide, phenol.
9, the preparation method of the described Cephem Derivative of claim 4 is characterized in that described solvent is water or comprises amides, ketone, nitrile, alcohols, or the admixture solvent of water and organic solvent with organic solvent that water dissolves each other.
10, the preparation method of the described Cephem Derivative of claim 9 is characterized in that described solvent is methyl alcohol, ethanol, Virahol, acetone, acetonitrile, DMF.
11, a kind of antibacterial combination comprises that the described Cephem Derivative of one of claim 1-3 is as activeconstituents and pharmaceutically acceptable vehicle or carrier.
12, the antibacterial combination of claim 11 is characterized in that oral preparations or injection formulations.
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