GB2047682A - 3-carbamoyloxymethyl- cephalosporins - Google Patents
3-carbamoyloxymethyl- cephalosporins Download PDFInfo
- Publication number
- GB2047682A GB2047682A GB7932673A GB7932673A GB2047682A GB 2047682 A GB2047682 A GB 2047682A GB 7932673 A GB7932673 A GB 7932673A GB 7932673 A GB7932673 A GB 7932673A GB 2047682 A GB2047682 A GB 2047682A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- compound
- compounds
- formula
- cephalosporin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 31
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 31
- -1 cephalosporin compound Chemical class 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 230000000903 blocking effect Effects 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- SXBDXXFTJVHSAF-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-3-en-8-one Chemical compound S1C=CCN2C(=O)C[C@H]21 SXBDXXFTJVHSAF-ZCFIWIBFSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
- 239000000243 solution Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- 150000001780 cephalosporins Chemical class 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000006260 foam Substances 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000012948 isocyanate Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000002513 isocyanates Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 3
- 229960001668 cefuroxime Drugs 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000002252 carbamoylating effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000003431 oxalo group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Inorganic materials [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 1
- GRNOZCCBOFGDCL-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanate Chemical compound ClC(Cl)(Cl)C(=O)N=C=O GRNOZCCBOFGDCL-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical class CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids 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
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 125000001485 cycloalkadienyl group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- RPNPLURUJVCOAA-UHFFFAOYSA-N dimethoxyphosphorylimino(oxo)methane Chemical compound COP(=O)(OC)N=C=O RPNPLURUJVCOAA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- HSZCJVZRHXPCIA-UHFFFAOYSA-N n-benzyl-n-ethylaniline Chemical compound C=1C=CC=CC=1N(CC)CC1=CC=CC=C1 HSZCJVZRHXPCIA-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 101150061972 zur gene Proteins 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65613—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. cephalosporins and analogs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A process for the preparation of a 3-carbamoyloxymethyl cephalosporin compound which comprises hydrolysing a 3-phosphonocarbamoyloxymethyl methyl cephalosporin compound. The hydrolysis is preferably effected at a pH in the range of pH3 to 4, for example using aqueous sodium hydrogen carbonate.
Description
SPECIFICATION
improvements in correlating to cephalosporin compounds
This invention is concerned with the preparation of cephalosporin compounds substituted at the 3-position
by a carbamoxyloxymethyl group.
The cephalosporin compounds in this specification are systematically named with reference to "cepham" after J. Amer. Chem. Soc., 1962, 84, 3400; the term "cephem" refers to the basic cepham structure with one
double bond.
Many cephalosporin compounds possessing a degree of antibacterial activity are known in the art. These
compounds possess A3 unsaturation and are ordinarily substituted at the 3-position by a methyl or
substituted methyl group, at the 4-position by a carboxy group, and at the 7ss-position by an acylamido
group. In some instances the compounds may additionally be substituted at other positions, for example at
the 2-position (e.g. by one or two methyl groups or a methylene group) and/or at the 7a-position (e.g. by a
lower alkyl, alkoxy or alkythio group).
One class of cephalosporin antibiotics which has attracted considerable interest comprises compounds
substituted at the 3-position by a carbamoyloxymethyl group, i.e. the group -CH2.0;CO.NH2; a number of
antibiotics of this type, possessing a variety of 7ss-acylamido groups, have been proposed.
These 3-carbamoyloxymethyl cephalosporin compounds may usefully be prepared by reacting a
3-hydroxymethyl cephalosporin compound with a substituted isocyanate, i.e. a compound of formula
R. NCO (I)
where R is a labile protecting group, e.g. a trichloroacetyl, 2,2,2-trichloroethoxycarbonyl or chlorosulphonyl
group. This reaction leads to formation of an N-mono-substituted 3-carbamoyloxymethyl cephalosporin
wherein the 3-position substituent has the formula -CH2.O.CO.NHR where R is as defined above; the labile group R may be cleaved from this product by, for example, hydrolytic,
reductive or acid-induced cleavage as appropriate, to yield the desired 3-carbamoyloxymethyl cephalos
porin.
A disadvantage of previously proposed processes of the above type is that the isocyanates of formula (I)
which have hitherto been suggested as appropriate carbamoylating agents tend to be somewhat difficult or
inconvenient to prepare, for example involving hazardous and/orexpensive reagents. Moreover these
reagents and the resulting isocyanates may be difficult or impossible to transport. Thus, for example, the
preparation of carbamoylating agents such as chlorosulphonyl isocyanate and trichloroacetyl isocyanate
typically involve reaction of sulphur trioxide with cyanogen chloride and trichloroacetamide with oxalyl
chloride respectively.
We have now discovered that 3-carbamoyloxymethyl cephalosporins may be prepared in high yield by
hydrolysis of 3-phosphonocarbamoyloxymethyl (3-CH20.CO.NH.PO(OH)2) cephalosporins. Such phospho
nocarbamoyloxymethyl cephalosporins may be prepared in relatively simple and economic manner, if
desired without isolation.
Thus according to one aspect of the presentinvention there is provided a process for the preparation of a
3-carbamoyloxymethyl cephalosporin compound which comprises hydrolysing a 3-phosphono carbamoylaxymethyl cephalosporin compound.
In a preferred embodiment of the process of the present invention, there is provided a process for the
preparation of compounds of general formula
[wherein R1 represents a protected amino group (e.g. an acylamido group, conveniently one which contains 1-40, e.g. 1-20, carbon atoms, or a precursor therefor); R2 represents hydrogen or a carboxyl blocking group (e.g. the ester-forming residue of an alcohol, phenol, silanol or stannanol, the residue preferably being one which may readily be split off at a later stage); R3 represents hydrogen or a lower (e.g. Cur~4) alkyl, alkylthio or alkoxy group e.g. a methoxy group;Z is
; and the dotted line bridging the 2-, 3- and 4-positions of the molecule indicates that the compounds may be ceph-2-em or ceph-3-em compounds] and, where appropriate, salts thereof, which comprises hydrblysing a compound of formula
(wherein R1, R2, R3, Z and the dotted line are as hereinbefore defined) and salts thereof, whereafter if necessary and/or desired any of the following reactions in any appropriate sequence may be carried out:
(i) conversion of a precursor for a desired acylamido into that said group, e.g. by removal of a protecting group,
(ii) conversion of a A2 isomer into a desired A3 isomer,
(iii) removal of any carboxyl blocking group or any hydroxyl or amino protecting groups, and
(iv) reduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally recovering the desired compound of formula II, if necessary and/or desired after separation of any isomers and/or after conversion of the compound to a salt thereof.
It should be noted that the cephalosporin formulae herein are skeletal formulae and are intended to embrace closely related analogues such as 2-methyl, 2-methylene and 2,2-dimethyl cephalosporins.
Preferred compounds of formula II which may be prepared by the process of the invention are compounds of formula
(wherein Rla represents an acylamido group, conveniently one which contains 1 to 40 e.g. 1 to 25, carbon atoms; and R3 is as defined above) and non-toxic derivatives thereof.
The term "non-toxic" as applied to the derivatives of the compounds of formula II' means those derivatives which are physiologically acceptable in the dosages at which they are administered. Such derivatives may include, for example, salts, physiologically acceptable esters, I-oxides and solvates, e.g.
hydrates, of the compounds of formula li' and, where appropriate, combinations thereof.
The compounds of formula II' and non-toxic derivatives thereof which may be prepared by the process of the invention are characteristed by antibacterial activity against a range of gram-positive and gram-negative organisms coupled with stability in the presence of serum.
The above compounds of formulae ll, ll' and Ill may be capable of forming base salts such as alkali metal, e.g. sodium or potassium, alkaline earth metal, e.g. calcium, ammonium and organic amine, e.g. procaine, 1-aminoadamantane, phenylethylbenzylamine, dibenzylethylene diamine, ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine and amino acid (e.g. lysine, arginine, ornithine and histidine in the d-, I- and dl-forms) salts.
A particularly preferred product of the process of the invention is (6R,7R)-3-carbamoyloxymethyl-7-[Z-2- (fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxysic acid, having the approved name of cefuroxime and non-toxic derivatives thereof, which may be prepared by hydrolysis of the corresponding compound (6R, 7R)-3-phosphonocarbamoyloxymethyi-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4- carboxylic acid or a salt thereof.
The hydrolysis of the 3-phosphonocarbamoyloxy-methyl cephalosporin is conveniently carried out in aqueous solution. The reaction medium may thus be water alone or in combination with a suitable water miscible inert organic solvent. Solvents which may be used include ethers such as tetrahydrofuran and dioxan.
The hydrolysis reaction of the process of the invention is generally effected at a pH below 5 and preferably at a pH in the range pH 3 to 4. In order to work in this range it may be appropriate to add either acid or base to the reaction mixture. In the hydrolysis, it may be desirable to buffer the aqueous system, e.g. with sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium phospate, calcium carbonate or calcium hydroxide, or add an acid or base, e.g. sodium hydroxide, during the course of the hydrolysis in order to maintain the pH within any desired limits. The use of aqueous sodium hydrogen carbonate has proved to be particularly convenient in the hydrolysis reaction.
The hydrolysis may, for example, be conducted at a temperature in the range of -5" to +1050C, e.g. +15 to +60 C, and may, where necessary, be monitored by, for example, chromatography. The reaction time may be significantly affected by both the temperature and pH of the reaction system.
After completion of the hydrolysis the desired 3-carbamoyloxymethyl cephalosporin of formula II may be isolated by, for example, conventional methods, e.g. by solvent extraction where the product is a carboxyl protected derivative such as an ester, or by acidification and precipitation or by extraction where the cephalosporin compound is a free acid or a salt.
The starting materials of formula lli for use in the process of the invention may conveniently be prepared from a corresponding 3-hydroxymethyl cephalosporin of formula
(wherein R1, R2 and R3, Z and the dotted line are as hereinbefore defined), for example, by reaction with dihalo-phosphinyl isocyanates of formula X2.PO.NCO (wherein each X represents a halogen atom, such as chlorine) followed by reaction with water, conveniently at a pH of 10 or less. The dihalophosphinyl isocyanates may be prepared in relatively simple and economic manner e.g. by reaction of an appropriate phosphorus pentahalide with a carbamic acid ester.If desired, the starting material of formula Ill for use in the process of the present invention may be prepared in situ and subsequently hydrolysed without isolation to give the desired 3-carbamoyloxymethyl cephalosporin product. However, if it is desired to isolate a compound of formula Ill, the initial reaction with water is desirably effected at a pH of from 5 to 10.
Acylamido groups which may be present at the 7-position of cephalosporin starting materials and products in the process of the invention e.g. as the group R1 in formulae (II) to (IV) may, for example, be selected from the wide range of side chain acylamido groups known in the ss-lactam antibiotic art. It will be appreciated that where the acylamido group carries substituents such as amino, hydroxy or mercapto groups, these substituents may, if necessary and/or desired, be protected by substitution with an appropriate group.
Thus, for example, amino groups may be protected by substitution with a mono- or di-vaient blocking group, suitable groups including acyl groups, for example lower alkanoyl such as acetyl, substituted lower alkanoyl, e.g. lower haloalkanoyl or phenylacetyl and aroyl such as benzyl or phthaloyl; lower alkoxycarbonyi or t- butoxycarbonyl and substituted lower alkoxycarbonyl groups e.g. lower haloalkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl; aryl-lower alkoxycarbonyl groups such as benzyloxycarbonyl; sulphonyl groups, for example lower alkylsulphonyl such as methanesulphonyl and aryl-sulphonyl such as benzene sulphonyl orp-toluene sulphonyl; ylidine groups formed by reaction with an aldehyde or ketone which forms a Schiff's base, for example acetone, methylethylketone, benzaldehyde, salicylaldehyde or ethyl acetoacetate; and divalent groups such that the nitrogen atoms forms part of a dihydropyridine ring (protecting groups of this last sort being obtained by, for example, reaction with formaldehyde and a (3-ketoester, e.g. acetoacetic ester, as described in Belgian Patent No. 771,694). Hydroxyl-and mercapto groups may for example, be protected by substitution with carboxylic or sulphonic acyl groups in like manner to amino groups, or, where appropriate, by etherification orthioetherification (e.g. to introduce a branched lower alkyl group such as isopropyl or t-butyl or an aralkyl group such as benzyl substituted by one or more methoxy groups, diphenylmethyl ortriphenylmethyl).The protecting groups may subsequently be removed from the cephalosporin product by methods well known in the art, for example by hydrolytic reductive or acid-induced cleavage as appropriate.
Where the acylamido group is substituted by a carboxyl group it may also be advantageous to protect this during the course of the reaction, for example by etherification to introduce an ester group as herein described in connection with the group R2.
Specific acyl groups which may be present in acylamido groups R1 are illustrated in the following list, which is not intended to be exhaustive:
(i) RUCnH2nCO- where RU is aryl (carbocyclic or hetercyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl, or a non-aromatic or mesionic group, and n is an integer from 1 to 4. Examples of this group include phenylacetyl wherein the phenyl group may if desired be substituted by, for example, one or more of fluoro, nitro, protected amino, protected hydroxy (e.g. esterified hydroxy such as acetoxy), methoxy, methylthio or methyl; N,N-bis (2-chloroethyl)aminophenylpropionyl; thien-2- and -3-ylacetyl; 3and 4-isoxazolylacetyl either substituted or unsubstituted; pyridylacetyl; tetrazolylacetyl; cyclohexadienylacetyl; cur a sydnonacetyl group.Where n is other than 0, especially where n is 1, the a-carbon atom of the acyl group may be substituted by, for example, an esterified hydroxy (e.g. acyloxy such asformyloxy or lower alkanoyloxy), etherified hydroxy (e.g. methoxy), protected amino (e.g. as herein before described), carboxy, esterified carboxy,triazolyl,tetrazolyl or cyan group our a halogen atom; examples of such a-substituted acyl groups include esterified 2-hydroxy-2-phenylacetyl, N-blocked 2-amino-2-phenylacetyl ca rboxy-2-phenylacetyl and esterified 2-ca rboxyacetyl phenylacetyl.
(ii) CnH2N+1CO- where n isO or an integer from 1 to 7. The alkyl group may be straight or branched and, if desired may be interrupted by an oxygen or sulphur atom and/or may be substituted by, for example, a cyano group, a carboxy or esterified carboxy group (e.g. an alkoxycarbonyl group), an esterified hydroxy group, a blocked amino group or a carboxycarbonyl (-CO.COOH) or esterified carboxycarbonyl group.
Examples of such groups include formyl, cyanoacetyl, butylthioacetyl, hexanoyl, heptanoyl, octanoyl, glutaroyl, esterified glutaroyl, and N-blocked (e.g. N-ethoxycarbonyl or N-benzoyl) and optionally esterified
R-5-amino-5-carboxypentanoyl (e.g. R-5-benzamido-5-diphenyl methoxycarbonyl pentanoyl or R-5 diphenylmethoxycarbonyl-5-isobutoxycarbonylaminopentanoyl).
where RU has the meaning defined under
(i) and in addition may be benzyl, RV and RW (which may be the same or different) each represents hydrogen, phenyl, benzyl, phenethyl or lower alkyl and Z is an oxygen or sulphur atom. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-phenoxypropionyl, 2-phenoxybutryl, methylthiophenoxyacetyl, phenylthioacetyl, chloro-and fluoro- phenylthioacetyl, pyridylthioacetyl and benzylthioacetyi.
(iv) Substituted glyoxylyl groups of the formula RY.CO*CO- where RY is an aliphatic, araliphatic or aromatic group, e.g. phenyl, thienyl or furyl or a fused benzene ring. Also included in this class are the a-carbonyl derivatives of the above substituted glyoxylyl groups, e.g. the a-alkoxyimino, a-aryl-oxyimino and a-acyloxyimino derivatives, especially those possessing the syn-configuration with respect to the 7-carboxamido group.Groups of this type, of which an example is the Z-2- (fur-2-yl)-2-methoxyiminoacetyl group, and which may be represented by the formula
[whel-ein R3 represents hydrogen or an organic group (especially a carbocyclic or heterocyclic aromatic
group such as phenyl, naphthyl, thienyl, thiazolyl e.g. aminothiazolyl, orfuryl) and R4 represents hydrogen,
an acyl group (e.g. a lower alkanoyl, alkenoyl, alkynoyl, haloalkanoyl, alkoxycarbonyl, haloalkoxycarbonyl,
alkythiocarbonyl or aralkyloxycarbonyl group or an aroyl or carbamoyl group) or an etherifying group (e.g. a
lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aralkyl group or carbocyclic or heterocyclic aryl
group, or any of these groups substituted by a carboxy, esterified carboxy, aminocarbonyl or N-substituted
aminocarbonyl group)], are described in greater detail in Belgian Patent Nos. 778630783449; 801997;
806450; 823651 and 843152.
Where R2 in formulae (II) to (IV) represents an esterifying group this may, for example be selected from the
wide range of esterifying groups known in the cephalosporin art. A range of groups of this type, together
with methods for their introduction and subsequent removal, are described in British Patent No. 1342241.
Representative esterifying groups thus include aryl lower alkyl groups such as p-methoxybenzyl,
p-nitrobenzyl and diphenylmethyl; lower alkyl groups such as t-butyl; and lower haloalkyl groups such as 2,2,2-trichlorethyl. It will of course be appreciated that R2 may represent an ester group in a compound which
is to be used in medicine in which case this group should be physiologically acceptable.When such an ester
group is employed it may not be necessary or desirable to effect deprotection of the carboxyl group Where at the end of a given preparative sequence the sulphoxide analogue of the compound of formula (II) is obtained, conversion to the corresponding sulphide may, for example, be effected by reduction of the
corresponding acyloxysulphonium or alkyloxysulphonium salt prepared in situ by a known method, such as
is described in British Patent Specification No. 1453049.
As also described in British Patent Specification No. 1453049 a ceph-2-em-4-carboxylic ester may be
coverted into a desired ceph-3-em compound by treatment of the former with a base.
The following Examples illustrate the present invention.
Notes on experimental
All temperatures are quoted in C. Structures of the products of Examples 2 and 3 were confirmed by
infrared and nuclear magnetic resonance spectra, the latter being effected at 100 MHz.
T.l.c. is thin-layer chromatography using pre-coated plates (Merck F254, 0.25 mm thick coating) which were
examined under ultraviolet light at 254 nm and were developed by spraying with ninhydrin in n-butanol and
heating to approx. 1400C or by exposure to iodine vapour.
PREPARATION 1 (6R, 7R)-3-Phosphonocarbamoyloxymethy/-7-fZ-2-(fur-2.yl)-2-methoxyiminoacetamidojcept-3-em-4- carboxylic acid
Dichlorophosphinyl isocyanate (5.28 g) in dioxan (20 ml) was added to a stirred suspension of (6R, 7R)-3-hydroxymethyl-7-[Z-2-(fu r-2-yl )-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid (11.44 g) in
dioxan (80 ml) at 16 in a water bath; after initial addition of the isocyanate the temperature rose to 240 and
eventually fell to 17". After 10 minutes the solution was filtered under nitrogen and 1 molar aqueous sodium
bicarbonate solution (192 ml) was added to give a pH of 7.1. The solution was extracted with ethyl acetate (2
x 150 ml) to remove lactone impurity. Ethyl acetate (150 ml) was then added to the aqueous phase (pH 8.2)
and the pH was adjusted to 0.5 by addition of concentrated hydrochloric acid. The resultant two phase
suspension was separated and the aqueous suspension extracted with n-butanol (3 x 250 ml). Water (30 ml)
was added to the butanol extract and the aqueous layer was run off. The organic phase was evaporated in
vacuo to a thick slurry. Filtration of this slurry afforded a solid which was washed with ether (3 x 50 ml) and
dried in vacuo for 20 hours to give the title compoundsolvated with ca 1 mole of n-butanol (5.54 g), [a]20 + 45 (c 0.93, pH 7 phosphate buffer); XmaX 273 nm (E1it'm 298).
The aqueous suspension was filtered to give a solid which was washed with n-butanol (30 ml) and ether
(100 mi) and dried in vacuo to give the title compound(4.37 g), [a]021 + 440 (c 0.96, pH 7 phosphate buffer); AmaX 273 nm (E1cm 317).
PREPARATION 2 (6R, 7R)-3-Phosphonocarbamoyloxymeth yl-7-fZ-2-(fur-2-yl)-2-meth oxyiminoacetamidolcep t-3-em-4- carboxylic acid trisodium salt
Portions (5.04 g and 5.73 g) of the first product obtained in Preparation 1 were dissolved in solutions of
sodium bicarbonate (2.52 g and 2.86 g) in water (35 ml). The solutions (pH 6.7) were applied to columns
containing Amberlite XAD-2 resin [1 kg. previously washed with methanol (5.litres) and water (20 litres)]. The
columns were eiuted with water and fractions (ca 50 ml) were collected and examined by TLC. Fractions 15 to
25 for each product were combined (pH 8.3 and 7.5) and freeze-dried to give a solid material 3.15 g and 2.80 9).
The two solids were combined, dissolved in water (50 ml) and re-chromatographed on the same column
[after washing through with water (2 litres)]. Fractions (ca 50 ml) were collected and examined byTLC.
Fractions 22 to 30 were combined and freeze-dried to give the title compound (1.02 g), [a]021 + 41.80 (c 1.037, H2O); xmax 275 nm (E11c'm 297).
PREPARATION 3
(a) (6R, 7R)-3-Dimethoxyphosphosphorylcarbamoyloxyethyl-7-[Z-2-für-2-yl]-2-
methoxyiminoacetamidojceph-3-em-4-carboxylic acid
A solution of dimethoxyphosphinyl isocyanate (7.25 g), in dry tetrahydrofuran (4 ml) was added to a
solution of (6R, 7R)-7-[Z-2-(fu r-2-yl)-2-methoxyi minoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (6.10 g) in dry THF (40 ml) and the resultant mixture was stirred at room temperature for 1.5 hours. The
mixture was then evaporated in vacuo to an oily gum which was dissolved in ethyl acetate (50 ml). The
resultant organic solution was extracted with saturated aqueous sodium bicarbonate solution (50 ml) and
the aqueous extract was washed with ethyl acetate.The aqueous extract was layered with ethyl acetate (30
ml) and was then acidified to pH 0.5 by addition of concentrated hydrochloric acid, and was then extracted
with ethyl acetate (3x30 ml) and the combined organic extracts were dried (sodium sulphate) and evaporated
in vacuo to a white foam. Trituration of this foam with di-isopropyl ether gave an off-white solid which was
redissolved in ethyl acetate. Addition of di-isopropyl ether (400 ml) to the ethyl acetate solution caused
precipitation of a solid which after filtration and drying afforded the title compound (8.27 g) as a white solid;
m.p. (M20) 72", [a] jz3 + 38 (c0.96, pH7 phosphate buffer).
(b) (R and SJ-i-Acetoxyethyl 66Rt 7R)-3-dimethoxyphosphoryl-carbamoyloxymethyl-7-[Z-2-Ffur-2-yl)-2- methoxyiminoacetamido]-ceph-3-em-4carboxylate and (Rand S)- 1-acetoxyethyl (4R, 6R, 7R)-3- dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(für-2-yl]-2-meth oxyimoacetamido]cept-2-em-4- carboxylate
Potassium carbonate (0.55 g) was added to a stirred mixture of (6R,7R)-3-dimethoxyphosphoryl
carbamoyloxymethyl-7-[Z-2-(fu r-2-yl )-2-methoxyiminoacetamido]ceph-3-em-4-carboxyl ic acid (4.26 g) in Sdimethylformamide (10 ml) at room temperature.
Stirring was continued for 1.5 hours by which time most of the potassium carbonate had dissolved.
The reaction mixture was then cooled to 0 and a solution of (R,S)-1-acetoxyethyl bromide (1.47 g) in DMF
(5 ml) was added. The resultant solution was stirred at 0 for 1 hour and was then partitioned between 2N-hydrn'chloric acid (100 ml) and ethyl acetate 100 ml). The aqueous phase was further extracted with ethyl
acetate (2x50ml) and the combined organic extracts were washed successively with 2N-hydrochloric acid (2x100 ml), water (2x100 ml),saturated aqueous sodium bicarbonate solution (2x100 ml), water (2x100ml), saturated brine (100 ml) and dried (sodium sulphate) and evaporated in vacuo to a foam.A solution of this
foam in ethyl acetate (10 ml) was precipitated from diisopropyl ether to give a mixture of the title esters (2.01
g) as a white solid; vmax (Nujol) 3180 to 3150 (2xNH), 1790 (ss-lactam),1764(CO2R), and 1680 and 1538 cm-l (CONH). The
n.m.r. spectrum (DMSO-d6) indicated an approximate A3:A2 -isomer ratio of 3:2.
(c) (R and S)- I-A cetoxyethyl IIS,6R, 7R)-3-Dimethoxy-phosphorylcarhamoyloxymethyl-7-JZ-2-(fur-2-yl)-2- methoxyiminoacetamidoJcept-3-em-4carboxylate, 1-oxide m-Chloroperbenzoic acid (0.9449) in dichloromethane (10 ml) was added at 0 to a stirred solution of two
batches of (R and S)-l-acetoxyethyl (6R,7R)-3-dimethyoxy-phosphorylca rbamoyloxymethyl-7-[Z-2-(fur-2-yl )
2-methoxyiminoacetamido]cept-3-em-4-carboxylate and its A2 isomer (ratio ca 3:2) (3.34 g) in dry
dichloromethane (20 ml).After 25 minutes reaction was not complete (by t.l.c.) so another portion of
m-chloroperbenzoic acid (93 mg) was added and the reaction mixture was stirred for a further 10 minutes and evaporated in vacuo to a foam. T.l.c. indicated incomplete oxidation so the foam was re-dissolved in dichloromethane and treated with further m-chloroperbenzoic acid (0.236 g) for 20 minutes by which time reaction was complete. The reaction mixture was then evaporated in vacuo to a foam which was dissolved in ethyl acetate (5 ml) and precicipated from excess di-isopropyl ether to give the tftle compound (3.033 g) as a pale-yellow solid, m.p. (M2130) 150 , [a]D2 + 67.50 (e 0.98, DMSO).
(d) (R and S)-A cetoxyethyl f6R, 7R)-Dimethoxyphosphorvl-carbamoyloxymethyl-7-JZ-2-(fur-2-yl)-2- methoxyiminoacetamidol cept-3-em-4-carboxylate Potassium iodide (2.50 g) and acetyl chloride (0.56 ml) were successively added, at 0 , to a solution of the product of (b) above (2.38 g) in dimethylformamide (15 ml).
The reaction mixture was stirred for 70 minutes at 0" and was then partitioned between ethyl acetate (100 ml) and 2N-hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (2x50ml) and the combined organic extracts were successively washed with 2N-hydrochloric acid (100 ml), aqueous sodium metabisulphite solution (2x100ml), 2N-hydrochloric acid (100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated brine (100 ml).The organic extract was dried (magnesium sulphate) and evaporated in vacuo to a yellow foam which on precipitation from di-isopropyl ether afforded the title ester (1.722 g) as a pale-yellow solid, m.p. (M720) 101 , [a]D25 +22.40 (cm.89, DMSO)..
(e) (R and S)-Acetoxyethyl (6R, 7R) 3-phosphonocarbamaoyl xymethyl-7-[Z-2-ffur-2-yly-2- methoxyiminoacetamidojceph-3-em-4-carh oxylate Bromotrimethylsilane (0.31 g) in dichloromethane (3 ml) was added to a cooled (0 ) stirred mixture of (R and S)-1 -acetoxyethyl (6R,7R)-3-dimethoxyphoxphorylca rba moyloxy-methyl-7-[Z-2-(fur-2-yl)-2- methoxyiminoacetamido]cept-3-em-4-carboxylate (0.62 g) andtrimethylsilylurethane (0.16 g) in dry dichloromethane (12 ml) in a nitrogen atmosphere. After 2.5 hours the reaction mixture was evaporated in vacuo to a foam.This foam was dissolved in ethyl acetate (30 ml) although a slight precipitate remained. The filtered organic solution was treated with saturated aqueous sodium bicarbonate solution (30 ml) and the aqueous solution was layered with butan-1 -ol (2omni) and acidified to pH 0.5 by addition of concentrated hydrochloric acid. The aqueous phase was extracted with butan-1-ol (2x15ml) and the combined organic extracts were evaporated in vacuo to give a solid.Trituration of this solid with di-isopropyl ether afford the title ester (0.396 g) as a solid; Vmax (Nujol) 3270 (NH), 1788 (ss-lactum),1734 (CO2R) and 1684 and 1540 cm- (CONH); T (DMSO-d6)0.18 (d, J 8Hz, NH), 2.9 to 3.4 (broad m, 2 superimposed q, CHCH3),4.14 (m,7-H, mixture of diastereoisomers), 4.76 (m, 6-H mixture of diastereoisomers), 7.92 (s,OCOCH3) and 8.52 (d, J 5Hz,
CHCH3).
EXAMPLE 1 {6R, 7Ry-3-Carbamoyloxymethyl-7-[Z-2-(fur-2-yly-2-methoxy-iminoacetamidoncept-3-em-4-carboxylic acid (cefuroxime) A solution of (6R,7R)-3-phosphonocarbamoyloxy-methyl-7-[Z-2-(fur-2-yl)-2-methOxyiminoacetamido]cept- 3-em-4-carboxylic acid (0.35 g) in water (4 ml) and dioxan (1 ml) was kept successively at 40"for 5 hours, room temperature for 16 hours, 400 for 6 hours and 200 for 16 hours. The conversion to the title compound was monitored by t.l.c. A precipitate was formed and this was filtered off. The pH was altered from 4 to 7 by addition of saturated aqueous sodium bicarbonate solution.
The resultant mixture was washed with ethyl acetate (25 ml) and the aqueous phase was acidifed to pH2 (with concentrated hydrochloric acid) which was extracted with ethyl acetate (3 x 25 ml). The organic extracts were combined and washed successively with water and saturated brine, dried (magnesium sulphate) and evaporated in vacuo to an oil. Trituration of this oil with ether afforded the title compound as a solid (41 mg) with ultraviolet (pH6 phosphate buffer) and n.m.r. (DMSO-d6) spectra in accord with an authentic specimen.
EXAMPLE 2
Cefuroxime
A solution of (6R, 7R)-3-phoshonocarbamoyloxy-methylJ-[Z-2-(fur-2-yl)-2- methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, trisodium salt, trihydrate (1.25 g) in water (40 ml) had its pH adjusted from 6.9 to 3.5 by addition of 2N-hydrochloric acid and saturated aqueous NaHCO3 and was kept at 40 for 3.75 hours.
The pH of the reaction mixture was kept at ca. 3.5 by periodic addition of portions of 2N-hydrochloric acid.
After 3.75 hours, saturated aqueous sodium bicarbonate was added to give a pH of 7 and the solution was washed with ethyl acetate (50 ml) and then covered with further ethyl acetate (50 ml). The organic phase was acidifed to pH 2 with orthosphosporic acid, and then extracted with ethyl acetate (50 ml). The combined organic phases were washed with water (2 x 50 ml) and saturated brine (50 ml), then dried over magnesium sulphate and evaporated in vacuo to give the title compound (0.600 g) as a white solid [a]D1 + 51 (c 1.00, DMSO), Xmax (pH6 phosphate buffer) 275 nm (E1 M m 422, E 17 900).
EXAMPLE 3 (R and S)- i-Acetoxyethyl (6R, 7RJ-3-carbamoyloxymethyl-7- [Z-2-)fur-2-yl)-2-methoxyiminoacetamidoiceph- 3-em-4-carboxylate
A solution of (R and S)-1 -acetoxyethyl (6R,7R)-3-phosphonocarbamoyloxymethyl-7-[Z -2-(fu r-2-yl)-2methoxy-iminoacetamido]ceph-3-em-4-carboxylate (0.226 g) in tetrahydrofuran ( 5 ml) and pH 4 buffer (20 ml) was kept at pH4 for 3.75 hours at 40".
The solution was poured. into saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic phase was washed with water (2 x 20 ml) and saturated brine (20 ml) then dried over magnesium sulphate and evaporated to an oil (0.092 g) which, after precipitation from ethyl acetate-petrol (b.p.40 to 60 ) gave the title ester (0.054 g) as a solid; [a]D2 + 57.3" (c 1.08, DMSO), Xmax (CHCl3) 281 nm (E' c/ m 289, E14 750).
Claims (6)
1. A process for the preparation of a 3-carbamoyl-oxymethyl cephalosporin compound which comprises hydrolysing a 3-phosphonocarbamoyloxymethyl cephalosporin compound.
2. A process for the preparation of compounds of general formula
[wherein R' represents a protected amino group; R2 represents a protected amino group; R2 represents hydrogen or a carboxyl blocking group; R3 represents hydrogen or a lower alkyl, alkythio or alkoxy group; Z is S or SO (a- or ss-); and the dotted line bridging the 2-, and 4-positions of the molecule indicates that the compounds may be ceph-2-em or ceph-3-em compounds] and, where appropriate, salts thereof, which comprises hydrolysing a compound of formula
(wherein R1, R2, R3, Z and the dotted line are as hereinbefore defined) and salts thereof, whereafter if necessary and/or desired any or the following reactions in any appropriate sequence may be carried out: (i) conversion of a precursor for a desired acylamido into that said group, (ii) conversion of a A2 isomer into a desired A3 isomer, (iii) removal of any carboxyl blocking group of any hydroxyl or amino protecting groups, and (iv) reduction of a cephalosporin sulphoxide product to yield the corresponding sulphide; and finally recovering the desired compound of formula II, if necessary and/or desired after separation of any isomers and/or after conversion of the compound to a salt thereof.
3. A process as claimed in claim 2 wherein the hydrolysis is effected at a pH below 5.
4. A process as claimed in claim 2 substantially as herein described in any one of the Examples.
5. Compounds of formula il as defined in claim 2 and salts thereof whenever prepared by a process as claimed in claim 2.
6. (6R, 7R)-3-Carbamoyloxymethyl-Z-2-(f ur-2-yl )-2-methoxyi minoacetamido]ceph-3-em-4-carboxylic acid and non-toxic derivatives thereof whenever prepared by a process as claimed in claim 2.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7932673A GB2047682B (en) | 1979-04-06 | 1979-09-20 | 3-carbamoyloxymethyl-cephalosporins |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7912215A GB2018764B (en) | 1978-04-07 | 1979-04-06 | Cephalosporin compounds |
GB7932673A GB2047682B (en) | 1979-04-06 | 1979-09-20 | 3-carbamoyloxymethyl-cephalosporins |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2047682A true GB2047682A (en) | 1980-12-03 |
GB2047682B GB2047682B (en) | 1983-04-20 |
Family
ID=26271160
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7932673A Expired GB2047682B (en) | 1979-04-06 | 1979-09-20 | 3-carbamoyloxymethyl-cephalosporins |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2047682B (en) |
-
1979
- 1979-09-20 GB GB7932673A patent/GB2047682B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB2047682B (en) | 1983-04-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
HU182686B (en) | Process for preparing 7-/2-/2-amino-thiazolyl/-2-/1-carboxy-1,1-dialkyl-alkoxiimino-acetamido/-cefem-sulphoxides | |
US4048311A (en) | 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins | |
US4258183A (en) | Process for the preparation of cephalosporin compounds | |
JPH0245636B2 (en) | ||
EP0453924A1 (en) | A process for synthesizing cephalosporin compounds | |
CA1122972A (en) | Cephalosporin compounds | |
US4284766A (en) | Process for the preparation of cephalosporin compounds | |
GB2047682A (en) | 3-carbamoyloxymethyl- cephalosporins | |
US3852277A (en) | 3-{8 ({60 -methoxy-4-substituted cinnamoyl)oxymethyl{9 -7-acylamidoceph-3-em-4-carboxylic acids | |
CS228920B2 (en) | Method of preparing chloromethylester of penicillanic acid derivative | |
US4252974A (en) | Cephalosporin compounds | |
US4138554A (en) | 7-[D-α-(4-Hydroxy-1,5-naphthyridine-3-carboxamido)-α-phenyl (and p-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acids | |
US4118490A (en) | 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins and pharmaceutical compositions containing them | |
EP0023045B1 (en) | Imidazolecarboxylic acid derivatives of penicillins and cephalosporins | |
US4081595A (en) | Reduction giving 3-cephem compounds | |
GB2034312A (en) | A process for the preparation of cephalosporins | |
US4211703A (en) | Phosphonoalkyl and esterified phosphonoalkyl substituted tetrazole thiols | |
CS216935B2 (en) | Method of maling the derivatives of the 7-beta-aminothiazolylactamido-3-cefem-4-carboxyle acid | |
US3994889A (en) | 3-Heterothio derivatives of (α-thiocarbonylaminol)-7α-methoxy-cephalosporins | |
IE48286B1 (en) | 3-phosphonocarbamoyl-oxymethyl cephalosporins and the production of 3-carbamoyloxymethyl cephalosporins | |
KR830000376B1 (en) | Process for preparing cephalosporin compound | |
US4112086A (en) | 7β-Acylamino-3-(phosphonoalkyl and esterified phosphonoalkyl substituted tetrazolylthiomethyl)cephalosporins | |
PL85224B1 (en) | ||
EP0018155A2 (en) | Novel cephalosporin compounds, a process for the preparation thereof, pharmaceutical compositions containing the same and the use thereof as a therapeutic agent against a microorganism | |
CA1086755A (en) | Process for the manufacture of 3-methylene-butyric acid derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |