NO833626L - PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC ACTIVE BETA LACTAMES - Google Patents
PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC ACTIVE BETA LACTAMESInfo
- Publication number
- NO833626L NO833626L NO833626A NO833626A NO833626L NO 833626 L NO833626 L NO 833626L NO 833626 A NO833626 A NO 833626A NO 833626 A NO833626 A NO 833626A NO 833626 L NO833626 L NO 833626L
- Authority
- NO
- Norway
- Prior art keywords
- hydrogen
- amino
- alkyl
- phenyl
- substituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 23
- 230000003115 biocidal effect Effects 0.000 title 1
- -1 2-phenylethenyl Chemical group 0.000 claims description 128
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000001589 carboacyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 9
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 7
- 125000006371 dihalo methyl group Chemical group 0.000 claims description 6
- 125000004970 halomethyl group Chemical group 0.000 claims description 6
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 229940098779 methanesulfonic acid Drugs 0.000 description 31
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 11
- 150000002367 halogens Chemical class 0.000 description 11
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 10
- 125000001841 imino group Chemical group [H]N=* 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- VRNJMUWKOQKNTP-UHFFFAOYSA-N aminooxymethanesulfonic acid Chemical compound NOCS(O)(=O)=O VRNJMUWKOQKNTP-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 150000002960 penicillins Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 description 3
- YYLQUHNPNCGKJQ-NHYDCYSISA-N (3R)-3-hydroxy-L-aspartic acid Chemical compound OC(=O)[C@@H](N)[C@@H](O)C(O)=O YYLQUHNPNCGKJQ-NHYDCYSISA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- BYHXLDZDSZVDJH-UHFFFAOYSA-N acetic acid;1,3-thiazole Chemical compound CC(O)=O.C1=CSC=N1 BYHXLDZDSZVDJH-UHFFFAOYSA-N 0.000 description 2
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 150000001734 carboxylic acid salts Chemical class 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229960002898 threonine Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DCEMCPAKSGRHCN-JCYAYHJZSA-N trans-2,3-epoxysuccinic acid Chemical compound OC(=O)[C@@H]1O[C@H]1C(O)=O DCEMCPAKSGRHCN-JCYAYHJZSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- IPJUIRDNBFZGQN-SCZZXKLOSA-N (2s,3r)-3-hydroxy-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 IPJUIRDNBFZGQN-SCZZXKLOSA-N 0.000 description 1
- GKLDLSWOQDYOQT-UHFFFAOYSA-N (3-aminoazetidin-1-yl)oxymethanesulfonic acid Chemical compound NC1CN(OCS(O)(=O)=O)C1 GKLDLSWOQDYOQT-UHFFFAOYSA-N 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 244000182067 Fraxinus ornus Species 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
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-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
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005276 alkyl hydrazino group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- LAPIVKPVIQAIDA-UHFFFAOYSA-L dipotassium methanesulfonate Chemical compound S(C)(=O)(=O)[O-].S(C)(=O)(=O)[O-].[K+].[K+] LAPIVKPVIQAIDA-UHFFFAOYSA-L 0.000 description 1
- CDMADVZSLOHIFP-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 CDMADVZSLOHIFP-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010915 one-step procedure Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 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
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 1
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LVTHXRLARFLXNR-UHFFFAOYSA-M potassium;1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound [K+].[O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LVTHXRLARFLXNR-UHFFFAOYSA-M 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- ABYVLIWKJMBHJO-UHFFFAOYSA-M sodium;bromomethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CBr ABYVLIWKJMBHJO-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002053 thietanyl group Chemical group 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
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Denne oppfinnelse er rettet på en ny familie av B-laktam antibiotika, og på bruken av slike forbindelser som antibakteriel- This invention is directed to a new family of B-lactam antibiotics, and to the use of such compounds as antibacterial-
le midler. Det er blitt oppdaget at $-laktamkjernen kan biolo-le means. It has been discovered that the $-lactam core can biologically
gisk aktiveres ved en substituent som har formelengisk is activated by a substituent having the formula
(eller salt derav) bundet til nitrogenatomet i kjernen. (3-laktamer som har en substituent (eller farma-søytisk akseptable salter derav) i 1-posisjon og en acylamino substituent i 3-posisjon viser aktivitet mot en rekke gram-nega-tive og gram-positive bakterier.Illustrerende medlemmer av den nye familie av 3-laktam antibiotika ifølge foreliggende oppfinnelse er de som omfattes av formelen (or salt thereof) bound to the nitrogen atom in the nucleus. (3-lactams having a substituent (or pharmaceutically acceptable salts thereof) in the 1-position and an acylamino substituent in the 3-position show activity against a variety of gram-negative and gram-positive bacteria. Illustrative members of the new family of 3-lactam antibiotics according to the present invention are those covered by the formula
eller en ester eller salt derav. or an ester or salt thereof.
Som brukt i formel I og videre utover i beskrivelsen, er symbolene definert som nedenfor. As used in formula I and further beyond in the description, the symbols are defined as below.
R^ er acyl; R 1 is acyl;
f*2 er hydrogen eller metoksy; ;R, og R^er like eller forskjellige og er hver hydrogen,;alkyl, alkenyl, alkynyl, cykloalkyl, fenyl, substituert fenyl eller en 4,5,6 eller 7-leddet heterosyklisk ring (heretter refe- ;rert til som R^) eller en av R^og R^er hydrogen og den andre er azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, alkoksykarbonyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, -CP^X^, ; eller er azido, amino (-Nr^), hydroksy, alkanoylamino, alkylsulfonyloksy, fenylsulfonyloksy, (substituert fenyl) sulfonyloksy, fenyl, substituert fenyl, cyano, -S-X2eller -O-X2; X2 er alkyl, substituert alkyl, fenyl, substituert fenyl, fenylalkyl, substituert fenylalkyl, alkanoyl, substituert alkanoyl, fenylkarbonyl, substituert fenylkarbonyl eller heteroarylkarbonyl; en av X^og X^er hydrogen og den andre er hydrogen eller alkyl, eller X^og X^sammen med karbonatomet til hvilke de er bundet danner en cykloalkylgruppe; X^ er formyl, alkanoyl, fenylkarbonyl,substituert fenylkarbonyl, fenylalkylkarbonyl, sunbstituert fenylalkylkarbonyl, karboksyl, alkoksykarbonyl, aminokarbonyl substituert aminokarbonyl eller cyano (-C=N); A er -CH=CH-, -CH2-CH=CH-, -(CH2)-n, -(CH2)n,<-0->,~(CH2)n, -NH-, eller -(CH2)n, -S-CH2; n er 0, 1, 2 eller 3; n' er 1 eller 2; Xg og X^er like eller forskjellige og er hver hydrogen eller alkyl, eller Xg er hydrogen og X^er amino, substituert amino, acylamino eller alkoksy; og R^og Rg er like eller forskjellige og er hver hydrogen, alkyl, alkenyl, alkynyl, fenyl, substituert fenyl, cykloalkyl eller R^, eller R^ og Rg sammen med karbonatomet til hvilke de er bundet er cykloalkyl eller R^, eller en av R^og Rg er hydrogen og den andre er azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, alkoksykarbonyl, 2-fenyletenyl, 2-fenyletynyl, karboksy, -CH^ , -S-X2, -0-X2 eller ; Listet nedenfor er definisjoner av forskjellige uttrykk anvendt for å beskrive 3-laktamer ifølge oppfinnelsen. Disse ;i ;definisjoner anvendes på uttrykkene som de er brukt gjennom beskrivelsen (untatt at de på annen måte er begrenset i spesielle tilfeller) enten individuelt eller som en del av en større gruppe. ;Uttrykkene "alkyl" og "alkoksy" refererer til både rette og forgrede kjeder. De kjeder som har 1 til 10 karbonatomer er foretrukne. ;Uttrykkene "cykloalkyl" og "cykloalkenyl" refererer til cykloalkyl og cykloalkenyl grupper som har 3, 4, 5, 6 eller 7 karbonatomer. ;Uttrykket "substituert alkyl" refererer til alkylgrupper substituert med en, eller fler, azido, amino (-NH2), halogen, hydroksy, karboksy, cyano, alkoksykarbonyl, aminokarbonyl, alkanoyloksy, alkoksy, fenyloksy, substituert fenyloksy, R^-oksy, merkapto, alkylthio, fenylthio, substituert fenylthio, alkyl-sulfinyl, eller alkylsulfonyl-grupper. ;Uttrykkene "alkanoyl", "alkenyl", "alkenyl" og "alkynyl" refererer til både rette og forgrenede kjeder. De kjeder som har 2 til 10 karbonatomer er foretrukne. ;Uttrykkene "halogen" og "halo" refererer til fluor, klor, brom og iod. ;Uttrykket "beskyttet karboksyl" refererer til en karboksyl-gruppe som er blitt estrifisert med en konvensjonell syrebeskyt-telses-gruppe. Disse gruppene er vel kjente; se for eksempel US-patent nr. 4.144.333, utgitt 13. mars 1979. De foretrukne beskyttede karboksylgrupper er benzyl, benzhydryl, t-butyl, og p-nitrobenzyl-estere. ;Uttrykket "substituert fenyl" refererer til en fenylgruppe substituert med 1, 2 eller 3 amino (-NI^), halogen, hydroksyl, trifluormetyl, alkyl (med 1 til 4 karbonatomer), alkoksy (med 1 til 4 karbonatomer), eller karboksylgrupper. ;Uttrykket "en 4, 5, 6 eller 7-leddet heterocyklisk rin" . ;(referert til som "R^") refererer til substituerte og usubsti-tuerte aromatiske og ikke-aromatiske grupper inneholdende en eller fler nitrogen, oksygen eller svovelatomer. Eksempler på substituenter er okso(=0),haloge, hydroksy, nitro, amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer, alkylsulfonyl, fenyl, substituert fenyl, 2-furylimino ; ; benzylimino og substituerte alkylgrupper (i hvilke ;alkylgruppene har 1 til 4 karbonatomer). En type "4, 5, 6 eller 7-leddete heterocykliske ringer" er "heteroaryl"-gruppen. Uttrykket "heteroaryl" refererer til de 4, 5, 6 eller 7-leddete heterocykliske ringer som er aromatiske. Eksempler på heteroaryl-grupper er substituert og usubstituert pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oksazolyl, triazinyl, og tetrazolyl. Eksempler på ikke-aromatiske heterocykler (det er helt eller delvis mettede heterocykliske ringer) er substituert og usubstituert azetinyl, oksetanyl, thietanyl, piperidinyl, ;piperazinyl, imidazolidinyl, oksazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl og heksahydroazepinyl. Eksempler på substituerte 4,5,6 eller 7-leddete heterocykliske ringer er 1-alky1-3-azetinyl, 2-okso-1-imidazolidinyl, 3-alkylsulfonyl-2-okso-1-imidazolidinyl, 3-benzylimino-2-okso-1-imidazolidinyl, 3-alkyl-2-okso-1-imidazolidinyl, 3-fenyl eller substituert fenyl)-2-okso-1-imidazolidinyl, 3-benzyl-2-okso-1-imidazolidinyl, 3-(2-aminoetyl)-2-okso-1-imidazolidinyl, 3-amino-2-okso-1-imidazolidinyl, 3- [(alkoksykarbonyl)amino] -2-okso-1 - imidazolidinyl, 3- [2- [(alkoksyk arbonyl)-amino] etyl) -2-okso-1-imidazolidinyl, 2-okso-1-pyrrolidinyl, 2-okso-3-oksazolidinyl, 4-hydroksy-6-metyl-2-pyrimidinyl, 2-okso-1-heksahydroazepinyl, 2-okso-3-pyrrolidinyl, 2-okso-3-furanyl, 2,3-diokso-1-piperazinyl, 2,5-diokso-1-piperazinyl, 4-alkyl-2,3-diokso-1-piperazinyl, og 4-fenyl-2,3-diokso-1-piperazinyl. ;Uttrykket "substituert amino" refererer til en gruppe som;har formelen -^^2i hvilken Y- er hydrogen, alkyl, fenyl, substituert fenyl, fenylalkyl eller substituert fenylalkyl, og Y2er alkyl, fenyl, substituert fenyl, fenylalkyl, substituert fenylalkyl, hydroksy, cyano, alkoksy, fenylalkoksy, eller amino (-NH2). ;Uttrykket "substituert alkanoyl" inkluderer forbindelser;som har formelen;substituert ; ; (i hvilken "substituert alkyl" er definert ;ovenfor) og fenylalkanoyl.;Uttrykket "acyl" refererer til alle organiske radikaler avledet fra en organisk syre (det er en karboksylsyre) ved fjerning av hydroksylgruppen. Visse acylgrupper er selvsagt foretrukne, men denne preferanse skal ikke sees på som en begrensning av denne oppfinnelse. Eksempler på acylgrupper er de acylgrupper som er blitt brukt i det siste til å acylere 6-laktam antibiotika inklusive 6-aminopenicillansyre og derivater av denne og 7-amino-cefalosporansyre og derivater av denne; se for eksempel Cephalosporins and Penicillins, edited by Flynn, Academic Press ;(1972), tysk Offenlegunsschrift nr. 2.716.677, publisert 10. oktober 1978, belgisk patent 867.994, publisert 11. desember 1978, US-patent nr. 4.152.432, utgitt 1. mai 1979, US-patent nr. 3.971.778, utgitt 27.juli 1976, US-patent nr. 4.172.199, utgitt 23. oktober 1979, og britisk patent nr. 1.348.894, publisert 27. mars 1974. Deler av disse referanser beskriver forskjellige acyl-grupper som inkorporeres heri som referanse. Den følgende liste av acyl-grupper er vist for å videre eksemp-lifisere uttrykket "acyl"; den skal ikke betraktes som en begrensning. Eksempler på acyl-grupper er: ;(a) Alifatiske grupper som har formelen; ; i hvilken R er alkyl; cykloalkyl; alkoksy; alkenyl; cykloalkenyl; cykloheksadienyl; eller alkyl eller alkenyl substituert med en eller flere halogen, cyano, nitro, amino, merkapto, alkylthio, eller cyanometylthio-grupper. ;(b) Karboksyliske aromatiske grupper som har formelen; i hvilke n er 0, 1, 2 eller 3; R^, Rc, og R^er hver uavhengig hydrogen, halogen, hydroksyl,nitro, amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer eller aminometyl; og Rg er amino, hydroksyl, et karboksylsalt, beskyttet karboksyl, formyloksy, et sulfosalt, et sulfoamino-salt, azido, halogen, hydrazino, alkylhydrazino, fenylhydrazino, eller (alkylthio)thioksymetyl thio. Foretrukne karbocykliske aromatiske acyl-grupper inkluderer de som har fomelen ; (Rg er fortrinnsvis et karboksylsyresalt eller et sulfonsyresalt);og ; (Re fortrinnsvis et karboksylsyresalt eller eller et sulfonsyresalt). (c) Heteroaromatiske grupper som har formelen i hvilke n er 0, 1, 2 eller 3; Re er som definert ovenfor; og R^ er en substituert eller usubstituert 5-, 6- eller 7-leddet heterocyklisk ring inneholdende 1,2,3 eller 4 (fortrinnsvis 1 eller 2) nitrogen, oksygen og svovelatomer. Eksempler på heterocykliske ringer er thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl og tetrazolyl. Eksempler på substituenter er halogen, hydroksyl, nitro, amino, beskyttet amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer, eller ; Foretrukne heteroaromatiske acyl-grupper inkluderer de grupper med de ovenfor angitte formler i hvilke R^er 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, eller 6-aminopyridin-2-yl. ;(d) £ \_( 4-substituerte-2 , 3-diokso-1 -piperazinyl)karbonyl) amino]arylacetyl-grupper har formelen ; i hvilken R^er en aromatisk gruppe (inklusive karboksykliske aromatiske grupper slik som de med formelen ; og heteroaromater som er inkludert i definisjonen av R^); og-R^er alkyl, substituert alkyl (i hvilken alkylgruppen er substituert med en eller flere halogen, cyano, nitro, amino, eller merkapto-grupper), arylmetylenamino (det er -N=CH-R i hvilken R er som ;g 9 ;definert ovenfor), arylkarbonylamino (det er; ; i hvilken R^er definert som ovenfor) eller alkylkarbonyl- ;amino.;Foretrukne £ [_( 4-substituerte-2,3-diokso-1-piperazinyl) karbonyl] amino]arylacetyl grupper inkluderer de i hvilke R^er etyl, fenylmetylenamino eller 2-furylmetylenamino. ;(e) Substituerte oksyimino-arylacetyl-grupper som har formelen ; i hvilken R^ er som definert ovenfor og R^er hydrogen, Rc, alkyl, cykloalkyl, alkylaminokarbonyl, arylaminokarbonyl (det er -C-NH-R i hvilken R er som definert ovenfor) eller substituert alkyl (i hvilken alkylgruppen er substituert med 1 eller flere halogen, cyano, nitro, amino, merkapto, alkylthio, aromatisk gruppe (som definert ved R g), karboksyl (inklusive salter derav), amido, alkoksykarbonyl,fenylmetoksykarbonyl, difenylmetoksy-karbonyl, hydroksyalkoksyfosfinyl, dihydroksyfosfinyl, hydroksy (fenylmetoksy)fosfinyl, eller dialkoksyfosfinyl-substituenter. ;Foretrukne substituerte oksyaminoarylacetyl-grupper inkluderer de i hvilke R ger 2-amino-4-thiazolyl. Også foretrukket er de grupper i hvilke R^ er metyl, etyl, karboksymetyl, 1-karboksy-1-metyletyl, 2 ,2,2-trifluoretyl eller 1-karboksycyklopropyl. ;(f) Acylamino-arylacetyl-grupper som har formelen; i hvilken R er definert som ovenfor og R. er amino, alkylamino, cyanolalkylamino, amido, alkylamido, cyanoalkyl-amido, ; Foretrukne acylamino-arylacetyl-grupper med ovennevnte formel inkluderer de grupper i hvilke R^er amino eller amido. Også foretrukket er de grupper i hvilke R^ er fenyl eller 2-tienyl. ;(g) £ [[3-substituerte-2-okso-1 -imidazolidinyl] karbonyl] amino] arylacetyl-grupper som har formelen ; ; i hvilken R er som definert ovenfor og R, er hydrogen, alkyl-;g k ;sulfonyl, arylmetylenamino (det er -N=CH-Rg i hvilke R^ er som definert ovenfor), ;0 -C-R (i hvilken Rm er hydrogen, alkyl eller halogensubstituert-alkyl), aromatisk gruppe (som definert for R yovenfor), alkyl eller substituert alkyl (i hvilken alkyl-gruppen er substituert med en eller flere halogen, cyano, nitro, amino eller merkapto-grupper). ;Foretrukne [[ [_3-substituerte-2-okso-1 -imidazolidinyl] karbonyl] amino]arylacetyl-grupper med ovenfor angitte formel inkluderer de i hvilke Rg er fenyl eller 2-tienyl. Også foretrukket er de grupper i hvilke R^er hydrogen, metylsulfonyl, fenylmetylenamino eller 2-furylmetylenamino. ;Uttrykkene "salt" og "salter" refererer til basiske salter dannet med uorganiske og organiske baser. Slike salter inkluderer ammoniumsalter, alkalisalter som natrium og kaliumsalter, ;(som er foretrukne), jordalkalimetallsalter som kalsium og magnesiumsalter, salter med organiske baser, for eksempel di-cykloheksylamin-salter, benzatin, N-metyl-D-glukamin, hydrobamin-salter, salter med aminosyrer som arginin, lysin og lignende. De ikke-toksiske farmasøytiske akseptable salter er foretrukne, selv om andre salter også er brukbare, for eksempel for å isolere eller rense produktet. ;Saltene dannes på konvensjonell måte ved å reagere den fri-syreformen av produktet med en eller flere ekvivalenter av den passende base forutsatt at det ønskede kation i et løsningsmiddel eller medium i hvilke saltet er uløselig, eller i vann og fjerning av vannet ved frysetørring. Ved nøytralisering av saltet med en uløselig syre som en kation-bytter i hydrogenformen (for eksempel polystyrensulfonsyreione-bytter som Dowex 50) eller med en vandig syre og ekstrasjon med et organisk løsningsmiddel, for eksempel etylacetat, diklormetan eller lignende, den fri syreform kan oppnås, og, hvis ønsket, et annet dannet salt. ;3-laktamene som har en ; ; H-substituent (eller salt ;derav) i 1-posisjon og en amino eller acylamino substituent i 3-posisjon inneholder i det minste ett kiralt senter - karbon-atom (i 3-posisjon til 3-laktamkjernen) til hvilken amino eller acylamino substituenten er bundet. Denne oppfinnelsen er rettet på de 3-laktamer som er blitt beskrevet ovenfor, i hvilke stereokjemien ved det kirale senter i 3-posisjonen i 3-laktamkjernen er den samme som konfigurasjonen ved karbonatomet i 6-posisjonen i naturlig forekommende penicilliner (for eksempel penicillin G) ;og som konfigurasjonen ved karbonatomet i 7-posisjonen i naturlig forekommende cefamyciner, (for eksempel cefamycin C). ;Med hensyn til de foretrukne 3-laktamer med formel I, er strukturformlene tegnet for å vise stereokjemien ved det kirale senter i 3-posisjon. ;Også inkludert i foreliggende oppfinnelse er rasemiske blandinger som inneholder ovenfor beskrevne 3-laktamer. ;3-laktamer som har en ; substituent (eller salt derav) i 1-posisjonen i 3-laktamkjernen og en acylaminosubstituent i 3-posisjon i 3-laktamkjernen har aktivitet mot en rekke gram-negative og gram-positive organismer. ; substituenten (eller salt derav) er essensiell for akti- ;viteten til forbindelsene ifølge foreliggende oppfinnelse. ;Forbindelsene ifølge foreliggende oppfinnelse kan brukes som midler til å bekjempe bakterieinfeksjoner (inklusive urin-rørsinfeksjoner og luftveisinfeksjoner) hos pattedyr, slik som husdyr (for eksempel hunder, katter, kuer, hester og lignende) og mennesker. ;For å bekjempe bakterieinfeksjoner hos pattedyr kan forbindelser ifølge foreliggende oppfinnelse administreres til et pattedyr med behov for dette i en mengde på ca. 1,4 mg/kg/dag til ca. 350 mg/kg/dag, fortrinnsvis ca. 14 mg/kg/dag til ca. ;100 mg/kg/dag. Alle typer administrasjon som er blitt brukt i det siste for å gi penicilliner og cefalosporiner på infeksjons-stedet er også tenkt brukt for den nye familie av 3-laktamer ifølge foreliggende oppfinnelse. Slike administrasjonsmetoder inkluderer orale, intravenøse, intramuskulære, og suppositoriske. ;3-laktamene ifølge foreliggende oppfinnelse kan fremstilles fra en aminosyre som har formelen ; Aminogruppen blir først beskyttet med en klassisk beskyttelses-gruppe (for eksempel t-butoksykarbonyl, benzyloksykarbonyl, o-nitrofenylsulfenyl, etc), til å gi en forbindelse som har formelen ; I formel III og videre utover i beskrivelsen refererer symbolet "A^" til en nitrogenbeskyttende gruppe. ;Karboksylgruppen av en beskyttet aminosyre med formel III omsettes så med ett amin med formelen ; Reaksjonen utføres i nærvær av et koblingsmiddel slik som 1-etyl-3-(3-dimetylaminopropyl)-karbodidimid eller dicykloheksylkarbo-diimid, og gir et salt av forbindelsen som har fomelen ; Hydroksylgruppen til en forbindelse med formel V (eller et salt derav) omdannes til en utgående gruppe, ved å bruke for eksempel et klassisk reagens slik som metansulfonylklorid (metansulfonyl refereres heretter til som "Ms"). ;Den fullt beskyttede forbindelse har formelen ; ; eller et salt derav,;blir cyklisert ved behandling med base, for eksempel kaliumkarbonat. Reaksjonen utføres ofrtrinnsvis i et organisk løsnings-middel slik som aceton, under refluks betingelser, og gir en forbindelse som har fomelen ; ; eller et salt derav.;Alternativt kan cyklisering av en forbindelse med formel V utføres uten først å omdanne hydroksylgruppen til en utgående gruppe. Behandling av en forbindelse med formel V (eller salt derav) med trifenylfosfin og dietylazodikarboksylat eller karbon-tetraklorid og trietylamin, gir en forbindelse med formel VII. ;Begge metodene vist ovenfor for ringslutning av en forbindelse med formel V resulterer i inversjon av stereokjemien ved karbon bundet til R^og R^substituenter. ;Avspalting av 3-amino substituenten på en forbindelse med formel VII kan utføres ved å bruke vanlig kjente teknikker. Hvis for eksempel beskyttelsesgruppen er t-butoksykarbonyl, kan trifluoredikksyre brukes for å avspalte denne gruppen fra aminogruppen. Hvis beskyttelsesgruppen er benzyloksykarbonyl, kan katalytisk (for eksempel palladium på trekull) hydrogenering brukes. Hvis beskyttelsesgruppen er o-nitrofenylsulfenyl, kan p-toluensulfosyre brukes sammen med p-tiokresol. Forbindelsen fra hvilke beskyttelsesgruppene er avspaltet har formelen ; eller et salt derav,;og er et nøkkelintermediat for å fremstille forbindelsene ifølge foreliggende oppfinnelse. Forbindelsene med formel VIII danner en del av foreliggende oppfinnelse. ;Vel kjente acyleringsteknikker kan brukes for å omdanne en forbindelse med formel VIII til den korresponderende forbindelse som har formelen ; ; eller et salt derav.;Eksempler på teknikker inkluderer reaksjon med en karboksylsyre (R^-OH) eller korresponderende karboksylsyrehalogenid eller karboksylsyreanhydrid. Reaksjonene med en karboksylsyre går lettest i nærvær av et karbodiimid slik som dicykloheksylkarbo-diimid og en substans som er istand til å danne et reaktivt intermediat in situ slik som N-hydroksybenzotriazol eller 4-dimetyl-aminopyridin. I disse tilfeller i hvilke acylgruppen (R^) inneholder reaktive funksjonelle grupper (slik som amino eller karboksylgrupper) kan det være nødvendig først å beskytte disse funksjonelle gruppene, deretter utføre acyleringsreaksjonen, og til slutt av spalte beskyttelsesgruppene for å oppnå det resulterende produkt. ;Produktene med formel I i hvilke R2er metoksy kan fremstilles fra den korresponderende forbindelse med formel VII i hvilken er benzyloksykarbonyl. Halogenering (fortrinnsvis klorering) ;av amidnitrogenet av en forbindelse med formel VII (A1 er benzyloksykarbonyl) i en forbindelse som har formelen ; ; eller et salt derav. ;Reagenser og prosedyrer for N-kloreringsamider er vel kjente. Eksempler på reagenser er tert. -butylhypokloritt, natriumhypoklo-ritt, og klor. Reaksjonen kan utføres i et organisk løsnings-middel (for eksempel en lavere alkanol slik som metanol) eller i et to-fase løsningsmiddelsystem (for eksempel vann/metylenklorid) i nærvær av en base slik som natriumborat dekahydrat. Reaksjonen utføres fortrinnsvis ved redusert temperatur. ;Reaksjon av en forbindelse med formel X som et metoksyleringsmiddel, for eksempel et alkalimetallmetoksyd, gir en forbindelse (i kombinasjon med dens enantiomer hvis R^og R^er de samme eller hvis X er en rasemisk blanding) som har fomelen ; ; eller et salt derav.;Reaksjonen kan utføres i et organisk løsningsmiddel, for eksempel et polart organisk løsningsmiddel slik som tetrahydrofuran, ved redusert temperatur. ;Alternativt kan en forbindelse med formel VII i hvilken A^;er benzyloksykarbonyl, omdannes til en forbindelse med formel XI ved å anvende en ett-trinns prosedyre. Metoksyleringsmiddelet kan først blandes med en forbindelse med formel VII (A^er bezyloksykarbonyl) og deretter tilsette N-kloreringsmiddelet til reaksjonsblandingen. ;Omdannelse av en forbindelse med formel XI til de ønskede produkter med formel I kan utføres ved å bruke prosedyrer beskrevet ovenfor for omdannelse av et intermediat med formel VII til et produkt ifølge foreliggende oppfinnelse. ;Utgangsmaterialene med formel II oppnås lett ved å bruke velkjente prosedyrer; se for eksempel Synthesis, side 216 (1979) ;og J. Org. Chem., 44:3967 (1979).;De følgende eksempler er spesifikke utførelser av denne oppfinnelse. ;Eksempel 1;f3S- [ 3a( Z) , 4g)] - 2- [[ Ll-( 2- amino- 4- tiazolyl)- 2-[[ 4- metyl- 2- okso-1 - ( sulf ometoksy ) - 3- azetidinyl) - amino] - 2- oksoetylidenJamino] oksy ;- 2- metylpropansyre, dikaliumsalt.;A) Aminoksymetansulfonsyre;Acetonoksim (1,46 g, 20 mmol) ble satt til en suspensjon av;en 60% mineraloljedispersjon av natriumhydrid (0,8 g, 20 mmol) i 16 ml tørr dimetylsulfoksyd. Dette ble fulgt av porsjonsvis tilsetting av natrium brom-metansulfonat (3,94 g, 20 mmol). Reaksjonen ble varmet til 90-95°C i 4 timer under nitrogen, avkjølt og vasket to ganger med 250 ml eter. Produktet størknet, ble vasket med 100 ml diklormetan, filtrert og tørket over ^ 2®$ til å gi 15,3 g råmateriale. Dette ble oppløst i 20 ml vann og tetrabutylammoniumhydrogensulfat (7,5 g, 22 mmol) ble tilsatt. ;Det resulterende ioneparede produkt ble ekstrahert to ganger med;200 ml diklormetan. Diklormetanløsningen ble tørket (Na2SO^, og konsentrert in vacuo. Hydrolyse av acetonoksimet ble utført ved varming i 120 ml 2N HC1 ved 130°C i 4 timer. Denne løsningen ble konsentrert in vacuo fra vann to ganger deretter fra acetonitril. Produktet stivner ved tilsetting av deklormetan, og ble filtrert og tørket in vacuo til å gi 2,5 g av tittelforbindelsen. B) 0- sulfometyl- g- N- t- butoksykarbonyl- L- treonin hydroksamat, kalium salt. ;Aminooksymetansulfonsyre (1,14g, 8,9 mmol) ble satt til en løsning av t-butoksykarbonyl-L-treonin (1,96 g, 8,9 mmol) i 16 ml vann og 4 ml tetrahydrofuran ved 0°C. pH ble justert til 4,5 med 1N KOH, og 1-etyl-e-(3-dimetylaminopropyl)karbodiimid hydroklorid (1,87 g, 9,7 mmol) i ml vann ble dråpevis tilsatt. Reaksjonsblandingen ble rørt ved omgivelsestemperatur i 2 timer, og under denne tid ble pH opprettholdt ved 4 til 4,5 ved av og til å tilsette 1N H2SO4. Produktet ble ioneparet med tetrabutylammonium hydrogensulfat (3,05 g, 8 mmol) ved pH 2,8 og ekstrahert fra den vandige løsning med fire 100 ml porsjoner diklormetan, Diklor-metanløsningen ble tørket (Na2S0^) og konsentrert in vacuo til å ;gi 4,5 g av produktet som tetrabutylammoniumsalt. Dette ble om-dannet til kaliumsalt ved ionebytting på 150 ml Dowex 50X (0,7 meqK<®>/ml), og etter lyofilisering, ble 2,63 g tittelforbindelse oppnådd. ;C) O- sulfometyl- a- N- t- butoksykarbonyl- L-( O- metansulfonyl-treonin ) hydroksamat , tetrabutylammonium salt ;Til en delvis løsning av O-sulfometyl-a-N-t-butoksykarbonyl-L-treonin hydroksamat, kaliumsalt (2,37g, 6,5 mmol) i 50 ml tørr pyridin ble dråpevis tilsatt ved 0-5°C under nitrogen 0,8 ml (overskudd) metansulfonylklorid. Reaksjonen ble rørt ved romtemperatur i 4 timer, og deretter konsentrert in vacuo. Residuet ble oppløst i 10 ml vann, og 2,0 g (6 mmol) tetrabutylammonium hydrogensulfat ble tilsatt ved pH 2,8. Det ioneparede materiale ble ekstrahert med kloroform. Kloroformen ble tørket og konsentrert in vacuo til å gi 2,6 g av råprodukt. ;D) [ 3S-( 3a, 4g)] - 3- L[( 1 , 1 dimetyloksy )- karbonyl] amino] - 4- metyl - 2- okso- 1-( sulfometoksy)- azetidin, kalium salt ;O-sulfometyl-a-N-t-butoksykarbonyl-L-(O-metansulfonyltreonin) hydroksamat, tetrabutylammonium salt (2,6 g, 4,0 mmol) ble opp-løst i 5 ml aceton og dråpevis tilsatt en reflukserende suspensjon av 2,2 g kaliumkarbonat i 65 ml aceton. Reflukseringen ble fortsatt i 3,5 time og reaksjonen ble avkjølt, filtrert og konsentrert in vacuo. Residuet ble løst i 10 ml 0,5 M pH 5,5 KH2P04, ;og pH ble justert til 2,8. Produkt ble ekstrahert fire ganger med 100 ml's porsjoner av diklormetan, og de kombinerte ekstrakter ble tørket og konsentrert in vacuo til å gi 1,52 g av rå tetra-buty lammonium-ionparet 3-laktam salt. Kaliumsaltet ble oppnådd ved ionebytting gjennom 50 ml Dowex 50X (0,7 meq K<æ>/ml) til å gi ved lyofilisering 0,53 g råmateriale, som ble videre renset ved kromatografi gjennom 100 ml HP-20 ved å anvende vann. De aktuelle fraksjoner ble kombinert og lyofilisert til å gi 0,245 g produkt. ;Analyse beregnet for Q<H>17N207SK'1,2H20:;C, 32,46; H, 5,28; N, 7,57; S, 8,66 ;Funnet: C, 32,52; H, 4,76; N, 7,43; S, 8,30 ;E) [ 3S - ( 3a , 43 ) 1 - 1 - sulf ometyl- 3- amino- 4- mety 1- 2- okso- 1 - azetidin ;[3S-(3a,43)] -3-[ [(1 ,1 -dimetyletoksy ) karbonyl] -amino] -4-metyl-2-okso-1-(sulfometoksy)azetidin, kaliumsalt (0,245 g, ;0,68 mmol) ble suspendert i 0,5 ml diklormetan og 0,5 ml anisol. Reaksjonsblandingen ble kjølt til 0°C, og trifluoredikksyre (1,0 ml) ble tilsatt under nitrogen. Reaksjonsblandingen ble rørt i 1 time og deretter konsentrert in vacuo til et residu som ble fordampet fra benzen to ganger. Dette ble behandlet med eter, ;og eteren ble dekantert til å gi det ønskede produkt som et hvitt fast-stoff. ;F) T3S- [ 3ct( Z) , 4g]] - 2-[[[ l -( 2- amino- 4- tiazolyl)- 2- L[ 4- metyl-2- okso- 1 - ( sulf ometoksy ) - 3- azetidinyl] - amino] - 2- oksotyliden) amino] oksy] - 2- metylpropionsyre, difenylmetyl ester, kalium salt ;( Z ) -2-amino-a- [[_2- (dif enylmetoksy) -1 ,1 -dimetyl-2-oksoetoksy];-imino] -4-tiazoledikksyre (0,30 g, 0,68 mmol) og 1-hydroksybenzo-triazolhydrat (0,10 g, 0,68 mmol) ble oppløst i 4 ml tørr dimetylformamid under nitrogen. Dette ble kjølt til 0°C, og N,N'-di-cykloheksylkarbodiimid (0,14 g, 0,68 mmol) ble porsjonsvis tilsatt. Etter tilsetting ble reaksjonen rørt ved 0°C i 1 time. Til dette ble satt en løsning av ovennevnte råa 3-amino-1-(sulfometoksy)azetidin (ca. 0,68 mmol) i 10 ml dimetylformamid og 0,5 ml N,N-diisopropyletylamin ved 0°C. Reaksjonen ble rørt ved 0°C i 1 time og deretter ved romtemperatur over natten. Løsningen ble filtrert, og filtratet ble konsentrert in vacuo. Residuet ble oppløst i 50 ml diklormetan og vasket med 2 ml vann. Ved fordamping av diklormetan, ble det oppnådd 0,372 g råprodukt. Dette ble passert gjennom 30 ml Dowex 50 (0,7 meq K<æ>/ml) ved å bruke vann, til å gi ved lyofilisering 0,211 g råprodukt, forurenset med hydroksybenzotriazol. G) [ 3S- [ 3ct( Z) , 4b11 - 2- IIll -( 2- amino- 4- tiazolyl)- 2- LI. 4- metyl- 2-okso- 1-( sulfometoksy)- 3- azetidinyl - amino] - 2- oksoetyliden) amino] okso] - 2- metyl- propansyre , dikaliumsalt [3S- [3ct(z) ,43]] -2-[[|_1 -(2-amino-4-tiazolyl)-2-[[4-metyl-2 -okso-1 - ( sulf ometoksy) - 3-azetidinyl] -amino] -2-oksoetyliden] amino] oksy]-2-metylpropionsyre, difenylmetyl ester, kaliumsalt (o,211 g) ble oppløst i 1,8 ml diklormetan, 0,5 ml anisol, og 1,5 ml trifluoredikksyre, og rørt under nitrogen ved 0°C i 2 timer. Reaksjonsblandingen ble konsentrert in vacuo og fordampet fra benzen to ganger. Residuet ble vasket med eter: etylacetat (1:1) og med eter: acetonitril (1:1) til å gi et hvitt fast-stoff. Dette ble oppløst i 1,0 ml av pH 5,5 0,5 M KH2P04, justert til pH 6,5 med 1N KOH, og kromatografert gjennom 40 ml av HP-20 med vann til å gi 53 mg av tittelforbindelsen, smeltepunkt 200°C, dec. ;Analyse beregnet for C1^7N5°9S2K2* 2'75H20: f*2 is hydrogen or methoxy; R, and R^ are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4,5,6 or 7-membered heterocyclic ring (hereinafter referred to as R ^) or one of R^ and R^ is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CP^X^, ; or is azido, amino (-N 1 ), hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2; X 2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, substituted phenylcarbonyl or heteroarylcarbonyl; one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ together with the carbon atom to which they are attached form a cycloalkyl group; X 1 is formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, unsubstituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl substituted aminocarbonyl or cyano (-C=N); A is -CH=CH-, -CH2-CH=CH-, -(CH2)-n, -(CH2)n,<-0->,~(CH2)n, -NH-, or -(CH2) n, -S-CH 2 ; n is 0, 1, 2 or 3; n' is 1 or 2; Xg and X^ are the same or different and are each hydrogen or alkyl, or Xg is hydrogen and X^ is amino, substituted amino, acylamino or alkoxy; and R^ and Rg are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R^, or R^ and Rg together with the carbon atom to which they are attached are cycloalkyl or R^, or one of R 1 and R 8 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH 2 , -S-X 2 , -O-X 2 or ; Listed below are definitions of various terms used to describe 3-lactams according to the invention. These ;i ;definitions are applied to the terms as they are used throughout the description (unless they are otherwise limited in special cases) either individually or as part of a larger group. ;The terms "alkyl" and "alkoxy" refer to both straight and branched chains. Those chains having 1 to 10 carbon atoms are preferred. The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups having 3, 4, 5, 6 or 7 carbon atoms. ;The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, substituted phenyloxy, R^-oxy, mercapto, alkylthio, phenylthio, substituted phenylthio, alkylsulfinyl, or alkylsulfonyl groups. ;The terms "alkanoyl", "alkenyl", "alkenyl" and "alkynyl" refer to both straight and branched chains. Those chains having 2 to 10 carbon atoms are preferred. ;The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine. The term "protected carboxyl" refers to a carboxyl group that has been esterified with a conventional acid protecting group. These groups are well known; see, for example, US Patent No. 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, and p-nitrobenzyl esters. ;The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NI^), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups . ;The term "a 4, 5, 6 or 7 membered heterocyclic rin" . ; (referred to as "R^") refers to substituted and unsubstituted aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Examples of substituents are oxo(=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino; ; benzylimino and substituted alkyl groups (in which the alkyl groups have 1 to 4 carbon atoms). One type of "4, 5, 6 or 7 membered heterocyclic rings" is the "heteroaryl" group. The term "heteroaryl" refers to the 4, 5, 6 or 7 membered heterocyclic rings that are aromatic. Examples of heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Examples of non-aromatic heterocycles (they are fully or partially saturated heterocyclic rings) are substituted and unsubstituted azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl. Examples of substituted 4,5,6 or 7-membered heterocyclic rings are 1-alkyl-1-3-azetynyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylimino-2-oxo -1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl or substituted phenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3-(2- aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-[(Alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-[2-[(Alkoxycarbonyl) -amino] ethyl) -2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-furanyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl. ;The term "substituted amino" refers to a group having the formula -^^2 in which Y- is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or substituted phenylalkyl, and Y 2 is alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, hydroxy, cyano, alkyloxy, phenylalkyloxy, or amino (-NH 2 ). ;The term "substituted alkanoyl" includes compounds;having the formula;substituted ; ; (in which "substituted alkyl" is defined above) and phenylalkanoyl. ;The term "acyl" refers to all organic radicals derived from an organic acid (that is, a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are of course preferred, but this preference should not be seen as a limitation of this invention. Examples of acyl groups are the acyl groups that have been used in the past to acylate 6-lactam antibiotics including 6-aminopenicillanic acid and derivatives thereof and 7-amino-cephalosporanic acid and derivatives thereof; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press ;(1972), German Offenlegunsschrift No. 2,716,677, published October 10, 1978, Belgian Patent 867,994, published December 11, 1978, US Patent No. 4,152,432 , issued May 1, 1979, US Patent No. 3,971,778, issued July 27, 1976, US Patent No. 4,172,199, issued October 23, 1979, and British Patent No. 1,348,894, issued March 27 1974. Parts of these references describe various acyl groups which are incorporated herein by reference. The following list of acyl groups is shown to further exemplify the term "acyl"; it should not be considered a limitation. Examples of acyl groups are: (a) Aliphatic groups having the formula; ; wherein R is alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups. ;(b) Carboxylic aromatic groups having the formula; in which n is 0, 1, 2 or 3; R 1 , R 2 , and R 2 are each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or aminomethyl; and Rg is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfosalt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or (alkylthio)thiooxymethyl thio. Preferred carbocyclic aromatic acyl groups include those having fomel; (Rg is preferably a carboxylic acid salt or a sulphonic acid salt); and ; (Re preferably a carboxylic acid salt or or a sulphonic acid salt). (c) Heteroaromatic groups having the formula in which n is 0, 1, 2 or 3; Re is as defined above; and R 1 is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, or ; Preferred heteroaromatic acyl groups include those groups of the above formulas in which R^ is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino- 1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl. (d) £ \_( 4-substituted-2 , 3-dioxo-1 -piperazinyl)carbonyl)amino]arylacetyl groups have the formula; in which R^ is an aromatic group (including carboxylic aromatic groups such as those of the formula ; and heteroaromatics included in the definition of R^); and-R^ is alkyl, substituted alkyl (in which the alkyl group is substituted with one or more halogen, cyano, nitro, amino, or mercapto groups), arylmethyleneamino (it is -N=CH-R in which R is as ;g 9 ; defined above), arylcarbonylamino (that is; ; in which R 2 is defined as above) or alkylcarbonyl- ;amino. Preferred £[_(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl groups include those in which R^ is ethyl, phenylmethyleneamino or 2-furylmethyleneamino. ;(e) Substituted oxyimino-arylacetyl groups having the formula; in which R^ is as defined above and R^ is hydrogen, Rc, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (that is -C-NH-R in which R is as defined above) or substituted alkyl (in which the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by R g), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkylphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, or dialkoxyphosphinyl substituents. Preferred substituted oxyaminoarylacetyl groups include those in which R is 2-amino-4-thiazolyl. Also preferred are those groups in which R^ is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl , 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.;(f) Acylamino-arylacetyl groups having the formula; in which R is defined as above and R. is amino, alkylamino, cyanolalkylamino, amido, alkylamido, cyanoalkylamido , ; Preferred a cylamino-arylacetyl groups of the above formula include those groups in which R 1 is amino or amido. Also preferred are those groups in which R 1 is phenyl or 2-thienyl. ;(g) £ [[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl groups having the formula; ; in which R is as defined above and R, is hydrogen, alkyl-;g k ;sulfonyl, arylmethyleneamino (that is -N=CH-Rg in which R^ is as defined above), ;0 -C-R (in which Rm is hydrogen , alkyl or halogen-substituted-alkyl), aromatic group (as defined for R above), alkyl or substituted alkyl (in which the alkyl group is substituted by one or more halogen, cyano, nitro, amino or mercapto groups). Preferred [[[_3-substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl groups of the above formula include those in which Rg is phenyl or 2-thienyl. Also preferred are those groups in which R^ is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino. ;The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali salts such as sodium and potassium salts, (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases, for example di-cyclohexylamine salts, benzathine, N-methyl-D-glucamine, hydrobamine salts , salts with amino acids such as arginine, lysine and the like. The non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful, for example to isolate or purify the product. The salts are formed in a conventional manner by reacting the free-acid form of the product with one or more equivalents of the appropriate base provided that the desired cation is in a solvent or medium in which the salt is insoluble, or in water and removal of the water by freeze-drying. By neutralizing the salt with an insoluble acid such as a cation exchanger in the hydrogen form (for example polystyrene sulfonic acid ion exchanger such as Dowex 50) or with an aqueous acid and extraction with an organic solvent, for example ethyl acetate, dichloromethane or the like, the free acid form can be obtained , and, if desired, another formed salt. ;3-lactams that have a ; ; H-substituent (or salt thereof) in the 1-position and an amino or acylamino substituent in the 3-position contains at least one chiral center - carbon atom (in the 3-position of the 3-lactam nucleus) to which the amino or acylamino substituent is bound. This invention is directed to the 3-lactams described above in which the stereochemistry at the chiral center in the 3-position of the 3-lactam core is the same as the configuration at the carbon atom in the 6-position in naturally occurring penicillins (for example, penicillin G ) ; and as the configuration at the carbon atom in the 7-position in naturally occurring cefamycins, (for example cefamycin C). With respect to the preferred 3-lactams of formula I, the structural formulas are drawn to show the stereochemistry at the chiral center in the 3-position. Also included in the present invention are racemic mixtures containing the 3-lactams described above. ;3-lactams that have a ; substituent (or salt thereof) in the 1-position of the 3-lactam nucleus and an acylamino substituent in the 3-position of the 3-lactam nucleus have activity against a number of gram-negative and gram-positive organisms. ; the substituent (or salt thereof) is essential for the activity of the compounds according to the present invention. The compounds according to the present invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory tract infections) in mammals, such as domestic animals (for example dogs, cats, cows, horses and the like) and humans. In order to combat bacterial infections in mammals, compounds according to the present invention can be administered to a mammal in need of this in an amount of approx. 1.4 mg/kg/day to approx. 350 mg/kg/day, preferably approx. 14 mg/kg/day to approx. ;100 mg/kg/day. All types of administration that have been used in the past to provide penicillins and cephalosporins at the site of infection are also intended to be used for the new family of 3-lactams according to the present invention. Such administration methods include oral, intravenous, intramuscular, and suppository. The 3-lactams according to the present invention can be prepared from an amino acid having the formula; The amino group is first protected with a classical protecting group (eg t-butoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfenyl, etc), to give a compound of the formula; In formula III and further throughout the description, the symbol "A^" refers to a nitrogen protecting group. The carboxyl group of a protected amino acid of formula III is then reacted with an amine of the formula; The reaction is carried out in the presence of a coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or dicyclohexylcarbodiimide, and gives a salt of the compound having the formula; The hydroxyl group of a compound of formula V (or a salt thereof) is converted to a leaving group, using, for example, a classical reagent such as methanesulfonyl chloride (methanesulfonyl hereinafter referred to as "Ms"). ;The fully protected compound has the formula ; ; or a salt thereof, is cyclized by treatment with a base, for example potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditions, and gives a compound having the formula; ; or a salt thereof. Alternatively, cyclization of a compound of formula V can be carried out without first converting the hydroxyl group into a leaving group. Treatment of a compound of formula V (or salt thereof) with triphenylphosphine and diethyl azodicarboxylate or carbon tetrachloride and triethylamine gives a compound of formula VII. Both methods shown above for cyclization of a compound of formula V result in inversion of the stereochemistry at the carbon attached to R₂ and R₂ substituents. Cleavage of the 3-amino substituent on a compound of formula VII can be carried out using commonly known techniques. For example, if the protecting group is t-butoxycarbonyl, trifluoroacetic acid can be used to cleave this group from the amino group. If the protecting group is benzyloxycarbonyl, catalytic (eg palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, p-toluenesulfonic acid can be used together with p-thiocresol. The compound from which the protecting groups are cleaved has the formula; or a salt thereof, and is a key intermediate for preparing the compounds of the present invention. The compounds of formula VIII form part of the present invention. Well-known acylation techniques can be used to convert a compound of formula VIII into the corresponding compound having the formula; ; or a salt thereof. ;Example techniques include reaction with a carboxylic acid (R^-OH) or corresponding carboxylic acid halide or carboxylic anhydride. The reactions with a carboxylic acid proceed most easily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming a reactive intermediate in situ such as N-hydroxybenzotriazole or 4-dimethylaminopyridine. In those cases in which the acyl group (R^) contains reactive functional groups (such as amino or carboxyl groups) it may be necessary to first protect these functional groups, then perform the acylation reaction, and finally cleave the protecting groups to obtain the resulting product. The products of formula I in which R 2 is methoxy can be prepared from the corresponding compound of formula VII in which is benzyloxycarbonyl. Halogenation (preferably chlorination) of the amide nitrogen of a compound of formula VII (A1 is benzyloxycarbonyl) in a compound of the formula; ; or a salt thereof. Reagents and procedures for N-chlorination amides are well known. Examples of reagents are tert. -butyl hypochlorite, sodium hypochlorite, and chlorine. The reaction can be carried out in an organic solvent (for example a lower alkanol such as methanol) or in a two-phase solvent system (for example water/methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is preferably carried out at a reduced temperature. ;Reaction of a compound of formula X as a methoxylating agent, for example an alkali metal methoxide, gives a compound (in combination with its enantiomer if R^ and R^ are the same or if X is a racemic mixture) having the fomel ; ; or a salt thereof. The reaction can be carried out in an organic solvent, for example a polar organic solvent such as tetrahydrofuran, at a reduced temperature. Alternatively, a compound of formula VII in which A is benzyloxycarbonyl can be converted to a compound of formula XI using a one-step procedure. The methoxylating agent can first be mixed with a compound of formula VII (A is bezyloxycarbonyl) and then the N-chlorinating agent added to the reaction mixture. Conversion of a compound of formula XI to the desired products of formula I can be carried out using procedures described above for conversion of an intermediate of formula VII to a product of the present invention. The starting materials of formula II are readily obtained using well known procedures; see, for example, Synthesis, page 216 (1979); and J. Org. Chem., 44:3967 (1979). ;The following examples are specific embodiments of this invention. ;Example 1;f3S- [ 3a( Z) , 4g)] - 2- [[ Ll-( 2- amino- 4- thiazolyl)- 2-[[ 4- methyl- 2- oxo-1 - ( sulf omethoxy ) - 3- azetidinyl) - amino] - 2- oxoethylideneJamino] oxy;- 2- methylpropanoic acid, dipotassium salt. ;A) Aminoxymethanesulfonic acid;Acetonoxime (1.46 g, 20 mmol) was added to a suspension of;a 60% mineral oil dispersion of sodium hydride (0.8 g, 20 mmol) in 16 mL of dry dimethyl sulfoxide. This was followed by the portionwise addition of sodium bromomethanesulfonate (3.94 g, 20 mmol). The reaction was heated to 90-95°C for 4 hours under nitrogen, cooled and washed twice with 250 ml of ether. The product solidified, was washed with 100 ml of dichloromethane, filtered and dried over ^2®$ to give 15.3 g of crude material. This was dissolved in 20 mL of water and tetrabutylammonium hydrogen sulfate (7.5 g, 22 mmol) was added. The resulting ion-paired product was extracted twice with 200 ml of dichloromethane. The dichloromethane solution was dried (Na2SO4, and concentrated in vacuo. Hydrolysis of the acetone oxime was carried out by heating in 120 ml of 2N HCl at 130°C for 4 hours. This solution was concentrated in vacuo from water twice then from acetonitrile. The product solidifies on addition of dechloromethane, and was filtered and dried in vacuo to give 2.5 g of the title compound.B) O-sulfomethyl-g-N-t-butoxycarbonyl-L-threonine hydroxamate, potassium salt. Aminoxymethanesulfonic acid (1.14g, 8.9mmol) was added to a solution of t-butoxycarbonyl-L-threonine (1.96g, 8.9mmol) in 16ml water and 4ml tetrahydrofuran at 0°C. The pH was adjusted to 4.5 with 1N KOH, and 1-ethyl-e-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.87 g, 9.7 mmol) in mL water was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, during which time the pH was maintained at 4 to 4.5 by occasionally adding 1N H 2 SO 4 . The product was ion-paired with tetrabutylammonium hydrogen sulfate (3.05 g, 8 mmol) at pH 2.8 and extracted from the aqueous solution with four 100 mL portions of dichloromethane. The dichloromethane solution was dried (Na 2 SO 4 ) and concentrated in vacuo to give 4.5 g of the product as tetrabutylammonium salt. This was converted to the potassium salt by ion exchange on 150 ml of Dowex 50X (0.7 meqK<®>/ml), and after lyophilization, 2.63 g of the title compound was obtained. ;C) O-sulfomethyl-α-N-t-butoxycarbonyl-L-(O-methanesulfonyl-threonine) hydroxamate, tetrabutylammonium salt ;For a partial solution of O-sulfomethyl-α-N-t-butoxycarbonyl-L-threonine hydroxamate, potassium salt (2 .37g, 6.5 mmol) in 50 ml dry pyridine was added dropwise at 0-5°C under nitrogen 0.8 ml (excess) methanesulfonyl chloride. The reaction was stirred at room temperature for 4 hours, and then concentrated in vacuo. The residue was dissolved in 10 ml of water, and 2.0 g (6 mmol) of tetrabutylammonium hydrogen sulfate was added at pH 2.8. The ion-paired material was extracted with chloroform. The chloroform was dried and concentrated in vacuo to give 2.6 g of crude product. ;D) [ 3S-( 3a, 4g)] - 3- L[( 1 , 1 dimethyloxy )- carbonyl] amino] - 4- methyl - 2- oxo- 1-( sulfomethoxy)- azetidine, potassium salt ;O- sulfomethyl-α-N-t-butoxycarbonyl-L-(O-methanesulfonylthreonine) hydroxamate, tetrabutylammonium salt (2.6 g, 4.0 mmol) was dissolved in 5 ml of acetone and added dropwise to a refluxing suspension of 2.2 g of potassium carbonate in 65 ml of acetone. Refluxing was continued for 3.5 hours and the reaction was cooled, filtered and concentrated in vacuo. The residue was dissolved in 10 ml of 0.5 M pH 5.5 KH 2 PO 4 , and the pH was adjusted to 2.8. Product was extracted four times with 100 mL portions of dichloromethane, and the combined extracts were dried and concentrated in vacuo to give 1.52 g of the crude tetrabutylammonium ion pair 3-lactam salt. The potassium salt was obtained by ion exchange through 50 ml of Dowex 50X (0.7 meq K<æ>/ml) to give on lyophilization 0.53 g of crude material, which was further purified by chromatography through 100 ml of HP-20 using water. The appropriate fractions were combined and lyophilized to give 0.245 g of product. ;Analysis calculated for Q<H>17N2O7SK'1,2H2O:;C, 32.46; H, 5.28; N, 7.57; S, 8.66; Found: C, 32.52; H, 4.76; N, 7.43; S, 8.30 ; E) [ 3S - ( 3a , 43 ) 1 - 1 - sulfomethyl- 3- amino- 4- methyl 1- 2- oxo- 1 - azetidine ; [3S-(3a, 43)] - 3-[[(1,1-dimethylethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-(sulfomethoxy)azetidine, potassium salt (0.245 g, 0.68 mmol) was suspended in 0.5 mL dichloromethane and 0.5 ml anisole. The reaction mixture was cooled to 0°C and trifluoroacetic acid (1.0 mL) was added under nitrogen. The reaction mixture was stirred for 1 hour and then concentrated in vacuo to a residue which was evaporated from benzene twice. This was treated with ether, and the ether was decanted to give the desired product as a white solid. ;F) T3S- [ 3ct( Z) , 4g]] - 2-[[[ l -( 2- amino- 4- thiazolyl)- 2- L[ 4- methyl-2- oxo- 1 - ( sulf omethoxy ) - 3- azetidinyl] - amino] - 2- oxotylidene) amino] oxy] - 2- methylpropionic acid, diphenylmethyl ester, potassium salt; ( Z ) -2-amino-a- [[_2- (diphenylmethoxy)-1 ,1 -dimethyl-2-oxoethoxy];-imino]-4-thiazoleacetic acid (0.30 g, 0.68 mmol) and 1-hydroxybenzotriazole hydrate (0.10 g, 0.68 mmol) were dissolved in 4 mL of dry dimethylformamide under nitrogen. This was cooled to 0°C and N,N'-dicyclohexylcarbodiimide (0.14 g, 0.68 mmol) was added portionwise. After addition, the reaction was stirred at 0°C for 1 hour. To this was added a solution of the above-mentioned crude 3-amino-1-(sulfomethoxy)azetidine (approx. 0.68 mmol) in 10 ml of dimethylformamide and 0.5 ml of N,N-diisopropylethylamine at 0°C. The reaction was stirred at 0°C for 1 hour and then at room temperature overnight. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of water. By evaporation of dichloromethane, 0.372 g of crude product was obtained. This was passed through 30 ml of Dowex 50 (0.7 meq K<æ>/ml) using water, to give on lyophilization 0.211 g of crude product, contaminated with hydroxybenzotriazole. G) [ 3S- [ 3ct( Z) , 4b11 - 2- IIll -( 2- amino- 4- thiazolyl)- 2- LI. 4- methyl- 2-oxo- 1-( sulfomethoxy)- 3- azetidinyl - amino] - 2- oxoethylidene) amino] oxo] - 2- methyl- propanoic acid, dipotassium salt [3S- [3ct(z) ,43]] - 2-[[|_1 -(2-amino-4-thiazolyl)-2-[[4-methyl-2-oxo-1-(sulfomethoxy)-3-azetidinyl]-amino]-2-oxoethylidene]amino] oxy]-2-methylpropionic acid, diphenylmethyl ester, potassium salt (0.211 g) was dissolved in 1.8 ml of dichloromethane, 0.5 ml of anisole, and 1.5 ml of trifluoroacetic acid, and stirred under nitrogen at 0°C for 2 hours . The reaction mixture was concentrated in vacuo and evaporated from benzene twice. The residue was washed with ether:ethyl acetate (1:1) and with ether:acetonitrile (1:1) to give a white solid. This was dissolved in 1.0 mL of pH 5.5 0.5 M KH 2 PO 4 , adjusted to pH 6.5 with 1N KOH, and chromatographed through 40 mL of HP-20 with water to give 53 mg of the title compound, mp 200 °C, dec.; Analysis calculated for C1^7N5°9S2K2* 2'75H20:
C, 28,44; H, 3,84; N, 11,85; S, 10,84 C, 28.44; H, 3.84; N, 11.85; S, 10.84
Funnet: C, 28,32; H, 3,36; N, 11,90; S, 10,37 Found: C, 28.32; H, 3.36; N, 11.90; S, 10.37
Eksempel 2 Example 2
[ 2S- [ 2a , 36 ( Z - LL3- [ L( 2- amino- 4- tiazolyl) - ( metoksyimino) acetyl] amino]- 2- metyl- 4- okso- 1- azetidinyl] oky] metansulfonsyre [ 2S- [ 2a , 36 ( Z - LL3- [ L( 2- amino- 4- thiazolyl) - ( methoxyimino) acetyl] amino]- 2- methyl- 4- oxo- 1- azetidinyl] oky] methanesulfonic acid
Ved å følge prosedyren fra eksempel 1, og ved å erstatte en ekvimolar mengde av (2)-2-amino-a- (metoksy)-imino -4-tiazoledikksyre med tiazoledikksyre anvendt i del (F) i eksempel 1, fremstilles tittelforbindelsen som mono-kaliumsalt som et hydro-skopisk fast-stoff etter oppløsning iacetonitril og fjerning av acetonitril under vacuum flere ganger. IR-SO^ (1030 cm ); B-laktam (1178 cm<-1>) Following the procedure of Example 1, and substituting an equimolar amount of (2)-2-amino-α-(methoxy)-imino-4-thiazoleacetic acid for the thiazoleacetic acid used in part (F) of Example 1, the title compound is prepared as mono-potassium salt as a hydroscopic solid after dissolution in acetonitrile and removal of acetonitrile under vacuum several times. IR-SO^ (1030 cm ); B-lactam (1178 cm<-1>)
Analyse: C1^4N507S2K•0,1CH3CNAnalysis: C1^4N5O7S2K•0.1CH3CN
C-38,11; H-4,82; N-15,92; S-12,56 C-38,11; H-4.82; N-15.92; S-12.56
Funnet : C-37,94; H-5,36; N-15,92; S-12,56 Found : C-37.94; H-5.36; N-15.92; S-12.56
Eksempel 3 Example 3
r2S-[ 2a, 3P( R)]] - U . 3 - Ull ( 4- etyl- 2 , 3- diokso- 1 - piperazinyl) karbonyl] amino] fenylacetylj amino] - 2- metyl- 4- okso- 1 - azetidinyl] oksy- metansulf onsyre r2S-[ 2a, 3P( R)]] - U . 3 - Wool ( 4- ethyl- 2 , 3- dioxo- 1 - piperazinyl) carbonyl] amino] phenylacetylj amino] - 2- methyl- 4- oxo- 1 - azetidinyl] oxy- methanesulfonic acid
Ved å følge prosedyren i eksempel 1, og erstatte a-£[(4-etyl By following the procedure of Example 1, substituting a-£[(4-ethyl
-2 , 3-diokso-1-piperazinyl)-karbonyl] amino] -f enyledikksyre med tiazoledikksyre anvendt i del (F) i eksempel 1, ble tittelforbindelsen oppnådd som mono-kaliumsalt som et hygroskopisk fast-stoff. IR - SO3"(1038 cm<-1>); B-laktam (1775 cm"<1>) -2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetic acid with thiazoleacetic acid used in part (F) of Example 1, the title compound was obtained as the monopotassium salt as a hygroscopic solid. IR - SO3"(1038 cm<-1>); B-lactam (1775 cm"<1>)
Analyse:<C>2Q<H>24<N>5<=gS>K-1,6H20Analysis:<C>2Q<H>24<N>5<=gS>K-1,6H20
C-41,53; H-4,74; N-12,11; S-5,54 C-41.53; H-4.74; N-12,11; S-5.54
Funnet : C-41,53; H-4,46; N-11,13; S-5,61 Found : C-41.53; H-4.46; N-11,13; S-5.61
Eksempel 4 Example 4
( S)- 3- benzyloksykarbonylamino)- 4- metyl- 2- okso- 1-( sulfometoksy)-azetidin (S)- 3- benzyloxycarbonylamino)- 4- methyl- 2- oxo- 1-( sulfomethoxy)-azetidine
Ved å følge prosedyren fra eksempel 1, delene (A) til (D) og erstatte benzyloksykarbonylserin med t-butoksykarbonyl-L-treonin anvendt i del (B), fremstilles tittelforbindelsen som kaliumsalt, IR- SO3"(1025 cm<-1>); B-laktam (1775 cm<-1>). By following the procedure of Example 1, parts (A) to (D) and substituting t-butoxycarbonyl-L-threonine for benzyloxycarbonyl-L-threonine used in part (B), the title compound is prepared as the potassium salt, IR-SO3"(1025 cm<-1> ); B-lactam (1775 cm<-1>).
Ved å følge prosedyren beskrevet tidligere fremstilles føl-gende forbindelser: By following the procedure described earlier, the following compounds are produced:
(3S-trans)- [[( 2-amino-4-tiazolyl) (metoksy-imino)acetyl] amino](3S-trans)- [[( 2-amino-4-thiazolyl) (methoxy-imino)acetyl] amino]
-4-metyl-2-okso-1-azetidinyl] -oksy] metansulfonsyre, monokaliumsalt -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic acid, monopotassium salt
(3S-trans)- [[( 2-amino-4-tiazolyl) [(2,2,2-trifluoretoksy) imino] acetyl] amino] -4-metyl-2-okso-1 -azetidinyl] oksy] metansulf onsyre , monokaliumsalt (3S-trans)- [[( 2-amino-4-thiazolyl) [(2,2,2-trifluoroethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid , monopotassium salt
(3S-trans)-[ [( 2-amino-4-tiazolyl) [(2-amino-2-oksoetoksy) imino] acetyl] amino] -4-metyl-2-okso-1 -azetidinyl] oksy] metansulf onsyre. monokaliumsalt (3S-trans)-[[(2-amino-4-thiazolyl)[(2-amino-2-oxoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid . monopotassium salt
(3S-trans)- [ j_( 2-amino-4-tiazolyl) [(karboksy-metoksy) imino] acetyl] amin(^ -4-metyl-2-okso-1-azetidinyl] -oksy] metansulf onsyre, dikaliumsalt (3S-trans)- [ j_( 2-amino-4-thiazolyl) [(carboxy-methoxy) imino] acetyl] amino(^ -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic acid, dipotassium salt
(3S-trans)-[[(2-amino-4-tiazolyl) [[(1-karboksy-cyklopropyl) oksy] imino] acetyl] amino] -4-metyl-2-okso-1 -azetidinyl] -oksy]metansulfonsyre, dikaliumsalt (3S-trans)-[[(2-amino-4-thiazolyl) [[(1-carboxy-cyclopropyl)oxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy] methanesulfonic acid, dipotassium salt
[3S- [3a(R) ,4b]] -[[3- [(aminofenylacetyl)-amino] -4-metyl-2-okso-1 -azetidinyl] oksy] metansulf onsyre, monokaliumsalt [3S- [3a(R) ,4b]] -[[3- [(aminophenylacetyl)-amino] -4-methyl-2-oxo-1 -azetidinyl] oxy] methanesulfonic acid, monopotassium salt
( 3S-trans ) - [[3- \_( f enylacetyl) amino] -4-metyl-2-okso-1 -azetidinyl] oksy]metansulfonsyre, monokaliumsalt (3S-trans)-[[3-\_(phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt
(3S-trans)-[[3-[(2-tienylacetyl)amino] -4-metyl-2-okso-1-azetidinyl] oksy] metansulf onsyre , monokaliumsalt (3S-trans)-[[3-[(2-thienylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt
( 3S-trans ) - [ [3-[( 2 , 6-dimetoksyf enyl) acetyl] -amino] -4-metyl -2-okso-1-azetidinyl] oksy] metansulf onsyre, monokaliumsalt [3S- [3a(R) ,48]] - [[3-LtLL (aminokarbonyl)-amino] -2-tienylacetyl -amino] -4-metyl-2-okso-1-azetidinyl] -oksy] metansulf onsyre , mono-kaliumsalt ( 3S - trans ) - [ [3-[( 2 , 6-dimethoxyphenyl) acetyl] -amino] -4-methyl -2-oxo-1-azetidinyl] oxy] methanesulfonic acid, monopotassium salt [3S- [3a(R ) ,48]] - [[3-LtLL (aminocarbonyl)-amino] -2-thienylacetyl -amino] -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic acid , mono-potassium salt
[3S- [3a(R) ,4B]] - [1.3- [(karboksyf enylacetyl) -amino] -4-metyl-2-okso-1-azetidinyl] oksy] metansulf onsyre , dikaliumsalt [3S- [3a(R) ,4B]] - [1,3- [(carboxyphenylacetyl)-amino]-4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid, dipotassium salt
[3S- |3ct(±) ,4B]] -[L3- L< f enylsulf oacetyl) -amino] -4 -metyl-2-okso-1-azetidinyl] oksy] metansulf onsyre, dikaliumsalt [3S- |3ct(±) ,4B]] -[L3- L< phenylsulf oacetyl) -amino] -4 -methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid, dipotassium salt
(3S-trans)] -[L3-[L(2 -amino-4-tiazolyl)-oksoacetyl] amino] -4-metyl-2-okso-1 -azetidinyl] -oksy] metansulf onsyre, monokaliumsalt (3S-trans)]-[L3-[L(2-amino-4-thiazolyl)-oxoacetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid, monopotassium salt
|3S- !_3a(R) ,46j] -[[3-[[[f [2-okso-3- [( f enylmetylen) amino] -1 - imidazolidinyl] karbonyl] amino] -fenylacetyl] amino] -4-metyl-2-okso-1-azetidinyl] oksy] -metansulfonsyre, monokaliumsalt |3S- !_3a(R) ,46j] -[[3-[[[f [2-oxo-3- [( phenylmethylene) amino] -1 - imidazolidinyl] carbonyl] amino] -phenylacetyl] amino] -4 -methyl-2-oxo-1-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt
[3S- [3a(Z) ,4B]] - [[3 - [ [2-f urany 1 (metoksy-imino) acetyl] amino][3S- [3a(Z) ,4B]] - [[3 - [ [2-f urany 1 (methoxy-imino) acetyl] amino]
-4-metyl-2-okso-1-azetidinyl] oksy] -metansulf onsyre , monokaliumsalt -4-methyl-2-oxo-1-azetidinyl]oxy]-methanesulfonic acid, monopotassium salt
j_3S(Z)] - [j_3 - [[ ( 2-amino-4-tiazolyl) (metoksy-imino) acetyl] amino] -2-okso-1-azetidinyl] oksy] metansulf onsyre, monokaliumsalt j_3S(Z)] - [j_3 - [[ ( 2-amino-4-thiazolyl) (methoxy-imino) acetyl] amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid, monopotassium salt
[3S(Z)]- [[3-[[(2-amino-4-tiazolyl) [(1 -karboksy-1 -metyletoksy) imino] acetyl] amino] -2-okso-1-azetidinyl] oksy] metansulf onsyre, dikaliumsalt [3S(Z)]- [[3-[[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidinyl] oxy] methanesulf onic acid, dipotassium salt
[3S(Z)] - [[3- [(_(2-amino-4-tiazolyl) [( 2 , 2,2-trifluoretoksy) imino] acetyl] amino] -2-okso-1-azetidinyl] oksy] metansulf onsyre , monokaliumsalt [3S(Z)] - [[3- [(_(2-amino-4-thiazolyl) [( 2 , 2,2-trifluoroethoxy) imino] acetyl] amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid, monopotassium salt
[3S(Z)] - [[3-[[(2-amino-4-tiazolyl) [( 2-amino-2-oksoetoksy) imino] acetyl] amino] -2-okso-1 -azetidinyl] -oksy] metansulf onsyre, monokaliumsalt [3S(Z)] - [[3-[[(2-amino-4-thiazolyl) [( 2-amino-2-oxoethoxy) imino] acetyl] amino] -2-oxo-1-azetidinyl] -oxy] methanesulfonic acid, monopotassium salt
[3S- [3a(S) ,46]] - LL 3- [[[(aminokarbonyl) amino] -2-tienylacetyl] amino] -2-okso-1-azetidinyl] oksy] -metansulf onsyre, monokaliumsalt [3S- [3a(S) ,46]] - LL 3- [[[(aminocarbonyl) amino] -2-thienylacetyl] amino] -2-oxo-1-azetidinyl] oxy] -methanesulfonic acid, monopotassium salt
[3S- [3a(±) ,46]] -[ [3-[( f enylsulf oacetyl) -amino] -2-okso-1-azetidinyl] oksy] metansulf onsyre, dikaliumsalt [3S- [3a(±) ,46]] -[ [3-[( phenylsulfoacetyl)-amino]-2-oxo-1-azetidinyl] oxy] methanesulfonic acid, dipotassium salt
[3S- [3a (R) ,48]] - [L3-[ [[ L ( 4-etyl-2 , 3-diokso-1 -piperazinyl) karbonyl] amino] fenylacetyl] amino] -2-okso-1-azetidinyl] oksy] metansulfonsyre, monokaliumsalt [3S- [3a (R) ,48]] - [L3-[ [[ L (4-ethyl-2, 3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -2-oxo-1- azetidinyl] oxy] methanesulfonic acid, monopotassium salt
[(3S(Z)] - [[3-[( f enoksyacetyl )amino] -2-okso-1 -azetidinyl] oksy] metansulfonsyre, monokaliumsalt [(3S(Z)] - [[3-[( phenoxyacetyl )amino] -2-oxo-1 -azetidinyl] oxy] methanesulfonic acid, monopotassium salt
( 3S-cis ) - [[( 2-amino-4-tiazolyl) (metoksy-imino) acetyl] amino](3S-cis)-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino]
-4-mety1-2-okso-1-azetidinyl] -oksy] metansulfonsyre, monokaliumsalt -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic acid, monopotassium salt
( 3S-cis ) - [[( 2-amino-4-tiazolyl) [( 2 , 2 , 2-trif luoetoksy ) imino] acetyl] amino] -4-metyl-2-okso-1 -azetidinyl] oksy] metansulf onsyre, monokaliumsalt (3S-cis)-[[(2-amino-4-thiazolyl) [(2,2,2-triluoethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]methanesulf onic acid, monopotassium salt
(3S-cis)-[[(2-amino-4-tiazolyl)[(karboksy-metoksy)imino] acetyl] amino] -4-metyl-2-okso-1-azetidinyl] -oksy] metansulf onsyre, dikaliumsalt (3S-cis)-[[(2-amino-4-thiazolyl)[(carboxy-methoxy)imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic acid, dipotassium salt
(3S-cis)-[[3-[[(2-amino-4-tiazolyl)](1-karboksy-1-metyletoksy ) imino] acetyl] amino] -2-okso-4-metyl-1-azetidinyl] oksy] metansulfonsyre dikaliumsalt (3S-cis)-[[3-[[(2-amino-4-thiazolyl)](1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-4-methyl-1-azetidinyl] oxy] methanesulfonic acid dipotassium salt
(3S-cis)-[[(2-amino-4-tiazolyl)[ [(1-karboksy-cyklopropyl) oksy] iminoj acetyl] amino] -4-metyl-2-okso-1 -azetidinyl]) -oksy] metansulfonsyre, dikaliumsalt (3S-cis)-[[(2-amino-4-thiazolyl)[ [(1-carboxy-cyclopropyl)oxy]imino acetyl]amino]-4-methyl-2-oxo-1-azetidinyl])-oxy] methanesulfonic acid, dipotassium salt
(3S-cis)-[[(2-amino-4-tiazolyl) [( 2-amino-2-oksoetoksy)imino] acetyl] amino] -4-metyl-2-okso-1 -azetidinyl] oksy] metansulf onsyre, monokaliumsalt (3S-cis)-[[(2-amino-4-thiazolyl) [( 2-amino-2-oxoethoxy)imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid , monopotassium salt
[3S- [3a(R),4a]]-[[3- [{karboksy f enylacetyl) -amino] - 4-metyl-2-okso-1-azetidinyl] oksy] metansulfonsyre, dikaliumsalt [3S- [3a(R),4a]]-[[3- [{carboxy phenylacetyl)-amino]-4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid, dipotassium salt
[3S- [3a(R) ,4a]] - [I.3- [ [[[ ( 4-etyl-2 ,3-diokso-1 -piperazinyl) karbonyl] amino] fenylacetyl] amino] -4-metyl-2-okso-1 -azetidinyl] oksy]metansulfonsyre, monokaliumsalt [3S- [3a(R) ,4a]] - [I.3- [ [[[ ( 4-ethyl-2 ,3-dioxo-1 -piperazinyl) carbonyl] amino] phenylacetyl] amino] -4-methyl- 2-oxo-1-azetidinyl]oxy]methanesulfonic acid, monopotassium salt
[3S- [.3a ( S ) , 4a]] - [[3-[[ [ (aminokarbonyl) -amino] -2-tienylacetyl)[3S- [.3a (S), 4a]] - [[3-[[ [(aminocarbonyl)-amino]-2-thienylacetyl)
-amino] -4-metyl-2-okso-1-azetidinyl] -oksy] metansulf onsyre , mono-kaliumsalt -amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]methanesulfonic acid, mono-potassium salt
j3S- [3a(R) ,4a]] -[L3- [(aminof enyl-acetyl)-amino] -4-metyl-2-okso-1-azetidinyl] oksy] -metansulfonsyre, monokaliumsalt j3S- [3a(R) ,4a]] -[L3- [(aminophenyl-acetyl)-amino]-4-methyl-2-oxo-1-azetidinyl] oxy]-methanesulfonic acid, monopotassium salt
Eksempel 5 Example 5
( 2a, 3a)- 1- sulfometoksy- 2-( aminokarbonyl)- 3-((( 1, 1- dimetyletoksy) karbonyl) amino)- 4- oksoazetidin A) Erytro-3-hydroksy-DL-asparaginsyre ble fremstilt fra trans-epoksyravsyre som beskrevet av C.W. Jones et al. (Can. J. Chem. 47.4363 (1969)). Trans-epoksy ravsyre ble fremstilt fra fumar-syre som beskrevet av G.B. Payne et al. (J. Org. Chem. 24, 54 (1 959) ) . ( 2a, 3a)- 1- sulfomethoxy- 2-( aminocarbonyl)- 3-((( 1, 1- dimethylethoxy) carbonyl) amino)- 4- oxoazetidine A) Erythro-3-hydroxy-DL-aspartic acid was prepared from trans -epoxysuccinic acid as described by C.W. Jones et al. (Can. J. Chem. 47, 4363 (1969)). Trans-epoxy succinic acid was prepared from fumaric acid as described by G.B. Payne et al. (J. Org. Chem. 24, 54 (1959) ) .
B) B- metyl erytro- 3- hydroksy- DL- asparaginB) B-methyl erythro-3-hydroxy-DL-asparagine
Til en løsning av 5,0 g (33,5 mmol) av erytro-3-hydroksy-DL-asparaginsyre i 50 ml tørr metanol ble satt 6 ml konsentrert saltsyre. Blandingen ble refluksert i 3 timer, avkjølt til romtemperatur, og fordampet in vacuo. Residuet ble tatt opp i 95% etanol, og pH ble justert til 8,0 ved tilsetning av pyridin. To a solution of 5.0 g (33.5 mmol) of erythro-3-hydroxy-DL-aspartic acid in 50 ml of dry methanol was added 6 ml of concentrated hydrochloric acid. The mixture was refluxed for 3 hours, cooled to room temperature, and evaporated in vacuo. The residue was taken up in 95% ethanol, and the pH was adjusted to 8.0 by adding pyridine.
Det hvite fast-stoffet ble filtrert og tørket til å gi 5,2 gThe white solid was filtered and dried to give 5.2 g
(95% utbytte) av ønsket metylester som har smeltepunkt 210°C, dec. (95% yield) of the desired methyl ester which has a melting point of 210°C, dec.
C) Erytro- 3- hydroksy- DL- asparaginC) Erythro-3-hydroxy-DL-asparagine
Det ovennevnte B-metyl aspartat (4,0 g, 24,5 mmol) ble opp-løst i 40 ml konsentrert ammoniak og rørt over natten ved romtemperatur. Reaksjonsblandingen ble fordampet in vacuo til et fast-stoff som ble oppløst i varmt vann. pH ble justert til 5,0 ved å bruke 6NHC1, og løsningen ble konsentrert in vacuo til omtrent 20 ml og deretter holdt over natten ved 5°C. De hvite krystaller ble oppsamlet og tørket til å gi 3,4 g (95% utbytte) av ønsket produkt som har smeltepunkt 233°C,dec. The above B-methyl aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of concentrated ammonia and stirred overnight at room temperature. The reaction mixture was evaporated in vacuo to a solid which was dissolved in hot water. The pH was adjusted to 5.0 using 6NHCl and the solution was concentrated in vacuo to about 20 mL and then kept overnight at 5°C. The white crystals were collected and dried to give 3.4 g (95% yield) of the desired product, m.p. 233°C,dec.
D) MT- butoksykarbonyl- erytro- 3- hydroksy- DL- asparagin, kaliumsalt D) MT- butoxycarbonyl- erythro- 3- hydroxy- DL- asparagine, potassium salt
Erytro-3-hydroksy-DL-asparagin (7,0 g, 47 mmol) ble suspendert i 50 ml vann og oppløst ved tilsetting av 3 N KOH. Denne løsningen ble justert til pH 10,0, og holdt på denne pH under dråpevis tilsetting av en løsning av di-T-butylkarbonat (15,5 g, 71 mmol) i 20 ml t-butanol. Reaksjonsblandingen ble rørt ved pH 10,0 over natten ved romtemperatur. T-butanol ble fjernet in vacuo og den vandige rest ble justert til pH 5,0 ved å bruke 6N HC1. Løsningen ble konsentrert in vacuo til et lite volum, og deretter ble pH justert til 3,0 (6N HC1). Fjerning av løsnings-middel in vacuo ga et fast stoff (20 g) inneholdende det ønskede produkt i fri syreform og i omtrent kvantitativt utbytte sammen med uorganiske salter. En del (2,9 g) av dette faste stoff ble tatt opp i vann og fortynnet KOH ved pH 6,5 og kromatografert gjennom 100 ml HP20 ved å bruke vann og deretter aceton-vann (1:9) til å gi det ønskede kaliumsalt som et residu (1,8 g). Erythro-3-hydroxy-DL-asparagine (7.0 g, 47 mmol) was suspended in 50 mL of water and dissolved by addition of 3 N KOH. This solution was adjusted to pH 10.0, and maintained at this pH during the dropwise addition of a solution of di-T-butyl carbonate (15.5 g, 71 mmol) in 20 mL of t-butanol. The reaction mixture was stirred at pH 10.0 overnight at room temperature. The t-butanol was removed in vacuo and the aqueous residue was adjusted to pH 5.0 using 6N HCl. The solution was concentrated in vacuo to a small volume and then the pH was adjusted to 3.0 (6N HCl). Removal of solvent in vacuo gave a solid (20 g) containing the desired product in free acid form and in approximately quantitative yield together with inorganic salts. A portion (2.9 g) of this solid was taken up in water and diluted with KOH at pH 6.5 and chromatographed through 100 mL HP 2 O using water and then acetone-water (1:9) to give the desired potassium salt as a residue (1.8 g).
E) Aminoksymetansulfonsyre, tetrabutylammoniumsalt E) Aminoxymethanesulfonic acid, tetrabutylammonium salt
Tetrabutylammonium-hydrogensulfat (1,02 g, 3 mmol) ble satt til en løsning av 0,635 g (5 mmol) aminoksymetansulfonsyre i 2 ml vann, og pH ble justert til 10,0 ved å bruke fortynnet KOH. Vannet ble fjernet in vacuo og residuet ble behandlet med metylenklorid. Etter filterring, ble filtratet tørket over natriumsul-fat og fordampet til å gi det ønskede produkt som et residu (1,06 g, 2,88 mmol). Tetrabutylammonium hydrogen sulfate (1.02 g, 3 mmol) was added to a solution of 0.635 g (5 mmol) of aminooxymethanesulfonic acid in 2 mL of water, and the pH was adjusted to 10.0 using dilute KOH. The water was removed in vacuo and the residue was treated with methylene chloride. After filtration, the filtrate was dried over sodium sulfate and evaporated to give the desired product as a residue (1.06 g, 2.88 mmol).
F) O- sulf orne tyl- ot- N- T- butoksykarbonyl- ery tro- 3- hydroksy- DL-asparagin hydroksamat, kaliumsalt F) O- sulf orne tyl- ot- N- T- butoxycarbonyl- erythro- 3- hydroxy- DL- asparagine hydroxamate, potassium salt
N-T-butoksykarbonyl-erytro-3-hydroksy-DL-asparagin, kaliumsalt (0,792 g, 2,77 mmol) ble oppløst i vann (3 ml) og justert til pH 2,4 (fortynnet H2S04). Løsningen ble konsentrert in vacuo til et residu, som ble konsentrert fra vann (2 ganger) og deretter fra benzen (2 ganger). Dette residuet ble oppløst i tørr acetonitril N-T-butoxycarbonyl-erythro-3-hydroxy-DL-asparagine, potassium salt (0.792 g, 2.77 mmol) was dissolved in water (3 mL) and adjusted to pH 2.4 (dilute H 2 SO 4 ). The solution was concentrated in vacuo to a residue, which was concentrated from water (2 times) and then from benzene (2 times). This residue was dissolved in dry acetonitrile
(4 ml) og tørr tetrahydrofuran (8 ml) og avkjølt til 0°C. Til denne rørte løsning ble satt 0,424 g (2,77 mmol) 1-hydroksybenzotriazol monohydrat fulgt av 0,572 g (2,77 mmol) N,N'-dicykloheksy1-karbodiimid. Blandingen ble rørt ved 0°C i 2 timer, og deretter ble ovennvente aminoksymetansulfonsyre, tetrabutylammoniumsalt (1,06 g, 2,88 mmol) i 5 ml aceton dråpevis tilsatt. Etter til-settingen ble reaksjonsblandingen rørt ved 0°C i 4 timer. Reaksjonen ble filtrert og konsentrert in vacuo til et residu. Vann (10 ml) ble tilsatt, og residuet ble behandlet ved 0°C inntil det størknet. Det faste stoff ble fjernet ved filtrering, og det vandige filtrat ble konsentrert til omtrent 3 ml. pH ble justert til 4,0, og fraksjoneringen ble utført over 80 ml Dowex 50 (K) ionebytter. Passende fraksjoner ble oppsamlet og konsentrert til et lite volum. pH ble justert til 3,4, og løsningen ble kromatografert over HP20 til å gi, etter lyofilisering, 502 mg (46%) av ønsket produkt som et fast stoff som har smeltepunkt 145°C, dek. (4 mL) and dry tetrahydrofuran (8 mL) and cooled to 0°C. To this stirred solution was added 0.424 g (2.77 mmol) of 1-hydroxybenzotriazole monohydrate followed by 0.572 g (2.77 mmol) of N,N'-dicyclohexyl-carbodiimide. The mixture was stirred at 0°C for 2 hours, and then the above aminooxymethanesulfonic acid, tetrabutylammonium salt (1.06 g, 2.88 mmol) in 5 mL of acetone was added dropwise. After the addition, the reaction mixture was stirred at 0°C for 4 hours. The reaction was filtered and concentrated in vacuo to a residue. Water (10 mL) was added and the residue was treated at 0°C until it solidified. The solid was removed by filtration, and the aqueous filtrate was concentrated to about 3 mL. The pH was adjusted to 4.0 and the fractionation was carried out over 80 ml of Dowex 50 (K) ion exchanger. Appropriate fractions were collected and concentrated to a small volume. The pH was adjusted to 3.4, and the solution was chromatographed over HP20 to give, after lyophilization, 502 mg (46%) of the desired product as a solid, mp 145°C, dec.
Analyse kalkulert forC10HlgN309SK«0,71H20: C, 29,42; H, 4,80 Analysis calcd for C10H12N309SK-0.71H2O: C, 29.42; Height, 4.80
N, 10,29; S, 7,85 Funnet : C, 29,42; H, 4,73; N, 10,04; S, 7,45 G) O- sulfometyl- a- N- T- butoksykarbonyl- erytro- 3- hydroksy- DL-asparagin hydroksamat, tetrabutyl- ammoniumsalt Til en løsning av ovennevnte aspargin hydroksamat, kaliumsalt (104 mg, 0,263 mmol) i 1 ml vann ble satt 2,63 ml 0,1M tetrabutylammonium hydrogensulfat i 0,5M pH 5,5 KH2P04 buffer. Løsningen ble konsentrert til tørrhet, og residuet ble behandlet med metylenklorid. Filtrering og fordamping av metylenklorid ga det ønskede produkt som et residu (156 mg, 0,26 mmol). H) ( 2a, 3a)- 1- sulfometoksy- 2-( aminokarbonyl)- 3-((( 1, 1- dimetyletoksy) karbonyl) amino)- 4- oksoazetidin, kaliumsalt Ovennevnte O-sulfometylhydroksamat, tetrabutylammoniumsalt (140 mg, 0,234 mmol) ble oppløst i 1,6 ml tørr metylenklorid og rørt ved 1 g tørket 3 A molekylsikt over natten. Løsningen ble fjernet via en sprøyte og fortynnet med 0,8 ml tørr metylenklorid. Til denne rørte løsning ved -50°C under argon ble tilsatt 0,12 ml (0,85 mmol) trietylamin fulgt av dråpvis tilsetting av 0,08 ml (0,42 mmol) trifluormetansulfonsyreanhydrid. Reaksjonen ble til-latt å varmes til -30°C over 1 time, og deretter ble 0,06 ml trietylamin tilsatt. Etter 5 minutter ble reaksjonen konsentrert in vacuo, og residuet ble oppløst i 2 ml aceton. Løsningen ble kjølt til 0°C, og en løsning av 79 mg kalium perfluorbutansulfo-nat i 1 ml aceton ble tilsatt. Eter ble deretter tilsatt, og de faste stoffer ble oppsamlet ved sentrifugering. Behandling av dette faste stoff ved røring med 2 ml Dowex 50 (K) i vann, filtrering og fjerning av vannet in vacuo ga rått ønsket kaliumsalt inneholdende ingen aminer. Kromatografi av dette rå kaliumsalt på HP20 ved å bruke vann ga 15 mg (20% utbytte) av ønsket kaliumsalt, etter lyofilisering og hadde smeltepunkt 149°C, dek. og IR (KBR) 1786 cm"<1>(B-laktam karbonyl) og 1696 cm"<1>(bred, amid og karbamat karbonyl). N, 10.29; S, 7.85 Found : C, 29.42; H, 4.73; N, 10.04; S, 7.45 G) O- sulfomethyl- a- N- T- butoxycarbonyl- erythro- 3- hydroxy- DL-asparagine hydroxamate, tetrabutyl- ammonium salt To a solution of the above asparagine hydroxamate, potassium salt (104 mg, 0.263 mmol) in To 1 ml of water was added 2.63 ml of 0.1 M tetrabutylammonium hydrogen sulfate in 0.5 M pH 5.5 KH 2 PO 4 buffer. The solution was concentrated to dryness and the residue was treated with methylene chloride. Filtration and evaporation of methylene chloride gave the desired product as a residue (156 mg, 0.26 mmol). H) ( 2a, 3a)- 1- sulfomethoxy- 2-( aminocarbonyl)- 3-((( 1, 1- dimethylethoxy) carbonyl) amino)- 4- oxoazetidine, potassium salt The above O-sulfomethylhydroxamate, tetrabutylammonium salt (140 mg, 0.234 mmol) was dissolved in 1.6 ml of dry methylene chloride and stirred through 1 g of dried 3 A molecular sieve overnight. The solution was removed via a syringe and diluted with 0.8 ml of dry methylene chloride. To this stirred solution at -50°C under argon was added 0.12 ml (0.85 mmol) of triethylamine followed by the dropwise addition of 0.08 ml (0.42 mmol) of trifluoromethanesulfonic anhydride. The reaction was allowed to warm to -30°C over 1 hour, and then 0.06 ml of triethylamine was added. After 5 minutes, the reaction was concentrated in vacuo, and the residue was dissolved in 2 ml of acetone. The solution was cooled to 0°C, and a solution of 79 mg of potassium perfluorobutanesulfonate in 1 ml of acetone was added. Ether was then added and the solids were collected by centrifugation. Treatment of this solid by stirring with 2 ml of Dowex 50 (K) in water, filtration and removal of the water in vacuo gave crude the desired potassium salt containing no amines. Chromatography of this crude potassium salt on HP20 using water gave 15 mg (20% yield) of the desired potassium salt, after lyophilization and mp 149°C, dec. and IR (KBR) 1786 cm"<1> (B-lactam carbonyl) and 1696 cm"<1> (broad, amide and carbamate carbonyl).
Claims (10)
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| DD (1) | DD222016A5 (en) |
| DE (1) | DE3336262A1 (en) |
| DK (1) | DK457983A (en) |
| ES (1) | ES8504814A1 (en) |
| FI (1) | FI833631A (en) |
| FR (1) | FR2534253B1 (en) |
| GB (1) | GB2129428B (en) |
| GR (1) | GR79704B (en) |
| HU (1) | HU190507B (en) |
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| EP0135194A1 (en) * | 1983-09-16 | 1985-03-27 | Takeda Chemical Industries, Ltd. | Azetidinones and their production |
| WO1985004876A1 (en) * | 1984-04-24 | 1985-11-07 | Takeda Chemical Industries, Ltd. | 2-azetidinone derivatives and process for their preparation |
| US4581170A (en) * | 1984-08-03 | 1986-04-08 | E. R. Squibb & Sons, Inc. | N-hydroxyl protecting groups and process and intermediates for the preparation of 3-acylamino-1-hydroxy-2-azetidinones |
| DE3588039T2 (en) * | 1984-08-06 | 1995-11-16 | Fujisawa Pharmaceutical Co | Azetidinone derivatives and process for their preparation. |
| UY34585A (en) | 2012-01-24 | 2013-09-02 | Aicuris Gmbh & Co Kg | B-LACTAMIC COMPOUNDS REPLACED WITH AMIDINE, ITS PREPARATION AND USE |
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1983
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