NO152448B - NEW PENICILLANIC ACID-L-OXYDES FOR USE AS INTERMEDIATES IN PENICILLANIC ACID-L, L-DIOXYD PREPARATION - Google Patents
NEW PENICILLANIC ACID-L-OXYDES FOR USE AS INTERMEDIATES IN PENICILLANIC ACID-L, L-DIOXYD PREPARATION Download PDFInfo
- Publication number
- NO152448B NO152448B NO823126A NO823126A NO152448B NO 152448 B NO152448 B NO 152448B NO 823126 A NO823126 A NO 823126A NO 823126 A NO823126 A NO 823126A NO 152448 B NO152448 B NO 152448B
- Authority
- NO
- Norway
- Prior art keywords
- penicillanic acid
- acid
- oxide
- compounds
- formula
- Prior art date
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- 239000000543 intermediate Substances 0.000 title 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 238000001727 in vivo Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 6
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims description 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- OSORMYZMWHVFOZ-UHFFFAOYSA-N phenethyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCC1=CC=CC=C1 OSORMYZMWHVFOZ-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229930182555 Penicillin Natural products 0.000 description 12
- 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 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- -1 β-lactam compound Chemical class 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 11
- 238000007254 oxidation reaction Methods 0.000 description 11
- 230000009102 absorption Effects 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 150000002960 penicillins Chemical class 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229930186147 Cephalosporin Natural products 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 229940124587 cephalosporin Drugs 0.000 description 6
- 150000001780 cephalosporins Chemical class 0.000 description 6
- 238000007256 debromination reaction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229930195708 Penicillin V Natural products 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 229940056360 penicillin g Drugs 0.000 description 4
- 229940056367 penicillin v Drugs 0.000 description 4
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WYUIPMUZDFHKMP-UHFFFAOYSA-N 5-chloro-1,3-dihydropyrrolo[3,2-b]pyridin-2-one Chemical compound ClC1=CC=C2NC(=O)CC2=N1 WYUIPMUZDFHKMP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 125000005643 gamma-butyrolacton-4-yl group Chemical group 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 235000019371 penicillin G benzathine Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 2
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 2
- 229960003324 clavulanic acid Drugs 0.000 description 2
- 229960003326 cloxacillin Drugs 0.000 description 2
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 2
- 229960001585 dicloxacillin Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 229960004273 floxacillin Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 2
- 229960001019 oxacillin Drugs 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- 125000005847 1-methyl-1-(alkanoyloxy)-ethyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940123930 Lactamase inhibitor Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000187433 Streptomyces clavuligerus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012267 brine Substances 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
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010073233 gamma-lactamase Proteins 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- ZYTYOUNYLKOKAR-UHFFFAOYSA-N morpholine;pyrrolidine Chemical compound C1CCNC1.C1COCCN1 ZYTYOUNYLKOKAR-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Denne oppfinnelse angår nye penicillansyre-l-oksyder for anvendelse som utgangsmateriale ved fremstilling av terapeutisk aktivt penicillansyre-1,1-dioksyd. This invention relates to new penicillanic acid 1-oxides for use as starting material in the production of therapeutically active penicillanic acid 1,1-dioxide.
En av de mest velkjente og en meget anvendt gruppe av antibakterielle midler er de såkalte g-laktam-antibiotika. One of the most well-known and a widely used group of antibacterial agents are the so-called g-lactam antibiotics.
Disse forbindelser er karakterisert ved at de har en kjerne bestående av en 2-azetidinon (/3-laktam) -ring knyttet til enten en tiazolidin- eller en dihydro-1,3-tiazin-ring. Når kjernen inneholder en tiazolidin-ring, omtales vanligvis forbindelsene med fellesnavnet penicilliner, mens når kjernen inneholder en di-hydrctiazin-ring, omtales forbindelsene som cefalosporiner. Typiske eksempler på penicilliner som er vanlig anvendt ved klinisk praksis, er benzylpenicillin (penicillin G), fenoksy-metylpenicillin (penicillin V), ampicillin og carbenicillin, og typiske eksempler på vanlige cefalosporiner er cefalotin, cefalexin og cefazolin. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (β-lactam) ring linked to either a thiazolidine or a dihydro-1,3-thiazine ring. When the core contains a thiazolidine ring, the compounds are usually referred to by the common name penicillins, while when the core contains a dihydrctiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin, and typical examples of common cephalosporins are cefalotin, cephalexin and cefazolin.
På tross av den omfattende anvendelse og omfattende god-tagelse av 3-laktam-antibiotika som verdifulle kjemoterapeutiske midler, så lider de likevel av den hovedmangel at et visst antall av dem ikke er aktive mot visse mikroorganismer. Man har tenkt at denne motstand til en spesiell mikroorganisme mot et gitt (3-laktam-antibiotikum i mange tilfeller oppstår på grunn av at mikroorganismen produserer en g-laktamase. Den sistnevnte substans er et enzym som spalter $-laktam-ringen i penicilliner Despite the extensive use and widespread acceptance of 3-lactam antibiotics as valuable chemotherapeutic agents, they nevertheless suffer from the main drawback that a certain number of them are not active against certain microorganisms. It has been thought that this resistance of a particular microorganism to a given (3-lactam antibiotic in many cases arises because the microorganism produces a γ-lactamase. The latter substance is an enzyme that cleaves the $-lactam ring in penicillins
og cef alosporiner slik at det dannes produkter som er fri for antibakteriell aktivitet. Visse substanser har imidlertid evne til å inhi-bere 8-laktamase, og når en B-laktamase-inhibitor anvendes sammen med et penicillin eller cefalosporin kan den øke eller forhøye den antibakterielle effektivitet til penicillinet eller cefalosporinet mot visse mikroorganismer. Det anses for å være en forhøyelse av and cefalosporins so that products are formed that are free of antibacterial activity. However, certain substances have the ability to inhibit 8-lactamase, and when a B-lactamase inhibitor is used together with a penicillin or cephalosporin, it can increase or increase the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered to be an elevation of
antibakteriell effektivitet når den antibakterielle aktivitet til en kombinasjon av en Ø-laktamase-inhiberende substans og et Ø-laktam-antibiotikum er betydelig større enn summen av de antibakterielle aktiviteter til de enkelte komponenter. antibacterial effectiveness when the antibacterial activity of a combination of a β-lactamase-inhibiting substance and a β-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Forsøk er i den senere tid gjort på å finne frem til penicillinforbindelser som er resistente overfor Ø-laktamaser. Dette har ført til utvikling av slike antibiotika som methacillin, oxacillin, cloxacillin, dicloxacillin og floxacillin. Disse forbindelser er imidlertid klinisk nyttige bare mot gram-positive bakterier, og de har bare lav aktivitet sammenlignet med penicilliner så som benzyl-penicillin og fenoksymetyl-penicillin, midler som vanligvis anvendes mot gram-positive infeksjoner. Dessuten vil ikke methacillin, oxacillin, cloxacillin, dicloxacillin og floxacillin forsterke den antibakterielle virkning av andre penicilliner eller cefalosporiner mot gram-negative organismer. Forbindelsene som fremstilles ved hjelp av de nye utgangsmaterialer ifølge foreliggende oppfinnelse, forsterker den antibakterielle aktivitet av penicilliner og cefalosporiner mot både gram-positive og gram-negative bakterier. Attempts have recently been made to find penicillin compounds that are resistant to Ø-lactamases. This has led to the development of such antibiotics as methacillin, oxacillin, cloxacillin, dicloxacillin and floxacillin. However, these compounds are clinically useful only against gram-positive bacteria, and they have only low activity compared to penicillins such as benzyl penicillin and phenoxymethyl penicillin, agents commonly used against gram-positive infections. In addition, methacillin, oxacillin, cloxacillin, dicloxacillin and floxacillin will not enhance the antibacterial action of other penicillins or cephalosporins against gram-negative organisms. The compounds produced using the new starting materials according to the present invention enhance the antibacterial activity of penicillins and cephalosporins against both gram-positive and gram-negative bacteria.
Chaikovskaya et al, Antibiotiki, 13, 155 (1968) har undersøkt en rekke /3-laktamase-inhibitorer, men fant ingen andre forbindelser enn methicillin med nyttig aktivitet. Spesielt var benzyl-penicillin-1,1-dioksyd fullstendig in-aktiv. Chaikovskaya et al, Antibiotics, 13, 155 (1968) have examined a number of β-lactamase inhibitors but found no compounds other than methicillin with useful activity. In particular, benzyl penicillin-1,1-dioxide was completely inactive.
Senere er clavulansyre, en /3-laktam-forbindelse oppnådd fra Streptomyces clavuligerus, funnet å være en god Ø-laktamase-inhibitor. Sistnevnte forbindelse er imidlertid kjemisk ustabil. Forbindelsene som fremstilles ved help av utgangsmaterialene ifølge foreliggende oppfinnelse, er betydelig mer stabile enn clavulansyre. Later, clavulanic acid, a β-lactam compound obtained from Streptomyces clavuligerus, has been found to be a good β-lactamase inhibitor. However, the latter compound is chemically unstable. The compounds produced with the help of the starting materials according to the present invention are significantly more stable than clavulanic acid.
I henhold til oppfinnelsen ifølge norsk patent-søknad 78.1970 er det således tilveiebragt en fremgangsmåte for fremstilling av visse nye kjemiske forbindelser som er nye medlemmer av den gruppe av antibiotika som er kjent som penicilliner, og som er nyttige som antibakterielle midler. Disse nye penicillin-forbindelser er penicillansyre-1,1-dioksyd, farmasøytisk godtagbare salter derav og estere derav som er lett hydrolyserbare in vivo. According to the invention according to Norwegian patent application 78.1970, there is thus provided a method for the production of certain new chemical compounds which are new members of the group of antibiotics known as penicillins, and which are useful as antibacterial agents. These new penicillin compounds are penicillanic acid 1,1-dioxide, pharmaceutically acceptable salts thereof and esters thereof which are readily hydrolyzable in vivo.
Dessuten er penicillansyre-1,1-dioksyd og dets estere som er lett hydrolyserbare in vivo, kraftige inhibitorer for mikrobielle Ø-laktamaser»Furthermore, penicillanic acid 1,1-dioxide and its esters, which are readily hydrolyzable in vivo, are potent inhibitors of microbial Ø-lactamases"
1,1-dioksyder av benzylpenicillin, fenoksymetyl-penicillin og visse estere derav er omtalt i U.S. patentskrifter nr. 3.197.466 og nr. 3.536.698, og i en artikkel av Guddal et al. i Tetrahedron Letters, No. 9, 381 (1962). Harrison et al. i Journal of the Chemical Society (London), Perkin I, 1772 (1976) har omtalt forskjellige penicillin-1,1-dioksyder og -1-oksyder, innbefattet metyl-ftalimidopenicillanat-1,1-dioksyd, metyl-6,6-dibrompenicillanat-1,1-dioksyd, metyl-penicillanat-la-oksyd, metyl-penicillanat-lø-oksyd, 6,6-dibrompenicillansyre-loc-oksyd og 6,6-dibrompenicillansyre-lØ-oksyd. 1,1-dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof are disclosed in U.S. Pat. patent documents no. 3,197,466 and no. 3,536,698, and in an article by Guddal et al. in Tetrahedron Letters, No. 9, 381 (1962). Harrison et al. in the Journal of the Chemical Society (London), Perkin I, 1772 (1976) has discussed various penicillin-1,1-dioxides and -1-oxides, including methyl phthalimidopenicillanate-1,1-dioxide, methyl-6,6- dibromopenicillanate-1,1-dioxide, methyl-penicillanate-la-oxide, methyl-penicillanate-lo-oxide, 6,6-dibromopenicillanic acid-loc-oxide and 6,6-dibromopenicillanate-lo-oxide.
I henhold til oppfinnelsen er det tilveiebragt nye penicillansyre-l-oksyder for anvendelse som utgangsmaterialer ved fremstilling av penicillansyre-1,1-dioksyd med formelen According to the invention, new penicillanic acid 1-oxides have been provided for use as starting materials in the production of penicillanic acid 1,1-dioxide with the formula
og de farmasøytisk godtagbare basesalter derav, hvor R er hydrogen, en esterdannende rest som er lett hydrolyserbar in vivo, eller benzyl eller 4-nitrobenzyl. and the pharmaceutically acceptable base salts thereof, wherein R is hydrogen, an ester-forming residue which is readily hydrolyzable in vivo, or benzyl or 4-nitrobenzyl.
Oksydasjon av forbindelsene med formlene II og III for fremstilling av forbindelsen med formel I og egenskapene for forbindelsen med formel I er beskrevet i norsk patentsøknad 78.1970. Oxidation of the compounds with formulas II and III for the production of the compound with formula I and the properties of the compound with formula I are described in Norwegian patent application 78.1970.
Uttrykket "esterdannende rester som er lett hydrolyserbare in vivo" er her ment å bety ikke-toksiske ester-rester som lett spaltes i blod og vev hos pattedyr, for å frigjøre den til-svarende frie syre. The term "ester-forming residues which are easily hydrolysable in vivo" is intended here to mean non-toxic ester residues which are easily cleaved in the blood and tissues of mammals, to release the corresponding free acid.
Typiske karboksybesfcyttende grupper er benzyl og 4-nitrobenzyl. Typical carboxy-protecting groups are benzyl and 4-nitrobenzyl.
Forbindelsene med formlene I, II og III er derivater av penicillansyre, som kan angis med struktur-formelen The compounds of the formulas I, II and III are derivatives of penicillanic acid, which can be indicated by the structural formula
I formelen IV angir brutt linje for tilknytning av en substituent til den bicykliske kjerne at substituenten er under planet for den bicykliske kjerne. Slik en substituent sies å være i a-konfigurasjon. Omvendt angir heltrukken linje for tilknytning av en substituent til den bicykliske kjerne at substituenten er tilknyttet over kjerne-planet. Denne sistnevnte konfigurasjon omtales som Ø-konfigurasjon. In formula IV, broken line for attachment of a substituent to the bicyclic nucleus indicates that the substituent is below the plane of the bicyclic nucleus. Such a substituent is said to be in a-configuration. Conversely, the solid line for attachment of a substituent to the bicyclic core indicates that the substituent is attached above the plane of the core. This latter configuration is referred to as the Ø configuration.
Når R"*" er en ester-dannende rest som er lett hydrolyserbar in vivo, er den en gruppe som begrepsmessig stammer fra en alkohol med formelen R^-OH slik at andelen COOR^" er av en slik natur at gruppen COOR"<*>" lett spaltes in vivo for å frigi en fri karboksy-gruppe (COOH) . Gruppene R"<*>" er velkjente i penicillin-industrien. I de fleste tilfeller forbedrer de absorpsjons-egenskapene til penicillin-forbindelsen. Dessuten bør R være av en slik natur at den gir farmasøytisk godtagbare egenskaper og at den frigir farmasøytisk godtagbare fragmenter når den spaltes in vivo. When R"*" is an ester-forming residue which is readily hydrolyzable in vivo, it is a group conceptually derived from an alcohol of the formula R^-OH such that the moiety COOR^" is of such a nature that the group COOR"< *>" is easily cleaved in vivo to release a free carboxy group (COOH). The groups R"<*>" are well known in the penicillin industry. In most cases, they improve the absorption properties of the penicillin compound. Moreover, R should be of such a nature that it provides pharmaceutically acceptable properties and that it releases pharmaceutically acceptable fragments when cleaved in vivo.
Som angitt ovenfor er gruppene R^" velkjente og er lette å identifisere for fagfolk i penicillin-industrien. Se for eksemple BRD off. skrift nr. 2.517.316. Typiske R -grupper er 3-ftalidyl, 4-krotonolaktonyl, y-butyrolakton-4-yl og gruppene med formlene As indicated above, the R groups are well known and are easily identified by those skilled in the penicillin industry. See for example BRD Off. Document No. 2,517,316. Typical R groups are 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone -4-yl and the groups of the formulas
hvor R"* og R^ hver er valgt fra gruppen bestående av hydrogen og alkyl med fra 1 til 2 karbonatomer, og R<5> er alkyl med fra 1 til 6 karbonatomer. Foretrukne grupper for R<1> er imidlertid alkanoyloksymetyl med fra 3 til 8 karbonatomer, 1-(alkanoyloksy)-etyl med fra 4 til 9 karbonatomer, 1-metyl-l-(alkanoyloksy)etyl med fra 5 til 10 karbonatomer, alkoksykarbonyloksymetyl med fra 3 til 6 karbonatomer, 1-(alkoksykarbonyloksy)etyl med fra 4 til 7 karbonatomer, 1-metyl-l-alkoksykarbonyloksy)etyl med fra 5 til 8 karbonatomer, 3-ftalidyl, 4-krotonolaktonyl og y-butyrolakton-4-yl. 4-krotonolaktonyl og y-butyrolakton-4-yl refererer til henholdsvis strukturene VIII og IX. De bølgete linjer er ment å betegne hver av de to' epimerer og blandinger derav. where R"* and R^ are each selected from the group consisting of hydrogen and alkyl having from 1 to 2 carbon atoms, and R<5> is alkyl having from 1 to 6 carbon atoms. However, preferred groups for R<1> are alkanoyloxymethyl having from 3 to 8 carbon atoms, 1-(alkanoyloxy)-ethyl with from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl with from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl with from 3 to 6 carbon atoms, 1-(Alkoxycarbonyloxy)ethyl with from 4 to 7 carbon atoms, 1-methyl-1-alkoxycarbonyloxy)ethyl with from 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and γ-butyrolacton-4-yl. 4-crotonolactonyl and γ-butyrolacton-4-yl refer to structures VIII and IX, respectively. The wavy lines are intended to denote each of the two epimers and mixtures thereof.
Penicillansyre-la-oksyd, forbindelsen med formel II hvor R<1> er hydrogen, kan fremstilles ved debromering av 6,6-dibrompenicillansyre-la-oksyd. Debromeringen kan utføres ved anvendelse av konvensjonell hydrogenolyseteknikk. Således blir en løsning av 6,6-dibrompenicillansyre-la-oksyd rørt eller ristet under en hydrogen-atmosfære, eller en atmosfære av hydrogen blandet med et inert fortynningsmiddel så som nitrogen eller argon, i nærvær av en katalytisk mengde av palladium-på-kalsiumkarbonat-katalysator. Konvensjonelle løsningsmidler for denne debromering er lavere alkanoler, så som metanol; etere, så som tetrahydrofuran og dioksan; lavmolekylære estere, så som etylacetat og butylacetat; vann; og blandinger av disse løsningsmidler. Det er imidlertid vanlig å velge forhold hvorunder dibromforbindelsen er løselig. Hydrogeno-lysen blir vanligvis utført ved romtemperatur og ved et trykk fra ca. atmosfæretrykk til ca. 3,4 kg/cm 2. Katalysatoren er vanligvis til stede i en mengde på fra ca. 10 vekt%, basert på dibromforbindelsen, opptil en mengde som er lik i vekt med dibromforbindelsen, selv om det kan anvendes større mengder. Omset-ningen varer vanligvis i ca. én time, hvoretter forbindelsen med formel II hvor R"*" er hydrogen, utvinnes ved enkel filtrering fulgt av fjerning av løsningsmidlet i vakuum. Penicillanic acid 1a-oxide, the compound of formula II where R<1> is hydrogen, can be prepared by debromination of 6,6-dibromopenicillanic acid 1a-oxide. The debromination can be carried out using conventional hydrogenolysis techniques. Thus, a solution of 6,6-dibromopenicillanic acid 1a-oxide is stirred or shaken under a hydrogen atmosphere, or an atmosphere of hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of palladium-on- calcium carbonate catalyst. Conventional solvents for this debromination are lower alkanols, such as methanol; ethers, such as tetrahydrofuran and dioxane; low molecular weight esters, such as ethyl acetate and butyl acetate; water; and mixtures of these solvents. However, it is common to choose conditions under which the dibromo compound is soluble. Hydrogenolysis is usually carried out at room temperature and at a pressure of approx. atmospheric pressure to approx. 3.4 kg/cm 2. The catalyst is usually present in an amount of from approx. 10% by weight, based on the dibromo compound, up to an amount equal in weight to the dibromo compound, although larger amounts may be used. The turnover usually lasts for approx. one hour, after which the compound of formula II where R"*" is hydrogen is recovered by simple filtration followed by removal of the solvent in vacuo.
6,6-dibrompenicillansyre-la-oksyd fremstilles ved oksydasjon av 6,6-dibrompenicillansyre med 1 ekvivalent av 3-klorperbenzosyre i tetrahydrofuran ved 0-25°C i ca. 1 time, 6,6-dibromopenicillanic acid 1a-oxide is produced by oxidation of 6,6-dibromopenicillanic acid with 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25°C for approx. 1 hour,
i samsvar med fremgangsmåten til Harrison et al., Journal of the Chemical Society (London), Perkin I, 1972 (1976). .6,6-dibrompenicillansyre fremstilles ved metoden til Clayton, Journal.of the Chemical Society (London), (C) 2123 (1969). according to the method of Harrison et al., Journal of the Chemical Society (London), Perkin I, 1972 (1976). .6,6-dibromopenicillanic acid is prepared by the method of Clayton, Journal of the Chemical Society (London), (C) 2123 (1969).
Penicillansyre-13-oksyd, forbindelsen med formelen Penicillanic acid 13-oxide, the compound with the formula
III hvor R"^ er hydrogen, kan fremstilles ved regulert oksydasjon av penicillansyre. Det kan således fremstilles ved behandling av penicillansyre med én molar-ekvivalent av 3-klorbenzosyre i et inert løsningsmiddel ved ca. 0°C i ca. én time. Typiske løsningsmidler som kan anvendes innbefatter klorerte hydrokarboner, så som kloroform og diklormetan; etere, så som dietyleter og tetrahydrofuran; og lavmolekylære estere, så som etylacetat og butylacetat. Produktet utvinnes ved konvensjonelle teknikker. III where R"^ is hydrogen, can be prepared by controlled oxidation of penicillanic acid. It can thus be prepared by treating penicillanic acid with one molar equivalent of 3-chlorobenzoic acid in an inert solvent at about 0°C for about one hour. Typical solvents which may be used include chlorinated hydrocarbons such as chloroform and dichloromethane; ethers such as diethyl ether and tetrahydrofuran; and low molecular weight esters such as ethyl acetate and butyl acetate. The product is recovered by conventional techniques.
Penicillansyre fremstilles som beskrevet i britisk patentskrift nr. 1.072.108. Penicillanic acid is produced as described in British Patent No. 1,072,108.
Forbindelser med formlene II og III hvor R^" er en ester-dannende rest som er lett hydrolyserbar in vivo, kan fremstilles direkte fra forbindelser med formler II og III hvor R"<*>"Compounds of formulas II and III wherein R^" is an ester-forming residue which is readily hydrolyzable in vivo can be prepared directly from compounds of formulas II and III wherein R"<*>"
er hydrogen, ved forestring ved anvendelse av standard-prosesser. is hydrogen, by esterification using standard processes.
I det tilfelle hvor R"'" er valgt fra gruppen bestående av 3- ftalidyl, 4-krotonolaktonyl, y-butyrolakton-4-yl og grupper In the case where R"'" is selected from the group consisting of 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl and groups
3 4 5 3 4 5
med formlene X og XI hvor R , R og R er som tidligere angitt, kan de fremstilles ved alkylering av den passende forbindelse med formel II eller III hvor R<1> er hydrogen, med et 3-ftalidyl-halogenid, et 4-krotonolaktonyl-halogenid, et y-butyrolakton-4- yl-halogenid eller en forbindelse med formel XII eller XIII. with formulas X and XI where R , R and R are as previously indicated, they can be prepared by alkylating the appropriate compound of formula II or III where R<1> is hydrogen, with a 3-phthalidyl halide, a 4-crotonolactonyl -halide, a γ-butyrolacton-4-yl halide or a compound of formula XII or XIII.
hvor Q er halogen, idet halogen og halogenid betegner klor, brom og jod. where Q is halogen, halogen and halide being chlorine, bromine and iodine.
Alternativt kan forbindelser med formel II hvor R er en ester-dannende rest som er lett hydrolyserbar in vivo, fremstilles ved oksydasjon av den passende ester av 6,6-dibrompenicillansyre , fulgt av debromering. Estrene av 6,6-dibrompenicillansyre fremstilles fra 6,6-dibrompenicillansyre ved standard-metoder. Oksydasjonen utføres f.eks. ved oksydasjon med én molar-ekvivalent av 3-klorperbenzosyre, så som tidligere beskrevet for oksydasjonen av 6,6-dibrompenicillansyre til 6,6-dibrompenicillansyre-lot-oksyd, og debromeringen utføres som tidligere beskrevet for debromeringen av 6,6-dibrompenicillansyre-la-oksyd. Alternatively, compounds of formula II where R is an ester-forming residue which is readily hydrolyzable in vivo can be prepared by oxidation of the appropriate ester of 6,6-dibromopenicillanic acid, followed by debromination. The esters of 6,6-dibromopenicillanic acid are prepared from 6,6-dibromopenicillanic acid by standard methods. The oxidation is carried out e.g. by oxidation with one molar equivalent of 3-chloroperbenzoic acid, as previously described for the oxidation of 6,6-dibromopenicillanic acid to 6,6-dibromopenicillanic acid lot-oxide, and the debromination is carried out as previously described for the debromination of 6,6-dibromopenicillanic acid la oxide.
På lignende måte kan forbindelsene med formel III In a similar way, the compounds of formula III
hvor R"<*>" er en ester-dannende rest som er lett hydrolyserbar in vivo, fremstilles ved oksydasjon av den passende ester av penicillansyre. De sistnevnte forbindelser fremstilles lett ved forestring av penicillansyre ved anvendelse av standard-metoder. Oksydasjonen utføres f.eks. ved oksydasjon med én molar-ekvivalent av 3-klorperbenzosyre, så som tidligere beskrevet for oksydasjonen av penicillansyre til penicillansyre-lø-oksyd. where R"<*>" is an ester-forming residue which is readily hydrolyzable in vivo, is prepared by oxidation of the appropriate ester of penicillanic acid. The latter compounds are easily prepared by esterification of penicillanic acid using standard methods. The oxidation is carried out e.g. by oxidation with one molar equivalent of 3-chloroperbenzoic acid, as previously described for the oxidation of penicillanic acid to penicillanic acid oxide.
Forbindelsene med formel II hvor R^" er benzyl eller 4-nitrobenzyl som karboksy-beskyttende gruppe, kan oppnås på to måter. De kan oppnås ved ganske enkelt å ta penicillansyre-la-oksyd og knytte den karboksy-beskyttende gruppe dertil. Alternativt kan de oppnås ved: (a) å binde den karboksy-beskyttende gruppe til 6,6-dibrompenicillansyre, (b) å oksydere den beskyttede 6,6-dibrompenicillansyre til et beskyttet 6,6-dibrompenicillansyre-la-oksyd ved anvendelse av 1 molar-ekvivalent av 3-klorperbenzosyre, og (c) å debromere det beskyttede 6,6-dibrompenicillansyre-la-oksyd ved hydrogenolyse. The compounds of formula II where R^" is benzyl or 4-nitrobenzyl as the carboxy-protecting group can be obtained in two ways. They can be obtained by simply taking penicillanic acid 1a-oxide and attaching the carboxy-protecting group thereto. Alternatively, they are obtained by: (a) attaching the carboxy-protecting group to 6,6-dibromopenicillanic acid, (b) oxidizing the protected 6,6-dibromopenicillanic acid to a protected 6,6-dibromopenicillanic acid 1a-oxide using 1 molar -equivalent of 3-chloroperbenzoic acid, and (c) debrominating the protected 6,6-dibromopenicillanic acid 1a-oxide by hydrogenolysis.
Forbindelsene med formel III hvor K<*>~ er en slik karboksy-beskyttende gruppe, kan oppnås ved ganske enkelt å tilknytte den beskyttende gruppe til penicillansyre-10-oksyd. Alternativt kan de oppnås ved: (a) å binde den karboksy-beskyttende gruppe til penicillansyre, og (b) å oksydere den beskyttende penicillansyre ved anvendelse av 1 molar-ekvivalent av 3-klorperbenzosyre, som tidligere beskrevet. The compounds of formula III where K<*>~ is such a carboxy-protecting group can be obtained by simply attaching the protecting group to penicillanic acid-10-oxide. Alternatively, they can be obtained by: (a) attaching the carboxy protecting group to penicillanic acid, and (b) oxidizing the protecting penicillanic acid using 1 molar equivalent of 3-chloroperbenzoic acid, as previously described.
Forbindelsene II og III hvor R er hydrogen er sure The compounds II and III where R is hydrogen are acidic
og vil danne salter med basiske midler. Slike farmasøytisk godtagbare salter ansees å ligge innen omfanget av oppfinnelsen. Disse salter kan fremstilles ved standard-teknikker, så som ved and will form salts with basic agents. Such pharmaceutically acceptable salts are considered to be within the scope of the invention. These salts can be produced by standard techniques, such as wood
å bringe de sure og basiske komponenter i kontakt, vanligvis i et molforhold på 1:1, i et vandig, ikke-vandig eller delvis vandig medium, etter som det passer. De utvinnes så ved filtrering, ved inndamping av løsningsmidler eller, når det dreier seg om vandige løsninger, ved lyofilisering, etter som det passer. Basiske midler som det er passende å anvende ved saltdannelsen, hører både til den organiske og den uorganiske type, og de innbefatter ammoniakk, organiske aminer, alkalimetalllhydroksyder, bringing the acidic and basic components into contact, usually in a 1:1 molar ratio, in an aqueous, non-aqueous or semi-aqueous medium, as appropriate. They are then recovered by filtration, by evaporation of solvents or, in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents suitable for use in salt formation are of both the organic and inorganic types and include ammonia, organic amines, alkali metal hydroxides,
-karbonater, -bikarbonater, -hydrider og -alkoksyder, og også jordalkalimetallhydroksyder, -karbonater, -hydrider og -alkoksyder. Representative eksempler på slike baser er primære aminer, så som n-propylamin, n-butylamin, anilin, cykloheksylamin, benzylamin og oktylamin; sekundære aminer, så som dietylamin, morfolin pyrrolidin og piperidin; tertiære aminer, så som trietylamin, N-etylpiperidin, N-metylmorfolin og 1,5-diazabicyklo[4.3.0]non-5-en; hydroksyder, så som natriumhydroksyd, kaliumhydroksyd, ammoniumhydroksyd og bariumhydroksyd; alkoksyder, så som natriumetoksyd og kaliumetoksyd; hydrider, så som kalsium- -carbonates, -bicarbonates, -hydrides and -alkoxides, and also alkaline earth metal hydroxides, -carbonates, -hydrides and -alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines, such as diethylamine, morpholine pyrrolidine and piperidine; tertiary amines, such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo[4.3.0]non-5-ene; hydroxides, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium-
hydrid og natriumhydrid; karbonater, så som kaliumkarbonat og natriumkarbonat; bikarbonater, så som natriumbikarbonat og kaliumbikarbonat; og alkalimetallsalter av langkjedete fettsyrer, så som natrium-2-etylheksanoat. hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; bicarbonates, such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids, such as sodium 2-ethyl hexanoate.
Foretrukne salter av forbindelsene med formlene II Preferred salts of the compounds of the formulas II
og III er natrium-, kalium- og trietylamin-saltene. and III are the sodium, potassium and triethylamine salts.
De følgende eksempler belyser oppfinnelsen ytterligere. Infrarøde (IR) spektra ble målt, og karakteristiske absorpsjons-bånd er angitt i bølge-tall (cm ^). Kjernemagnetiske resonans-spektra (NMR) ble målt ved 60 MHz og toppunkt-stillinger er ut-trykt i deler pr. million (ppm) nedover fra tetrametylsilan. De følgende forkortelser for toppunkt-former anvendes: s, singlett, q, kvartett; m, multiplett. The following examples further illustrate the invention. Infrared (IR) spectra were measured, and characteristic absorption bands are given in wavenumber (cm^). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz and peak positions are expressed in parts per million (ppm) down from tetramethylsilane. The following abbreviations for vertex forms are used: s, singlet, q, quartet; m, multiplet.
EKSEMPEL 1 EXAMPLE 1
Penicillansyre- lct- oksyd Penicillanic acid lct oxide
Til 1,4 g av prehydrogenert 5%ig palladium-på-kalsiumkarbonat i 50 ml vann ble det satt en løsning av 1,39 g benzyl-6,6-dibrompenicillanat-la-oksyd i 50 ml tetrahydrofuran. Blandingen ble ristet under en hydrogenatmosfære ved ca. 3,15 kg/cm<2> og ved 25°C i 1 time, og den ble så filtrert. Filtratet ble inndampet i vakuum for å fjerne hovedmengden av tetrahydro-furanet, og den vandige fase ble ekstrahert med eter. Eter-ekstraktene ble inndampet i vakuum for å gi 0,5 g av et materiale som i stor grad viste seg å være benzyl-penicillanat-la-oksyd. To 1.4 g of prehydrogenated 5% palladium-on-calcium carbonate in 50 ml of water was added a solution of 1.39 g of benzyl-6,6-dibromopenicillanate-1a-oxide in 50 ml of tetrahydrofuran. The mixture was shaken under a hydrogen atmosphere at approx. 3.15 kg/cm<2> and at 25°C for 1 hour, and it was then filtered. The filtrate was evaporated in vacuo to remove the bulk of the tetrahydrofuran, and the aqueous phase was extracted with ether. The ether extracts were evaporated in vacuo to give 0.5 g of a material which proved to be largely benzyl penicillanate-1a-oxide.
Benzyl-penicillanat-la-oksydet ble kombinert med ytterligere 2,0 g benzyl-6,6-dibrompenicillanat-la-oksyd og oppløst i 50 ml tetrahydrofuran. Løsningen ble satt til 4,0 g 5%ig palladium-på-kalsiumkarbonat, i 50 ml vann, og den resulterende blanding ble ristet under en hydrogen-atmosfære, ved ca. 3,15 kg/cm<2> og 25°C, natten over. Blandingen ble filtrert, og filtratet ble ekstrahert med eter. Ekstraktene ble inndampet i vakuum, og residuet ble renset ved kromatografering på silikagel, og eluert med kloroform. Dette gav 0,50 g med materiale. The benzyl penicillanate 1a oxide was combined with an additional 2.0 g of benzyl 6,6-dibromopenicillanate 1a oxide and dissolved in 50 ml of tetrahydrofuran. The solution was added to 4.0 g of 5% palladium-on-calcium carbonate, in 50 ml of water, and the resulting mixture was shaken under a hydrogen atmosphere, at approx. 3.15 kg/cm<2> and 25°C, overnight. The mixture was filtered and the filtrate was extracted with ether. The extracts were evaporated in vacuo, and the residue was purified by chromatography on silica gel, and eluted with chloroform. This gave 0.50 g of material.
Det sistnevnte materiale ble hydrogenert ved ca. The latter material was hydrogenated at approx.
3,15 kg/cm<2> ved 25°C i vann-metanol (1:1) med 0,50 g av 5%ig palladium-på-kalsiumkarbonat i 2 timer. Ved dette punkt ble 3.15 kg/cm<2> at 25°C in water-methanol (1:1) with 0.50 g of 5% palladium-on-calcium carbonate for 2 hours. At this point was
det tilsatt ytterligere 0,50 g med 5%ig palladium-på-kalsiumkarbonat, og hydrogeneringen ble fortsatt ved 3,15 kg/cm 2 og 25°C natten over. Reaksjonsblandingen ble filtrert, ekstrahert med eter, og ekstraktene ble kastet. Den gjenværende vandige fase ble justert til pH 1,5 og så ekstrahert med etylacetat. Etylacetat-ekstraktene ble tørket (Na2S04) og så inndampet i vakuum for å gi 0,14 g penicillansyre-la-oksyd. NMR-spektret (CDCl3/DMSO-d6) viste absorpsjoner ved 1,4 (s, 3H), 1,64 (s, 3H), 3,60 (m, 2H), 4,3 (s, 1H) og 4,54 (m, 1H) ppm. IR-spektret til produktet (KBr-plater) viste absorpsjoner ved 1795 og 1745 cm . an additional 0.50 g of 5% palladium-on-calcium carbonate was added, and the hydrogenation was continued at 3.15 kg/cm 2 and 25°C overnight. The reaction mixture was filtered, extracted with ether, and the extracts were discarded. The remaining aqueous phase was adjusted to pH 1.5 and then extracted with ethyl acetate. The ethyl acetate extracts were dried (Na 2 SO 4 ) and then evaporated in vacuo to give 0.14 g of penicillanic acid 1a oxide. The NMR spectrum (CDCl3/DMSO-d6) showed absorptions at 1.4 (s, 3H), 1.64 (s, 3H), 3.60 (m, 2H), 4.3 (s, 1H) and 4 .54 (m, 1H) ppm. The IR spectrum of the product (KBr plates) showed absorptions at 1795 and 1745 cm.
EKSEMPEL 2 EXAMPLE 2
Penicillansyre- lg- oksyd Penicillanic acid-lg-oxide
Til 1,0 g prehydrogenert 5%ig palladium-på-kalsiumkarbonat i 30 ml vann ble det satt en løsning av 1,0 g 6,6-dibrompenicillansyre-la-oksyd. Blandingen ble ristet under en hydrogen-atmosfære, ved ca. 3,15 kg/cm 2 i én time. Reaksjonsblandingen ble så filtrert og filtratet konsentrert i vakuum for å fjerne metanolen. Den gjenværende vandige fase ble fortynnet med et likt volum vann, justert til pH 7 og vasket med eter. To 1.0 g of prehydrogenated 5% palladium-on-calcium carbonate in 30 ml of water was added a solution of 1.0 g of 6,6-dibromopenicillanic acid 1a-oxide. The mixture was shaken under a hydrogen atmosphere, at approx. 3.15 kg/cm 2 for one hour. The reaction mixture was then filtered and the filtrate concentrated in vacuo to remove the methanol. The remaining aqueous phase was diluted with an equal volume of water, adjusted to pH 7 and washed with ether.
Den vandige fase ble så surgjort til pH 2 med fortynnet salt-syre og ekstrahert med etylacetat. Etylacetat-ekstraktene ble tørket (Na2S0^) og inndampet i vakuum for å gi penicillansyre-la-oksyd. The aqueous phase was then acidified to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were dried (Na 2 SO 4 ) and evaporated in vacuo to give penicillanic acid 1a oxide.
EKSEMPEL 3 EXAMPLE 3
Penicillansyre- lg- oksyd Penicillanic acid-lg-oxide
Til en rørt løsning av 2,65 g (12,7 mmol) penicillansyre i kloroform ved 0°C ble det satt 2,58 g med 85%ig ren 3-klorperbenzosyre. Etter 1 time ble reaksjonsblandingen filtrert og filtratet ble inndampet i vakuum. Residuet ble oppløst i en liten mengde kloroform. Løsningen ble sakte konsentrert inntil det begynte å komme en utfeining til syne. Ved dette punkt ble inndampingen stoppet og blandingen ble fortynnet med eter. Ut-felningen ble fjernet ved filtrering, vasket med eter og tørket, for å gi 0,615 g penicillansyre-lg-oksyd, sm.p. 140-3°C. IR-spektret til produktet (CHCl^-løsning) viste absorpsjoner ved 1775 og 1720 cm"<1>. NMR-spektret (CDCl3/DMSO-d6) viste absorpsjoner ved 1,35 (s, 3H), 1,76 (s, 3H), 3,36 (m, 2H), To a stirred solution of 2.65 g (12.7 mmol) of penicillanic acid in chloroform at 0°C was added 2.58 g of 85% pure 3-chloroperbenzoic acid. After 1 hour, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a small amount of chloroform. The solution was slowly concentrated until a blur began to appear. At this point the evaporation was stopped and the mixture was diluted with ether. The precipitate was removed by filtration, washed with ether and dried to give 0.615 g of penicillanic acid 1g oxide, m.p. 140-3°C. The IR spectrum of the product (CHCl^ solution) showed absorptions at 1775 and 1720 cm"<1>. The NMR spectrum (CDCl3/DMSO-d6) showed absorptions at 1.35 (s, 3H), 1.76 (s , 3H), 3.36 (m, 2H),
4,50 (s, 1H) og 5,05 (m, 1H) ppm. Fra NMR-spektret viste produktet seg å være ca. 90% rent. 4.50 (s, 1H) and 5.05 (m, 1H) ppm. From the NMR spectrum, the product turned out to be approx. 90% clean.
Undersøkelse av kloroform-eter-moderluten viste at Examination of the chloroform-ether mother liquor showed that
den inneholdt ytterligere penicillansyre-lft-oksyd, og også noe penicillansyre-la-oksyd. it contained additional penicillanic acid lft oxide, and also some penicillanic acid la oxide.
Fremstilling av utgangsmaterialer. Production of starting materials.
Benzyl- 6, 6- dibrompenicillanat Benzyl- 6, 6- dibromopenicillanate
Til en løsning av 54 g (0,165 mol) 6,6-dibrompenicillansyre i 350 ml N,N-dimetylacetamid ble det satt 22,9 ml (0,165 mol) trietylamin og løsningen ble rørt i 4 0 minutter. Benzylbromid (19,6 ml, 0,165 mol) ble tilsatt, og den resulterende blanding To a solution of 54 g (0.165 mol) of 6,6-dibromopenicillanic acid in 350 ml of N,N-dimethylacetamide was added 22.9 ml (0.165 mol) of triethylamine and the solution was stirred for 40 minutes. Benzyl bromide (19.6 mL, 0.165 mol) was added and the resulting mixt
ble rørt ved romtemperatur i 4 8 timer. Det ut f el te trietylamin-hydrobromid ble frafiltrert, og filtratet ble satt til 1500 ml isvann, justert til pH 2. Blandingen ble ekstrahert med eter, og ekstraktene ble vasket suksessivt med mettet natriumbikarbonat, vann og saltløsning. Den tørkede (MgSO^) eter-løsning ble inndampet i vakuum for å gi et hvitt, fast stoff, som ble omkrystalli-sert fra isopropanol. Dette gav 70,0 g (95% utbytte) av tittel-forbindelsen, sm.p. 75-76°C. IR-spektret (KBr-plate) viste absorpsjoner ved 1795 og 1740 cm<-1>. NMR-spektret (CDCl^) viste absorpsjoner ved 1,53 (s, 3H), 1,58 (s, 3H), 4,50 (s, 1H), 5,13 was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered off, and the filtrate was added to 1500 ml of ice water, adjusted to pH 2. The mixture was extracted with ether, and the extracts were washed successively with saturated sodium bicarbonate, water and brine. The dried (MgSO 4 ) ether solution was evaporated in vacuo to give a white solid, which was recrystallized from isopropanol. This gave 70.0 g (95% yield) of the title compound, m.p. 75-76°C. The IR spectrum (KBr plate) showed absorptions at 1795 and 1740 cm<-1>. The NMR spectrum (CDCl 2 ) showed absorptions at 1.53 (s, 3H), 1.58 (s, 3H), 4.50 (s, 1H), 5.13
(s, 2H), 5,72 (s, 1H) og 7,37 (s. 5H) ppm. (s, 2H), 5.72 (s, 1H) and 7.37 (s, 5H) ppm.
Benzyl- 6, 6- dibrompenicillanat- la- oksyd Benzyl- 6, 6- dibromopenicillanate- la- oxide
Til en rørt løsning av 13,4 g (0,03 mol) benzyl-6,6-dibrompenicillanat i 200 ml diklormetan ble det satt en løsning av 6,12 g (0,03 mol) 3-klorperbenzosyre i 100 ml diklormetan, To a stirred solution of 13.4 g (0.03 mol) of benzyl-6,6-dibromopenicillanate in 200 ml of dichloromethane was added a solution of 6.12 g (0.03 mol) of 3-chloroperbenzoic acid in 100 ml of dichloromethane,
ved ca. 0°C. Det ble fortsatt med røring i 1 1/2 time ved ca. 0°C, og reaksjonsblandingen ble filtrert. Filtratet ble vasket suksessivt med 5%ig natriumbikarbonat og vann, og det ble så tørket (Na2S04). Fjerning av løsningsmidlet ved inndamping i vakuum gav 12,5 g av tittel-produktet som en olje. Oljen ble at approx. 0°C. Stirring was continued for 1 1/2 hours at approx. 0°C, and the reaction mixture was filtered. The filtrate was washed successively with 5% sodium bicarbonate and water, and then dried (Na 2 SO 4 ). Removal of the solvent by evaporation in vacuo gave 12.5 g of the title product as an oil. The oil stayed
brakt til fast tilstand ved finfordeling under eter. Filtrering gav så 10,5 g benzyl-6,6-dibrompenicillanat-la-oksyd som et fast stoff. IR-spektret (CDC1,) viste absorpsjoner ved 1800 og 1750 brought to a solid state by fine distribution under ether. Filtration then gave 10.5 g of benzyl-6,6-dibromopenicillanate-1a-oxide as a solid. The IR spectrum (CDC1,) showed absorptions at 1800 and 1750
-1 J -1 J
cm . NMR-spektret av produktet (CDC13) viste absorpsjoner ved 1,3 (s, 3H) , 1,5 (s, 3H) , 4,5 (s, 1H) , 5,18 (s, 2H) , 5,2 (s, 1H.) og 7,3 (s, 5H) ppm. cm. The NMR spectrum of the product (CDCl 3 ) showed absorptions at 1.3 (s, 3H) , 1.5 (s, 3H) , 4.5 (s, 1H) , 5.18 (s, 2H) , 5.2 (s, 1H.) and 7.3 (s, 5H) ppm.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80432077A | 1977-06-07 | 1977-06-07 | |
| US87938178A | 1978-02-21 | 1978-02-21 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO823126L NO823126L (en) | 1978-12-08 |
| NO152448B true NO152448B (en) | 1985-06-24 |
| NO152448C NO152448C (en) | 1985-10-02 |
Family
ID=27122691
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO781970A NO151746C (en) | 1977-06-07 | 1978-06-06 | ANALOGUE PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE PENICILLANIC ACID-1,1-DIOXYD |
| NO823126A NO152448C (en) | 1977-06-07 | 1982-09-15 | NEW PENICILLANIC ACID-L-OXYDES FOR USE AS INTERMEDIATES IN PENICILLANIC ACID-L, L-DIOXYD PREPARATION |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO781970A NO151746C (en) | 1977-06-07 | 1978-06-06 | ANALOGUE PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE PENICILLANIC ACID-1,1-DIOXYD |
Country Status (35)
| Country | Link |
|---|---|
| AR (1) | AR224111A1 (en) |
| AT (2) | AT360649B (en) |
| AU (1) | AU513636B2 (en) |
| BE (1) | BE867859A (en) |
| BG (2) | BG34615A3 (en) |
| CH (1) | CH634073A5 (en) |
| CS (1) | CS208472B2 (en) |
| DD (2) | DD148585A5 (en) |
| DE (2) | DE2857263C3 (en) |
| DK (1) | DK155740C (en) |
| EG (1) | EG13869A (en) |
| FI (1) | FI66003C (en) |
| FR (2) | FR2393804A1 (en) |
| GB (1) | GB2000138B (en) |
| GR (1) | GR72255B (en) |
| HK (1) | HK13184A (en) |
| HU (1) | HU180042B (en) |
| IE (1) | IE47079B1 (en) |
| IL (2) | IL54867A (en) |
| IN (1) | IN149747B (en) |
| IT (1) | IT1096381B (en) |
| KE (1) | KE3355A (en) |
| LU (1) | LU79774A1 (en) |
| MY (1) | MY8500092A (en) |
| NL (2) | NL180009C (en) |
| NO (2) | NO151746C (en) |
| NZ (1) | NZ187476A (en) |
| OA (1) | OA05964A (en) |
| PH (3) | PH26810A (en) |
| PL (1) | PL114501B1 (en) |
| PT (1) | PT68146A (en) |
| SE (2) | SE436206B (en) |
| SG (1) | SG65383G (en) |
| SU (1) | SU860706A1 (en) |
| YU (1) | YU41829B (en) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU77306A1 (en) * | 1977-05-09 | 1979-01-18 | ||
| DE2912511C2 (en) * | 1977-06-07 | 1982-06-24 | Pfizer Inc., 10017 New York, N.Y. | Pharmaceutical composition containing penicillanic acid |
| DK155942C (en) * | 1977-12-23 | 1989-10-23 | Pfizer | METHOD OF ANALOGUE FOR THE PREPARATION OF 6-AMINOPENICILLANIC ACID-1,1-DIOXIDE AND PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION AND BASIS SALTS. |
| JPS54126735A (en) * | 1978-03-24 | 1979-10-02 | Toyama Chem Co Ltd | Bactericidal composition for medical use |
| US4241050A (en) * | 1978-09-01 | 1980-12-23 | Pfizer Inc. | Penam 1,1-dioxides as beta-lactamase inhibitors |
| CA1158639A (en) * | 1978-12-11 | 1983-12-13 | Eric M. Gordon | 6-bromopenicillanic acid sulfone |
| IE49881B1 (en) * | 1979-02-13 | 1986-01-08 | Leo Pharm Prod Ltd | B-lactam intermediates |
| SE449103B (en) * | 1979-03-05 | 1987-04-06 | Pfizer | SET TO PENICILLANIC ACID-1,1-DIOXIDE AND ESSERS THEREOF |
| US4420426A (en) | 1979-03-05 | 1983-12-13 | Pfizer Inc. | 6-Alpha-halopenicillanic acid 1,1-dioxides |
| US4714761A (en) * | 1979-03-05 | 1987-12-22 | Pfizer Inc. | 6,6-dihalopenicillanic acid 1,1-dioxides and process |
| GB2045236A (en) * | 1979-03-26 | 1980-10-29 | Hoechst Uk Ltd | Oxapenem derivatives |
| US4244951A (en) | 1979-05-16 | 1981-01-13 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
| US4309347A (en) * | 1979-05-16 | 1982-01-05 | Pfizer Inc. | Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide |
| IE49768B1 (en) * | 1979-05-21 | 1985-12-11 | Leo Pharm Prod Ltd | 6beta-halopenicillanic acid derivatives |
| DE3051044C2 (en) * | 1979-06-19 | 1989-03-30 | Leo Pharmaceutical Products Ltd. A/S (Loevens Kemiske Fabrik Produktionsaktieselskab), Ballerup, Dk | |
| US4256733A (en) * | 1979-09-26 | 1981-03-17 | Pfizer Inc. | Acetoxymethyl penam compounds as β-lactamase inhibitors |
| US4432970A (en) * | 1979-11-23 | 1984-02-21 | Pfizer Inc. | 6-beta-Halopenicillanic acid 1,1-dioxides as beta-lactamase inhibitors |
| IL61880A (en) * | 1980-01-21 | 1984-11-30 | Bristol Myers Co | 2beta-chloromethyl-2alpha-methylpenam-3alpha-carboxylic acid sulfone derivatives,their preparation and pharmaceutical compositions containing them |
| US4432903A (en) * | 1980-09-08 | 1984-02-21 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
| US4488994A (en) * | 1980-09-08 | 1984-12-18 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
| US4474698A (en) * | 1980-12-11 | 1984-10-02 | Pfizer Inc. | Process for preparing esters of penicillanic acid sulfone |
| US4419284A (en) * | 1981-03-23 | 1983-12-06 | Pfizer Inc. | Preparation of halomethyl esters (and related esters) of penicillanic acid 1,1-dioxide |
| DE3261759D1 (en) * | 1981-07-15 | 1985-02-14 | Kanebo Ltd | Novel ester of 1,1-dioxopenicillanic acid, process for production thereof, and use thereof as beta-lactamase inhibitor |
| PT76527B (en) * | 1982-04-19 | 1985-12-09 | Gist Brocades Nv | A process for the preparation of penicillanic acid 1,1-dioxide and derivatives thereof |
| US4502988A (en) * | 1983-08-08 | 1985-03-05 | Eli Lilly And Company | Oxidation process |
| EP0139047A1 (en) * | 1983-10-18 | 1985-05-02 | Gist-Brocades N.V. | Process for the preparation of 6,6-dibromopenicillanic acid 1,1-dioxide |
| US4647457A (en) * | 1983-12-16 | 1987-03-03 | Hoffmann-La Roche Inc. | Penicillanic acid derivatives |
| DE3780112T2 (en) * | 1986-04-10 | 1992-12-24 | Leo Pharm Prod Ltd | METHOD FOR PRODUCING PENICILLANIC ACID DERIVATIVES. |
| GB8808701D0 (en) * | 1988-04-13 | 1988-05-18 | Erba Carlo Spa | Beta-lactam derivatives |
| CN102977120B (en) * | 2012-12-14 | 2015-05-27 | 江西富祥药业股份有限公司 | Method for preparing and crystallizing sulbactam pivoxyl |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3197466A (en) * | 1961-10-30 | 1965-07-27 | Smith Kline French Lab | Penicillin sulfoxides and process |
| LU77306A1 (en) * | 1977-05-09 | 1979-01-18 | ||
| EP0000636A1 (en) * | 1977-07-13 | 1979-02-07 | Glaxo Group Limited | Penem compounds, processes for their preparation, their use in pharmaceutical compositions and azetidinones used in their preparation |
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1978
- 1978-05-04 IN IN327/DEL/78A patent/IN149747B/en unknown
- 1978-05-09 PH PH21116A patent/PH26810A/en unknown
- 1978-05-16 YU YU1170/78A patent/YU41829B/en unknown
- 1978-05-18 OA OA56500A patent/OA05964A/en unknown
- 1978-05-20 EG EG322/78A patent/EG13869A/en active
- 1978-05-30 BG BG7942176A patent/BG34615A3/en unknown
- 1978-05-30 BG BG7839910A patent/BG34614A3/en unknown
- 1978-06-01 CS CS783579A patent/CS208472B2/en unknown
- 1978-06-02 AU AU36838/78A patent/AU513636B2/en not_active Ceased
- 1978-06-02 GB GB7826308A patent/GB2000138B/en not_active Expired
- 1978-06-05 DE DE2857263A patent/DE2857263C3/en not_active Expired
- 1978-06-05 GR GR56439A patent/GR72255B/el unknown
- 1978-06-05 DE DE2824535A patent/DE2824535C3/en not_active Expired
- 1978-06-06 IT IT24270/78A patent/IT1096381B/en active Protection Beyond IP Right Term
- 1978-06-06 NO NO781970A patent/NO151746C/en unknown
- 1978-06-06 AT AT411278A patent/AT360649B/en active Protection Beyond IP Right Term
- 1978-06-06 CH CH618078A patent/CH634073A5/en not_active IP Right Cessation
- 1978-06-06 FR FR787816893A patent/FR2393804A1/en active Granted
- 1978-06-06 FI FI781800A patent/FI66003C/en not_active IP Right Cessation
- 1978-06-06 PL PL1978207396A patent/PL114501B1/en unknown
- 1978-06-06 PT PT68146A patent/PT68146A/en unknown
- 1978-06-06 SU SU782624408A patent/SU860706A1/en active
- 1978-06-06 DK DK251478A patent/DK155740C/en not_active IP Right Cessation
- 1978-06-06 SE SE7806628A patent/SE436206B/en not_active IP Right Cessation
- 1978-06-06 IE IE1140/78A patent/IE47079B1/en not_active IP Right Cessation
- 1978-06-06 NL NLAANVRAGE7806126,A patent/NL180009C/en not_active IP Right Cessation
- 1978-06-06 BE BE188352A patent/BE867859A/en not_active IP Right Cessation
- 1978-06-06 IL IL54867A patent/IL54867A/en unknown
- 1978-06-06 LU LU79774A patent/LU79774A1/en unknown
- 1978-06-06 HU HU78PI630A patent/HU180042B/en unknown
- 1978-06-06 NZ NZ187476A patent/NZ187476A/en unknown
- 1978-06-07 DD DD78218400A patent/DD148585A5/en unknown
- 1978-06-07 DD DD78205839A patent/DD140888A5/en unknown
- 1978-08-18 AR AR272228A patent/AR224111A1/en active
- 1978-09-08 PH PH21587A patent/PH16465A/en unknown
- 1978-09-08 PH PH21586A patent/PH21116A/en unknown
- 1978-09-19 FR FR787826789A patent/FR2393805A1/en active Granted
-
1980
- 1980-03-07 AT AT0128580A patent/AT364084B/en not_active IP Right Cessation
-
1981
- 1981-02-19 IL IL62168A patent/IL62168A0/en unknown
-
1982
- 1982-09-15 NO NO823126A patent/NO152448C/en unknown
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1983
- 1983-10-27 SE SE8305916A patent/SE447995B/en not_active IP Right Cessation
- 1983-11-02 SG SG653/83A patent/SG65383G/en unknown
- 1983-11-22 KE KE3355A patent/KE3355A/en unknown
-
1984
- 1984-02-16 HK HK131/84A patent/HK13184A/en not_active IP Right Cessation
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1985
- 1985-12-30 MY MY92/85A patent/MY8500092A/en unknown
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1993
- 1993-06-11 NL NL930064C patent/NL930064I2/en unknown
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