NO147565B - PROCEDURE FOR PREPARING DERIVATIVES OF 6-AMINOPENICILLANIC ACID - Google Patents
PROCEDURE FOR PREPARING DERIVATIVES OF 6-AMINOPENICILLANIC ACID Download PDFInfo
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- NO147565B NO147565B NO740341A NO740341A NO147565B NO 147565 B NO147565 B NO 147565B NO 740341 A NO740341 A NO 740341A NO 740341 A NO740341 A NO 740341A NO 147565 B NO147565 B NO 147565B
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- Prior art keywords
- acid
- salt
- tertiary amine
- formula
- acetone
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- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical class [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 16
- -1 amide acetal Chemical class 0.000 claims description 48
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 150000003512 tertiary amines Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 239000012429 reaction media Substances 0.000 claims description 10
- 239000000376 reactant Substances 0.000 claims description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 5
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 230000000630 rising effect Effects 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 16
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BWWVAEOLVKTZFQ-NTZNESFSSA-N Amdinocillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)=CN1CCCCCC1 BWWVAEOLVKTZFQ-NTZNESFSSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000004992 fission Effects 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- YVWHMWGVWOQIFR-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O.CC(C)=O YVWHMWGVWOQIFR-UHFFFAOYSA-N 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- HAFWELDDNUXLCK-ODZAUARKSA-N (z)-but-2-enedioic acid;hydrate Chemical compound O.OC(=O)\C=C/C(O)=O HAFWELDDNUXLCK-ODZAUARKSA-N 0.000 description 1
- DLYZPQGVPVAEME-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethyl-1-phenylmethanamine Chemical compound COC(OC)(N(C)C)C1=CC=CC=C1 DLYZPQGVPVAEME-UHFFFAOYSA-N 0.000 description 1
- BCMOEKZVKFIWCA-UHFFFAOYSA-N 1-(dimethoxymethyl)pyrrolidine Chemical compound COC(OC)N1CCCC1 BCMOEKZVKFIWCA-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- DBPMHMYHCBTONS-UHFFFAOYSA-N 4-(dimethoxymethyl)morpholine Chemical compound COC(OC)N1CCOCC1 DBPMHMYHCBTONS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 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
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- AIPVTTKYSPOWFO-UHFFFAOYSA-N azepane-1-carbaldehyde Chemical compound O=CN1CCCCCC1 AIPVTTKYSPOWFO-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZYFYTWZIMOACBS-UHFFFAOYSA-N butan-1-ol;ethanol;hydrate Chemical compound O.CCO.CCCCO ZYFYTWZIMOACBS-UHFFFAOYSA-N 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- WHHZFNIQVXYNSF-UHFFFAOYSA-N formamide;propan-2-one Chemical compound NC=O.CC(C)=O WHHZFNIQVXYNSF-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- JQTXMZSDDDXZNZ-UHFFFAOYSA-N n-benzyl-1,1-dimethoxy-n-methylmethanamine Chemical compound COC(OC)N(C)CC1=CC=CC=C1 JQTXMZSDDDXZNZ-UHFFFAOYSA-N 0.000 description 1
- KVEFEYBJNJQGHD-UHFFFAOYSA-N naphthalene-2-sulfonic acid trihydrate Chemical compound O.O.O.C1=C(C=CC2=CC=CC=C12)S(=O)(=O)O KVEFEYBJNJQGHD-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- KIDBBTHHMJOMAU-UHFFFAOYSA-N propan-1-ol;hydrate Chemical compound O.CCCO KIDBBTHHMJOMAU-UHFFFAOYSA-N 0.000 description 1
- HHAVHBDPWSUKHZ-UHFFFAOYSA-N propan-2-ol;propan-2-one Chemical compound CC(C)O.CC(C)=O HHAVHBDPWSUKHZ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 239000011734 sodium Substances 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
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Fremgangsmåte for fremstilling av derivater av 6-aminopenicillansyre.Process for the preparation of derivatives of 6-aminopenicillanic acid.
Description
Nærværende oppfinnelse vedrorer en forbedret fremgangsmåte for fremstilling av derivater av o-aminopenicillansyre. The present invention relates to an improved process for the production of derivatives of o-aminopenicillanic acid.
Forbindelsene som fremstilles etter fremgangsmåten ifolge nærværende oppfinnelse har den generelle formel hvor R^, R_ og R., er like eller forskjellige substituenter og hver betyr et C2_~ C4 alkylradikal eller en fenyl- eller benzylgruppe, idet R^ dessuten kan bety hydrogen' og R-^ og R£ sammen med nitrogenatomet kan bety en 5-8 leddet heterocyklisk ring, hvori et av leddene kan være et oksygenatom. The compounds produced according to the method according to the present invention have the general formula where R^, R_ and R., are the same or different substituents and each means a C2_~C4 alkyl radical or a phenyl or benzyl group, R^ may also mean hydrogen' and R-^ and R£ together with the nitrogen atom can mean a 5-8 membered heterocyclic ring, in which one of the members can be an oxygen atom.
Forbindelsene med formel I kan isoleres som zwitterion eller som et salt, f.eks. alkalimetallsalter og ammonium-eller amin-saltene, eller salter med sterke syrer, såsom saltsyre, fosforsyre, salpetersyre, p-toluensulfonsyre, vinsyre eller maleinsyre. The compounds of formula I can be isolated as a zwitterion or as a salt, e.g. alkali metal salts and the ammonium or amine salts, or salts with strong acids, such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, tartaric acid or maleic acid.
Salter kan også fremstilles med andre antibiotika med sur eller basisk karakter, og da spesielt med sure antibiotika, med hvilke nærværende forbindelser danner synergistiske blandinger, som f.eks. penicilliner. Salts can also be prepared with other antibiotics of an acidic or basic nature, and then especially with acidic antibiotics, with which the present compounds form synergistic mixtures, such as e.g. penicillins.
Det er hensiktsmessig å anvende syrer som danner salter med de fremstilte forbindelser, og som har øn- It is appropriate to use acids which form salts with the prepared compounds, and which have
skede egenskaper med hensyn til absorpsjon og bruk i klinisk praksis. Eksempler på slike salter er pamoat eller nafsylat, eller salter som inneholder probenecid, hvorved sistnevnte forbindelse forsinker utskillelsen av de aktive forbindelsene, som resulterer i forlenget virkning. sheath properties with regard to absorption and use in clinical practice. Examples of such salts are pamoate or nafsylate, or salts containing probenecid, whereby the latter compound delays the excretion of the active compounds, resulting in prolonged action.
De fremstilte forbindelser anvendes hensiktsmessig for par-enteral behandling. The prepared compounds are suitably used for parenteral treatment.
Således administreres forbindelsene med fordel ved injeksjon av en vandig, steril losning eller suspensjon av selve zwitterionet eller av et egnet salt derav alene eller i kombinasjon med en buffer. Thus, the compounds are advantageously administered by injection of an aqueous, sterile solution or suspension of the zwitterion itself or of a suitable salt thereof alone or in combination with a buffer.
Forbindelsene med formel I har hittil blitt fremstilt som beskrevet i de britiske patenter nr. 1.293.590 og 1.315.566, nemlig ved å la et reaktivt derivat av et amid eller et tio-amid med den generelle formel II The compounds of formula I have hitherto been prepared as described in British Patent Nos. 1,293,590 and 1,315,566, namely by adding a reactive derivative of an amide or a thio-amide of the general formula II
hvor y R2 og har oven angitte betydning, og where y R2 and have the meaning stated above, and
hvor R^ betyr 0 eller S, where R^ means 0 or S,
f.eks. en forbindelse med den generelle formel (III) e.g. a compound of the general formula (III)
hvor R^, R2 og R^ har oven angitte betydning, og where R^, R2 and R^ have the meaning indicated above, and
hvor Alk betyr et lavere alkylradikal, where Alk means a lower alkyl radical,
reagere med et 6-aminopenicillansyre-derivat med den generelle formel IV react with a 6-aminopenicillanic acid derivative of the general formula IV
hvor R^ betyr en usubstituert elJLer where R 1 means an unsubstituted ore
substituert alkyl- eller aralkylgruppe5 eller med en silylester av 6-aminopenicillansyre. substituted alkyl or aralkyl group 5 or with a silyl ester of 6-aminopenicillanic acid.
Når -COOR^ betyr en estergruppe må reaksjonen følges av en avspaltning av nevnte estergruppe for derved å gi forbindelsene med formel I. When -COOR^ denotes an ester group, the reaction must be followed by a cleavage of said ester group to thereby give the compounds of formula I.
Man har nå funnet at forbindelsene med formel I med fordel It has now been found that the compounds of formula I with advantage
kan fremstilles ved å la et reaktivt derivat av en forbindelse med formel II can be prepared by allowing a reactive derivative of a compound of formula II
reagere med et salt av 6-aminopenicillansyre ("6-APA"), react with a salt of 6-aminopenicillanic acid ("6-APA"),
og fremgangsmåten er særpreget ved det som er angitt i kravets karakteriserende del. and the method is characterized by what is stated in the characterizing part of the claim.
Det er overraskende at nærværende fremgangsmåte resulterer i utmerkede utbytter (ca. 70 til 90%) og produkter med hoy renhet, da det er velkjent at reaktive derivater av amider ofte reagerer med syrer. således kan syreamidhalogenider reagere med syrer under dannelse av syrehalogenider, mens syreamidacetaler kan danne estere under en slik reaksjon. It is surprising that the present process results in excellent yields (about 70 to 90%) and high purity products, as it is well known that reactive derivatives of amides often react with acids. thus, acid amide halides can react with acids to form acid halides, while acid amide acetals can form esters during such a reaction.
Videre er nærværende fremgangsmåte enklere enn tidligere kjente metoder. Den kan gjennomfores i ett trinn, mens tidligere fremgangsmåter omfatter fremstillingen av f.eks. en silylester eller en benzylester av 6-APA, etterfulgt av en overfor-ing i amidinopenicillansyre-esteren og til slutt avspaltning av estergruppen. Furthermore, the present method is simpler than previously known methods. It can be carried out in one step, while previous methods include the production of e.g. a silyl ester or a benzyl ester of 6-APA, followed by conversion into the amidinopenicillanic acid ester and finally cleavage of the ester group.
Reaksjonen utfores i ett trinn ved å opplose eller suspendere reaktantene i et organisk losningsmiddel, fortrinnsvis i fravær av vann på grunn av at de reaktive derivatene av forbindelsene med formel II hydrolyseres i nærvær av vann. The reaction is carried out in one step by dissolving or suspending the reactants in an organic solvent, preferably in the absence of water because the reactive derivatives of the compounds of formula II are hydrolysed in the presence of water.
Reaksjons-betingelsene avhenger av de anvendte reaktantene, og The reaction conditions depend on the reactants used, and
er derfor beskrevet mer i detalj i det følgende. is therefore described in more detail below.
Når man i nærværende fremgangsmåte anvender et syreamidacetal som reaktant, så er det foretrukne reaksjonsmedium metylenklorid, kloroform, aceton med en mindre mengde formamid, metanol og metylformat. I de første tre reaksjonsmedier er det nødvendig med nærvær av et sterkt tertiært amin for å oppnå de ønskede utbytter av forbindelsene med formel I med høy renhet, mensff-eks. i metanol kan reaksjonen utføres uten tilsetning av et separat tertiært amin på grunn av det faktum at det svakt alkaliske syreamidacetalet er i stand til å danne et salt med "6-APA" i dette medium. When an acid amide acetal is used as reactant in the present method, the preferred reaction medium is methylene chloride, chloroform, acetone with a smaller amount of formamide, methanol and methyl formate. In the first three reaction media, the presence of a strong tertiary amine is necessary to obtain the desired yields of the compounds of formula I with high purity, while ff-ex. in methanol the reaction can be carried out without the addition of a separate tertiary amine due to the fact that the weakly alkaline acid amide acetal is able to form a salt with "6-APA" in this medium.
Som eksempler på sterke tertiære aminer, som kan anvendes ifølge ovenstående, kan nevnes trietylamin, og N,N-diisopropyl-etylamin, mens f.eks. pyridin, N-metylmorfolin eller trietanol-amin er for svake for dette formål. As examples of strong tertiary amines, which can be used according to the above, mention can be made of triethylamine and N,N-diisopropylethylamine, while e.g. pyridine, N-methylmorpholine or triethanolamine are too weak for this purpose.
Den ovenstående reaksjon kan utføres ved anvendelse av ekvivalente mengder av reaktantene, men det foretrekkes imidlertid å anvende et mindre overskudd av syreamidacetalet og av det tertiære aminet (i bqgge tilfeller ca. 20 - 30%). Som utgangsmateriale er det naturligvis mulig å anvende et salt av "6-APA" og det tertiære aminet, enten ved å anvende et salt som er tidligere fremstilt, eller ved å la "6-APA" reagere delvis med det tertiære aminet før tilsetning av syreamidacetalet. Reaksjonen utføres ved ca. romtemperatur eller under denne, fortrinnsvis ved en temperatur mellom 0 The above reaction can be carried out using equivalent quantities of the reactants, but it is however preferred to use a smaller excess of the acid amide acetal and of the tertiary amine (in most cases approx. 20 - 30%). As starting material, it is of course possible to use a salt of "6-APA" and the tertiary amine, either by using a salt previously prepared, or by allowing "6-APA" to partially react with the tertiary amine before adding the acid amide acetal. The reaction is carried out at approx. room temperature or below, preferably at a temperature between 0
og 5°C, men reaksjonen kan utføres ved ennå lavere temperaturer, f.eks. ved ca. -25°C. Reaksjonstiden avhenger av temperaturen og det anvendte reaksjonsmediet og om et tertiært amin er anvendt eller ikke. Den vil vare fra 1 - and 5°C, but the reaction can be carried out at even lower temperatures, e.g. at approx. -25°C. The reaction time depends on the temperature and the reaction medium used and whether a tertiary amine is used or not. It will last from 1 -
6 timer. 6 hours.
Når i nærværende metode et di-lavere-alkylsulfatkompleks anvendes som reaktant, så er det foretrukne reaksjonsmedium metylenklorid eller metanol. Her er det nødvendig å anvende i det minste en ekvivalent av et sterkt tertiært amin for å beskytte (3-laktamringen i sluttforbindelsen med formel I og i "6-APA" mot di-laverealkylsulfatkomplekset, som ellers vil fore til en åpning av nevnte (3-laktamring. Det foretrekkes å anvende ca. 1,5 - 3 ekvivalenter av det tertiære aminet, og et overskudd av di-lavere-alkylsulfat-komplekset (ca. 20 - 30%). Ved å anvende metylenklorid som reaksjonsmedium er det hensiktsmessig å la det meste av "6-APA" opplose seg som et tertiært aminsalt for tilsetning av di-laverealkylsulfatkomplekset. Den foretrukne reaksjonstemperatur er 0 - 5°C, men såvel hoyere (ca. romtemperatur) som lavere temperaturer (ca. -10°C) kan anvendes. Reaksjonstiden avhenger av temperaturen, reaksjonsmediet og de anvendte reaktanter, og vil beløpe seg til 1-6 timer. When in the present method a di-lower alkyl sulphate complex is used as reactant, the preferred reaction medium is methylene chloride or methanol. Here it is necessary to use at least one equivalent of a strong tertiary amine to protect the (3-lactam ring in the final compound of formula I and in "6-APA" against the di-lower alkyl sulfate complex, which would otherwise lead to an opening of said ( 3-lactam ring. It is preferred to use about 1.5 - 3 equivalents of the tertiary amine, and an excess of the di-lower alkyl sulfate complex (about 20 - 30%). By using methylene chloride as the reaction medium, it is convenient allowing most of the "6-APA" to dissolve as a tertiary amine salt for addition of the di-lower alkyl sulfate complex. The preferred reaction temperature is 0 - 5°C, but both higher (about room temperature) and lower temperatures (about -10° C) can be used.The reaction time depends on the temperature, the reaction medium and the reactants used, and will amount to 1-6 hours.
Når det i nærværende fremgangsmåte anvendes et syreamid-halogenid som reaktant, kan bare metylenklorid, kloroform og et lignende inert reaksjonsmedium anvendes på grunn av at syreamid-halogenidene er meget reaktive. I dette tilfelle er det hensiktsmessig å anvende 2-3 ekvivalenter av et tertiært amin for å beskytte (3-laktamringen i sluttproduktet og i "6-APA". Det er hensiktsmessig å la det meste av "6-APA" opplose seg som et tertiært aminsalt for tilsetning av syreamid-halogenidet. Reaksjonen bor utfores ved lave temperaturer og med starttemperatur på ca. -50°C. Reaksjonstemperaturen får oke til ca. 0°C, og reaksjonen fullfores i lopet av ca. 3/4 time. When in the present method an acid amide halide is used as reactant, only methylene chloride, chloroform and a similar inert reaction medium can be used because the acid amide halides are very reactive. In this case it is convenient to use 2-3 equivalents of a tertiary amine to protect the (3-lactam ring in the final product and in "6-APA". It is convenient to allow most of the "6-APA" to dissolve as a tertiary amine salt for addition of the acid amide halide. The reaction should be carried out at low temperatures and with an initial temperature of approximately -50° C. The reaction temperature is allowed to increase to approximately 0° C, and the reaction is completed in the course of approximately 3/4 hour.
Den erholdte reaksjonsblandingen, som inneholder det stabile tertiære aminsaltet av en eller flere forbindelser med formel I, eller i visse tilfelle zwitterionet selv, filtreres for fjerning av en eventuell rest av ureagert "6-APA", og den klare losningen blir deretter fordampet i vakuum. Den gjenværende rest opploses i et egnet losningsmiddel, hvori syren med formel I utfelles ved tilsetning av et annet losningsmiddel, hvori syren bare er lite lbselig, eller fortrinnsvis ved å frigjore zwitterionet ved tilsetning av en uorganisk eller organisk syre. Det foretrekkes, og da spesielt ved fremstilling av storre mengder, å fjerne eventuelle gjenværende rester av reaksjonsmediet ved tilsetning av et hoytkokende losningsmiddel, f.eks. metyletylketon og, hvis onsket, sammen med syren som anvendes for frigjoring av zwitterionet, og deretter for-dampning av losningsmiddelblandingen i vakuum. Kombinasjonen av tertiært amin, losningsmiddel og syre kan hensiktsmessig velges slik at zwitterionet utfelles og det The resulting reaction mixture, containing the stable tertiary amine salt of one or more compounds of formula I, or in certain cases the zwitterion itself, is filtered to remove any residual unreacted "6-APA" and the clear solution is then evaporated in vacuo . The remaining residue is dissolved in a suitable solvent, in which the acid of formula I is precipitated by adding another solvent, in which the acid is only slightly soluble, or preferably by releasing the zwitterion by adding an inorganic or organic acid. It is preferred, and especially when producing large quantities, to remove any remaining residues of the reaction medium by adding a high-boiling solvent, e.g. methyl ethyl ketone and, if desired, together with the acid used to release the zwitterion, and then evaporation of the solvent mixture in vacuo. The combination of tertiary amine, solvent and acid can suitably be chosen so that the zwitterion is precipitated and the
under noytralisasjonen dannede aminsaltet holdes opplost i losningsmidlet. the amine salt formed during the neutralization is kept dissolved in the solvent.
For frigivelse av zwitterionet kan man anvende p-toluensulfonsyre opplost i aceton eller metyletylketon, men andre syrer og løsningsmidler kan likeledes anvendes, avhengig av de anvendte reaktantene. To release the zwitterion, p-toluenesulfonic acid dissolved in acetone or methyl ethyl ketone can be used, but other acids and solvents can also be used, depending on the reactants used.
De ved ovennevnte utforelsesformer anvendte utgangsmaterialene er velkjente forbindelser, eller de kan fremstilles ved hjelp av konvensjonelle metoder for fremstilling av analoge forbindelser . The starting materials used in the above-mentioned embodiments are well-known compounds, or they can be produced using conventional methods for producing analogous compounds.
Nærværende fremgangsmåte resulterer i et råprodukt med hoy renhet (97 - 98% bestemt ved jodometrisk titrering). The present method results in a crude product with high purity (97 - 98% determined by iodometric titration).
Av stabilitetsgrunner er det av betydning at sluttproduktet inneholder så lite forurensninger som mulig, da aelv små mengder forurensningsrester nedsetter stabiliteten. For reasons of stability, it is important that the final product contains as few contaminants as possible, as even small amounts of contamination residues reduce stability.
Råproduktet kan således ytterligere renses ved rekrystal-lisasjon fra et egnet losningsmiddel eller en blanding av løs-ningsmidler . I visse tilfeller kan det være hensiktsmessig å overfore råproduktet til dets hydratform, som således re-krystalliseres fra et egnet losningsmiddel eller en blanding av løsningsmidler, f.eks. formamid - aceton, for dannelse av den onskede vannfrie forbindelse med formel I. The raw product can thus be further purified by recrystallization from a suitable solvent or a mixture of solvents. In certain cases, it may be appropriate to transfer the crude product to its hydrate form, which is thus re-crystallized from a suitable solvent or a mixture of solvents, e.g. formamide - acetone, to form the desired anhydrous compound of formula I.
Forbindelsene med formel I kan isoleres som sådanne eller i form av et salt, f.eks. alkalimetallsaltene og ammonium- eller amin-saltene, eller som salter med farmasoytisk aksepterbare sterke syrer, såsom saltsyre, fosforsyre, salpetersyre, p-toluensulfonsyre, vinsyre og maleinsyre. The compounds of formula I can be isolated as such or in the form of a salt, e.g. the alkali metal salts and the ammonium or amine salts, or as salts with pharmaceutically acceptable strong acids, such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, tartaric acid and maleic acid.
De fremstilte forbindelser forekommer i flere isomere former The compounds produced occur in several isomeric forms
avhengig av de forskjellige substituenter, depending on the different substituents,
mens 6-aminopenicillansyre-res;ten har den samme konfigurasjonen som den som fås ved fermenteringsprosessen. while the 6-aminopenicillanic acid residue has the same configuration as that obtained by the fermentation process.
Forbindelsene med formel I innehar verdifull antibakteriell aktivitet, og toksisiteten er ekstremt lav som beskrevet i de britiske patenter nr. 1.293.590 og 1.315.566. The compounds of formula I possess valuable antibacterial activity and toxicity is extremely low as described in British Patent Nos. 1,293,590 and 1,315,566.
Oppfinnelsen skal ytterligere illustreres ved hjelp av folgende eksempler. The invention shall be further illustrated by means of the following examples.
EKSEMPEL 1 EXAMPLE 1
6- f ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (2,48 g), trietylamin (1,62 ml), og 1-heksametyleniminkarboksaldehyd-dimetylacetal (2,98 g) ble omrort i metylenklorid (40 ml) ved 0 - 5°C i 2,5 timer. Etter filtrering ble filtratet fordampet i vakuum og resten ble opptatt i aceton (50 ml). Losningen ble noytralisert ved tilsetning av p-toluensulfonsyre-monohydrat (1,9 g) i aceton (25 ml) under omroring og tilsetning av krystallkimer for krystallisasjon ved romtemperatur. Blandingen ble holdt ved 0 - 5° i 1,5 timer og ble så filtrert. Utbytte (U): 82%, Renhet (R): 97%. 6- f (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml), and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (2.98 g) were stirred in methylene chloride (40 ml) at 0 - 5°C for 2.5 hours. After filtration, the filtrate was evaporated in vacuo and the residue was taken up in acetone (50 ml). The solution was neutralized by adding p-toluenesulfonic acid monohydrate (1.9 g) in acetone (25 ml) with stirring and adding crystal seed for crystallization at room temperature. The mixture was kept at 0-5° for 1.5 hours and then filtered. Yield (U): 82%, Purity (R): 97%.
EKSEMPEL 2 EXAMPLE 2
6- f( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre En suspensjon av 6-aminopenicillansyre (2,48 g) i 40 ml kloroform ble omrort i 4,5 timer ved 0 - 5°C med trietylamin (1,62 ml) og 1-heksametylenimin-karboksaldehyd-dimetylacetal (2,25 g). Den resulterende, svakt uklare losningen ble filtrert med "Dicalite". Filtratet ble inndampet i vakuum for å gi en olje som ble opptatt i aceton (50 ml). Den rene forbindelsen ble utfelt ved tilsetning av en losning av p-toluensulfonsyre-monohydrat (1,9 g) i aceton (25 ml) under omroring ved romtemperatur i 1/2 time, etterfulgt av en time ved 0 - 5°C. Den krystallinske forbindelsen ble filtrert fra, vasket med aceton og torket i en ekssikator. 6-f(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid A suspension of 6-aminopenicillanic acid (2.48 g) in 40 ml of chloroform was stirred for 4.5 hours at 0 - 5°C with triethylamine (1.62 ml) and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (2.25 g). The resulting slightly cloudy solution was filtered with "Dicalite". The filtrate was evaporated in vacuo to give an oil which was taken up in acetone (50 mL). The pure compound was precipitated by adding a solution of p-toluenesulfonic acid monohydrate (1.9g) in acetone (25ml) with stirring at room temperature for 1/2 hour, followed by one hour at 0-5°C. The crystalline compound was filtered off, washed with acetone and dried in a desiccator.
U: 82%, R: 98,5% U: 82%, R: 98.5%
EKSEMPEL 3 EXAMPLE 3
6-|" ( heksahydro- lH- azepin- l- yl)- metylenaminoj- penicillansyre 6-aminopenicillansyre (2,48 g) ble suspendert i en blanding av formamid (0,5 ml) og aceton (25 ml, Merck p.a.). 1,62 6-|" (hexahydro-1H-azepin-1-yl)-methyleneaminoj-penicillanic acid 6-aminopenicillanic acid (2.48 g) was suspended in a mixture of formamide (0.5 ml) and acetone (25 ml, Merck p.a.) .1.62
ml trietylamin og 2,3 7 ml 1-heksametyleniminkarboksaldehyd-dimetylacetal ble tilsatt. Blandingen ble omrort i 5 timer ved 0°C og ble så filtrert med "Dicalite". Ved O - 5°C ble en opplosning av p-toluensulfonsyre-monohydrat (1,9 g) i 25 ml aceton tilsatt under omroring og tilsetning av krystallkimer for krystallisasjon. Bunnfallet som ble dannet ble filtrert fra og vasket med aceton. U: 67%, R: 98% ml of triethylamine and 2.37 ml of 1-hexamethyleneiminecarboxaldehyde-dimethylacetal were added. The mixture was stirred for 5 hours at 0°C and then filtered with "Dicalite". At 0 - 5°C a solution of p-toluenesulfonic acid monohydrate (1.9 g) in 25 ml of acetone was added with stirring and addition of crystal seed for crystallization. The precipitate that formed was filtered off and washed with acetone. U: 67%, R: 98%
EKSEMPEL 4 EXAMPLE 4
6- f( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (2,48 g), 1,95 ml N,N-diisopropyletyl-amin og 2,3 7 ml 1-heksametyleniminkarboksaldehyd-dimetylacetal ble omrort i 3,5 timer ved 0 - 5°C i 40 ml metylenklorid. Etter filtrering med "Dicalite" og inndampning av filtratet ble den oljeaktige resten opplost i tert.-butanol (50 ml). Under omroring ble 8-n, 1,44 ml hydrogenklorid i isopropanol tilsatt ved romtemperatur, etterfulgt av en ytterligere mengde 20 ml tert.-butanol. Bunnfallet ble filtrert fra, vasket med tert.-butanol og eter og torket. U:69%,R:97% 6-f(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), 1.95 ml of N,N-diisopropylethylamine and 2.37 ml of 1-hexamethyleneiminecarboxaldehyde- dimethyl acetal was stirred for 3.5 hours at 0-5°C in 40 ml of methylene chloride. After filtration with "Dicalite" and evaporation of the filtrate, the oily residue was dissolved in tert-butanol (50 ml). With stirring, 8-n, 1.44 ml of hydrogen chloride in isopropanol was added at room temperature, followed by an additional amount of 20 ml of tert-butanol. The precipitate was filtered off, washed with tert-butanol and ether and dried. U:69%,R:97%
EKSEMPEL 5 EXAMPLE 5
6-[" ( heksahydro- lH- azepin- l- yl) - metylenamino] - penicillansyre 6-aminopenicillansyre (2,48 g), trietylamin (1,62 ml) og 1-heksametyleniminkarboksaldehyd-dimetylacetal (2,37 ml) 6-[" (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde-dimethyl acetal (2.37 ml)
ble omrort i 3 timer ved 0 - 5°c i metylenklorid (40 ml). Etter filtrering med "Dicalite" ble filtratet inndampet i vakuum. Resten i aceton (50 ml) ble tilsatt iseddik(0,66 ml) under omrøring. Bunnfallet som ble dannet ble suget fra og torket. U: 57%, R: 98% was stirred for 3 hours at 0-5°C in methylene chloride (40 ml). After filtration with "Dicalite", the filtrate was evaporated in vacuo. To the residue in acetone (50 ml) was added glacial acetic acid (0.66 ml) with stirring. The precipitate that formed was sucked off and dried. U: 57%, R: 98%
EKSEMPEL.' 6 EXAMPLE.' 6
6- 1 ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre Ved å folge fremgangsmåten i eksempel 5, men ved å erstatte eddiksyre med benzosyre (1,4 g) ble et godt utbytte av den onskede forbindelsen erholdt. U: 70%, R: 97% 6-1 (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid By following the procedure in example 5, but by replacing acetic acid with benzoic acid (1.4 g), a good yield of the desired compound was obtained. U: 70%, R: 97%
EKSEMPEL 7 EXAMPLE 7
6- I ( heksahydro- lH- azepin- l- yl)- metylenamino|- penicillansyre 6-aminopenicillansyre (2,48 g), trietylamin (1,62 ml) og 1-heksametyleniminkarboksaldehyd-dimetylacetal (2,37 ml) 6- I (hexahydro-1H-azepin-1-yl)-methyleneamino|-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde-dimethyl acetal (2.37 ml)
ble omrort i metylenklorid (40 ml) ved 0 - 5°C i 3,5 timer. Etter filtrering med "Dicalite" ble filtratet inndampet i vakuum. Resten i aceton (15 ml) ble tilsatt eter (60 ml) under omroring ved romtemperatur. Blandingen ble holdt ved 0 - 5°C i 1,5 timer og ble så filtrert for å gi den krystallinske forbindelsen. U: 70%, R: 97,5%was stirred in methylene chloride (40 mL) at 0-5°C for 3.5 hours. After filtration with "Dicalite", the filtrate was evaporated in vacuo. To the residue in acetone (15 mL) was added ether (60 mL) with stirring at room temperature. The mixture was kept at 0-5°C for 1.5 hours and then filtered to give the crystalline compound. U: 70%, R: 97.5%
EKSEMPEL 8 EXAMPLE 8
6-|~ ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (10,0 g), trietylamin (7,0 ml) og 1-heksametyleniminkarboksaldehyd-dimetyl-acetal (10,9 ml) 6-|~ (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (10.0 g), triethylamine (7.0 ml) and 1-hexamethyleneiminecarboxaldehyde-dimethyl-acetal (10.9 ml )
ble omrort i metanol (50 ml) ved 0-5°C i 1,5 timer. Etter filtrering ble filtratet inndampet i vakuum og resten ble opptatt i metyletylketon (45 ml) inneholdende p-toluensulfon-syremonohydrat (8,0 g). Losningsmidlet ble fjernet i vakuum og metyletylketon (50 ml) ble tilsatt til resten. Det tilsynelatende pH ble justert til 7,2 ved tilsetning av trietylamin. Etter omroring i en time ved 0 - 5°C ble krystallene filtrert fra og vasket med metyletylketon. U: 83%, R: 97% was stirred in methanol (50 mL) at 0-5°C for 1.5 hours. After filtration, the filtrate was evaporated in vacuo and the residue was taken up in methyl ethyl ketone (45 ml) containing p-toluenesulfonic acid monohydrate (8.0 g). The solvent was removed in vacuo and methyl ethyl ketone (50 mL) was added to the residue. The apparent pH was adjusted to 7.2 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 83%, R: 97%
EKSEMPEL 9 EXAMPLE 9
6-[~ ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (10,0 g) og 1-heksametyleniminkarboksaldehyd-dimetylacetal (10,9 ml) ble omrort i metanol (50 6-[~ (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (10.0 g) and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (10.9 ml) were stirred in methanol (50
ml) ved 20 - 25°C i 5 timer. Etter filtrering ble filtratet inndampet i vakuum og resten ble suspendert i metyletylketon (45 ml). Losningsmidlet ble fjernet i vakuum og metyletylketon (50 ml) ble tilsatt til resten. Det tilsynelatende pH ble justert til 7,5 ved tilsetning av p-toluensulfonsyre-monohydrat. Etter omroring i en time ved 0 - 5°C ble . krystallene filtrert fra og vasket med metyletylketon. ml) at 20 - 25°C for 5 hours. After filtration, the filtrate was evaporated in vacuo and the residue was suspended in methyl ethyl ketone (45 mL). The solvent was removed in vacuo and methyl ethyl ketone (50 mL) was added to the residue. The apparent pH was adjusted to 7.5 by addition of p-toluenesulfonic acid monohydrate. After stirring for one hour at 0 - 5°C, . the crystals filtered off and washed with methyl ethyl ketone.
U: 78%, R: 99,5% U: 78%, R: 99.5%
EKSEMPEL 10 EXAMPLE 10
6- 1" ( heksahydro- lH- azepin- l- yl) - metylenamino] - pencillansyre 6-aminopenicillansyre (21,6 g), trietylamin (23,6 ml) og N-formylheksametylenimin-dimetylsulfatkompleks (32,9 g) ble omrort i metanol (85 ml) ved 0 - 5°C i 2 timer. Etter filtrering ble filtratet inndampet i vakuum og resten ble opptatt i metyletylketon (110 ml), inneholdende p-toluensulfonsyre-monohydrat (14,3 g). Losningsmidlet ble fjernet i vakuum og metyletylketon (HO ml) ble tilsatt til resten. Det tilsynelatende pH ble justert til 7,3 ved tilsetning av trietylamin. Etter omroring i en time ved 0 - 5°c ble krystallene filtrert fra og vasket med metyletylketon. U: 74%, R: 98%6- 1" (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (21.6 g), triethylamine (23.6 ml) and N-formylhexamethyleneimine-dimethylsulphate complex (32.9 g) were stirred in methanol (85 ml) at 0-5°C for 2 hours. After filtration, the filtrate was evaporated in vacuo and the residue taken up in methyl ethyl ketone (110 ml), containing p-toluenesulfonic acid monohydrate (14.3 g). The solvent was removed in vacuo and methyl ethyl ketone (10 mL) was added to the residue. The apparent pH was adjusted to 7.3 by addition of triethylamine. After stirring for one hour at 0-5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 74%, R: 98%
EKSEMPEL 11 EXAMPLE 11
6- f ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (21,6 g) og trietylamin (17,8 ml) ble omrort i metylenklorid (85 ml) ved 0 - 5° i 2 timer. Etter tilsetning av 1-heksametyleniminkarboksaldehyd-dimetylacetal (22,4 g), ble omroringen fortsatt ved 0 - 5°c i 2 timer. Reaksjonsblandingen ble deretter filtrert og filtratet inndampet i vakuum. Resten ble opptatt i metyletylketon (110 ml), inneholdende p-toluensulfonsyre-monohydrat (19,0 g). Losningsmidlet ble fjernet i vakuum og metyletylketon (110 ml) ble tilsatt til resten. Det tilsynelatende pH ble justert til 7,3 ved tilsetning av trietylamin. Etter omroring i en time ved 0 - 5°C ble krystallene filtrert fra og vasket med metyletylketon. U: 84%, R: 99% 6-f (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (21.6 g) and triethylamine (17.8 ml) were stirred in methylene chloride (85 ml) at 0 - 5° in 2 hours. After addition of 1-hexamethyleneimine carboxaldehyde dimethyl acetal (22.4 g), stirring was continued at 0-5°C for 2 hours. The reaction mixture was then filtered and the filtrate evaporated in vacuo. The residue was taken up in methyl ethyl ketone (110 ml), containing p-toluenesulfonic acid monohydrate (19.0 g). The solvent was removed in vacuo and methyl ethyl ketone (110 mL) was added to the residue. The apparent pH was adjusted to 7.3 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 84%, R: 99%
EKSEMPEL 12 EXAMPLE 12
6- f( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (21,6 g) og trietylamin (31,4 ml) ble omrort i metylenklorid (85 ml) ved O - 5°C i 2 timer. Etter tilsetning av N-formylheksametylenimin-dimetylsulfatkompleks (32,9 g), ble omroringen fortsatt ved 0 - 5°C i 2 timer. Deretter ble reaksjonsblandingen filtrert fra og filtratet ble inndampet i vakuum. Resten ble opptatt i metyletylketon (110 ml), inneholdende p-toluensulfonsyre-monohydrat (19,0 g). Losningsmidlet ble fjernet i vakuum og metyletylketon (110 ml) ble tilsatt til resten. Det tilsynelatende pH ble justert til 7,2 ved tilsetning av trietylamin. Etter omroring i en time ved 0 - 5°C ble krystallene filtrert fra og vasket med metyletylketon. U: 68%, R: 97,5%6-f(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (21.6 g) and triethylamine (31.4 ml) were stirred in methylene chloride (85 ml) at 0 - 5°C for 2 hours. After addition of N-formylhexamethyleneimine-dimethylsulphate complex (32.9 g), stirring was continued at 0-5°C for 2 hours. The reaction mixture was then filtered off and the filtrate was evaporated in vacuo. The residue was taken up in methyl ethyl ketone (110 ml), containing p-toluenesulfonic acid monohydrate (19.0 g). The solvent was removed in vacuo and methyl ethyl ketone (110 mL) was added to the residue. The apparent pH was adjusted to 7.2 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 68%, R: 97.5%
EKSEMPEL 13 EXAMPLE 13
6-| ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (2,2 g), pyridin (0,81 ml), og 1-heksametyleniminkarboksaldehyd-dimetylacetal (5,5 ml) ble omrort i metanol (30 ml) ved 0 - 5°C i 1,5 timer. Den resulterende, svakt uklare losningen ble filtrert med filter-hjelp. Filtratet ble inndampet i vakuum. Resten ble opplost i aceton (50 ml). Losningen ble noytralisert ved tilsetning av p-toluensulfonsyre-monohydrat (1,9 g) under omroring og 6-| (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.2 g), pyridine (0.81 ml), and 1-hexamethyleneimine carboxaldehyde dimethylacetal (5.5 ml) were stirred in methanol (30 ml) at 0 - 5°C for 1.5 hours. The resulting slightly cloudy solution was filtered with filter aid. The filtrate was evaporated in vacuo. The residue was dissolved in acetone (50 mL). The solution was neutralized by adding p-toluenesulfonic acid monohydrate (1.9 g) with stirring and
tilsetning av krystallkimer for krystallisasjon ved 0 - 5°. Krystallene som ble dannet ble filtrert fra og vasket med addition of crystal seeds for crystallization at 0 - 5°. The crystals that formed were filtered off and washed with
aceton (10 ml) og eter (20 ml). U: 65%, R: 97% acetone (10 mL) and ether (20 mL). U: 65%, R: 97%
EKSEMPEL 14 EXAMPLE 14
6-[ ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre 6-aminopenicillansyre (2,2 g) og trietylamin (4,2 ml) ble omrort i torr kloroform (25 ml) i en time ved romtemperatur. Losningen som ble dannet ble avkjolt til -45°C. 1,82 g av syreamid-kloridet, som ble fremstilt ved reaksjon mellom N-formylheksametylenimin og oksalylklorid, i torr kloroform 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.2 g) and triethylamine (4.2 ml) were stirred in dry chloroform (25 ml) for one hour at room temperature . The resulting solution was cooled to -45°C. 1.82 g of the acid amide chloride, which was prepared by reaction between N-formylhexamethyleneimine and oxalyl chloride, in dry chloroform
(15 ml) ble langsomt tilsatt, hvorved temperaturen steg til -25°c. I lopet av 3/4 timer fikk temperaturen stige til 0°c. Losningen ble inndampet i vakuum. Resten ble omrort med aceton (25 ml) og filtrert. Filtratet ble inndampet i vakuum og resten ble opptatt i metyletylketon. Ved tilset- (15 ml) was slowly added, whereby the temperature rose to -25°c. In the course of 3/4 hours the temperature was allowed to rise to 0°c. The solution was evaporated in vacuo. The residue was stirred with acetone (25 mL) and filtered. The filtrate was evaporated in vacuo and the residue was taken up in methyl ethyl ketone. In case of addi-
ning av p-toluensulfonsyre (1,7 g) ble zwitterionet utfelt. ning of p-toluenesulfonic acid (1.7 g) the zwitterion was precipitated.
U: 62%, R: 97% U: 62%, R: 97%
EKSEMPEL 15 EXAMPLE 15
6-[ ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre-trihydrat 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate
27 g av et produkt som er fremstilt ifolge eksemplene 1-14 27 g of a product prepared according to examples 1-14
ble suspendert i aceton (50 ml) og opplost ved tilsetning av vann (32 ml). Ved tilsetning av aceton (200 ml) ble det rene trihydratet utfelt. Det ble filtrert fra, vasket med aceton og luft-torket. was suspended in acetone (50 mL) and dissolved by the addition of water (32 mL). On addition of acetone (200 ml) the pure trihydrate was precipitated. It was filtered off, washed with acetone and air-dried.
EKSEMPEL 16 EXAMPLE 16
6- f ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre-p- toluensulfonat 6- f (hexahydro- 1H- azepin- 1- yl)- methyleneamino]- penicillanic acid p- toluenesulfonate
En opplosning av p-toluensulfonsyre-monohydrat (9,5 g) i isopropanol (50 ml) ble tilsatt under omroring ved romtemperatur til en suspensjon av 6-[(heksahydro-lH-azepin-l-yl)metylenamino|-penicillansyretrihydrat (19 g) i isopropanol (100 ml). Den resulterende losningen ble filtrert og saltet ble utfelt ved tilsetning av isopropyleter (100 ml) fulgt av tilsetning av krystallkimer for krystallisasjon, og en ytterligere tilsetning av isopropyleter (50 ml). Krystallene ble suget fra og vasket med isopropyleter. U: 78%,R:100% [a]^°:+182° (C=l, 1. ON HC1) A solution of p-toluenesulfonic acid monohydrate (9.5 g) in isopropanol (50 mL) was added with stirring at room temperature to a suspension of 6-[(hexahydro-1H-azepin-1-yl)methyleneamino|-penicillanic acid trihydrate (19 g) in isopropanol (100 ml). The resulting solution was filtered and the salt was precipitated by the addition of isopropyl ether (100 mL) followed by the addition of crystal seed for crystallization, and a further addition of isopropyl ether (50 mL). The crystals were sucked off and washed with isopropyl ether. U: 78%,R:100% [a]^°:+182° (C=l, 1. ON HC1)
EKSEMPEL 17 EXAMPLE 17
6-[ ( hek. sahydro- lH- azepin- 1- yl) - metylenamino] - penicillansyre-benzensulfonat 6-[(hec. sahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid benzenesulfonate
6-[(heksahydro-lH-azepin-l-yl)-metylenamino]-penicillansyre-trihydrat (19 g) i aceton (125 ml) ble opplost ved langsom tilsetning av benzensulfonsyre (8 g) i aceton (125 ml) med omroring ved 0 - 5°C, hvorpå benzensulfonatet ble utfelt spontant. Det ble suget fra, vasket med aceton (25 ml) og eter (25 ml) og omkrystallisert fra metanol-eter (110 - 200 ml). 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (19 g) in acetone (125 mL) was dissolved by slow addition of benzenesulfonic acid (8 g) in acetone (125 mL) with stirring at 0 - 5°C, whereupon the benzene sulphonate precipitated spontaneously. It was suctioned off, washed with acetone (25 ml) and ether (25 ml) and recrystallized from methanol-ether (110 - 200 ml).
U: 80%, R: 100% [a]^°:+192°(C=l, 0.IN HCl) U: 80%, R: 100% [a]^°:+192°(C=1, 0.IN HCl)
EKSEMPEL 18 EXAMPLE 18
6-[( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre-maleat- monohydrat 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]- penicillanic acid maleate monohydrate
Til en omrort suspensjon av 6-[ (heksahydro-lH-azepin-l-yl)-metylenamino]-penicillansyre-trihydrat (19 g) i aceton (125 ml) ble en opplosning av maleinsyre (6 g) i aceton (125 ml) To a stirred suspension of 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (19 g) in acetone (125 ml) was added a solution of maleic acid (6 g) in acetone (125 ml )
tilsatt ved romtemperatur. Losningen som ble dannet ble filtrert og saltet ble utfelt ved tilsetning av cyklo- added at room temperature. The solution formed was filtered and the salt was precipitated by addition of cyclo-
heksan (100 ml). Loseligheten av maleatet i vann (5%) er lavere enn den til p-toluensulfonat og benzensulfonat. hexane (100 mL). The solubility of the maleate in water (5%) is lower than that of p-toluenesulfonate and benzenesulfonate.
87%, R: 100% [a]^°+200° (C=l, 0. IN HCl) 87%, R: 100% [a]^°+200° (C=1, 0. IN HCl)
EKSEMPEL 19 EXAMPLE 19
6-[( heksahydro- lH- azepin- l- yl)- metylenamino]- penicillansyre-2- naftalensulfonat 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid-2-naphthalenesulfonate
En filtrert losning av 6-f (heksahydro-lH-azepin-l-yl)-metylenamino]-penicillansyre-trihydrat (3,8 g) og 2-naftalen-sulfonsyre-trihydrat (2,6 g) i aceton (50 ml) ble inndampet i vakuum. Resten ble triturert med eter (75 ml) og krystallisert ved triturering med etylacetat (25 ml). Saltet er svakt loselig i vann. U:60%,R:100% [a]^°:169 (C=l, 0.IN HCl) A filtered solution of 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (3.8 g) and 2-naphthalene-sulfonic acid trihydrate (2.6 g) in acetone (50 ml ) was evaporated in vacuo. The residue was triturated with ether (75 ml) and crystallized by trituration with ethyl acetate (25 ml). The salt is slightly soluble in water. U:60%,R:100% [a]^°:169 (C=1, 0.IN HCl)
EKSEMPEL 20 EXAMPLE 20
Natrium- 6[ ( heksahydro- lH- azepin- l- yl)- metylenamino]- penicil-lanat Sodium 6[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
6-[(heksahydro-lH-azepin-l-yl)-metylenamino|-penicillansyre-trihydrat (11,4 g) i isopropyleter (50 ml) ble opplost ved tilsetning av en losning av natrium-2-etylheksanoat (5,1 g) 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino|-penicillanic acid trihydrate (11.4 g) in isopropyl ether (50 ml) was dissolved by adding a solution of sodium 2-ethyl hexanoate (5.1 d)
i aceton (45 ml) ved omroring ved romtemperatur, hvorpå saltet ble utfelt spontant. Isopropyleter (75 ml) ble tilsatt og bunn- in acetone (45 ml) with stirring at room temperature, whereupon the salt precipitated spontaneously. Isopropyl ether (75 mL) was added and bottom
fallet ble filtrert fra. Saltet ble omkrystallisert fra 95%'ig n-propanol-eter. U: 81%, R: 98% the case was filtered out. The salt was recrystallized from 95% n-propanol ether. U: 81%, R: 98%
EKSEMPEL 21 EXAMPLE 21
6-( N, N- dimetylformamidino- N')- penicillansyre 6-(N,N-dimethylformamidino-N')-penicillanic acid
En suspensjon av 6-aminopenicillansyre (2,48 g) i 40 ml metylenklorid ble omrort i 2 timer ved 0 - 5°C med trietylamin (1,62 ml) og 1,1-dimetoksytrimetylamin (1,55 g) . Den resulterende svakt uklare losningen ble filtrert med "Dicalite" og filtratet ble inndampet i vakuum. Den oljeaktige resten ble opplost i aceton (50 ml) og p-toluensulfonsyre-monohydrat A suspension of 6-aminopenicillanic acid (2.48 g) in 40 ml of methylene chloride was stirred for 2 hours at 0-5°C with triethylamine (1.62 ml) and 1,1-dimethoxytrimethylamine (1.55 g). The resulting slightly cloudy solution was filtered with "Dicalite" and the filtrate was evaporated in vacuo. The oily residue was dissolved in acetone (50 mL) and p-toluenesulfonic acid monohydrate
(2,14 g) ble tilsatt under omroring ved 0 - 5°c. Bunnfallet ble filtrert fra, vasket med aceton og omkrystallisert fra aceton-vann-aceton (10-8-30 ml). Det analytisk rene produktet som således ble erholdt hadde et smeltepunkt på 173 - 174°C. (2.14 g) was added with stirring at 0 - 5°c. The precipitate was filtered off, washed with acetone and recrystallized from acetone-water-acetone (10-8-30 ml). The analytically pure product thus obtained had a melting point of 173 - 174°C.
(spaltning). [a]^°: + 318° (c = 1, H20). U: 90% (fission). [α]^°: + 318° (c = 1, H 2 O). U: 90%
EKSEMPEL 2 2 EXAMPLE 2 2
6- ( N ,, N- dipropylf ormamidino- N1 )- penicillansyre En suspensjon av 6-aminopenicillansyre (5,0 g) i 80 ml metylenklorid ble omrort i 3,75 timer ved 0 - 5°C med trietylamin (3,24 ml) og N- (dimetoksymetyl) -diprppylarnin (5,25 g) . Etter inndampning i vakuum av filtratet ble den oljeaktige resten opplost i aceton (50 ml). Tilsetning av p-toluensulfonsyre-monohydrat (3,8 g) bevirket utfelling av et fast stoff som ble krystallisert fra 96% etanol-etylacetat (50 - 125 ml) 6-(N,,N-dipropylformamidino-N1)-penicillanic acid A suspension of 6-aminopenicillanic acid (5.0 g) in 80 ml of methylene chloride was stirred for 3.75 hours at 0-5°C with triethylamine (3.24 ml) and N-(dimethoxymethyl)-dipyrpyralnine (5.25 g). After evaporation in vacuo of the filtrate, the oily residue was dissolved in acetone (50 ml). Addition of p-toluenesulfonic acid monohydrate (3.8 g) precipitated a solid which was crystallized from 96% ethanol-ethyl acetate (50 - 125 ml).
for å gi den analytisk rene forbindelsen med et smeltepunkt på 154 - 156°C (spaltning). [oc]£°: + 305° (c=l, H20) . U: 64% to give the analytically pure compound with a melting point of 154 - 156°C (decomposition). [oc]£°: + 305° (c=1, H 2 O) . U: 64%
EKSEMPEL 2 3 EXAMPLE 2 3
6-( N- benzyl- N- metylformamidino- N')- penicillansyre 6-aminopenicillansyre (4,96 g), trietylamin (3,24 ml), og N- (dimetoksymetyl)-N-metylbenzylamin (5,84 g) ble omrort i 6-(N-benzyl-N-methylformamidino-N')-penicillanic acid 6-aminopenicillanic acid (4.96 g), triethylamine (3.24 ml), and N-(dimethoxymethyl)-N-methylbenzylamine (5.84 g) was reshuffled in
2 timer i metylenklorid (80 ml) ved 0 - 5°C. Etter filtrering med filter-hjelp ble filtratet inndampet i vakuum. Den oljeaktige resten ble opptatt i aceton (75 ml) og zwitterionet ble utfelt ved tilsetning av p-toluensulfonsyre-monohydrat 2 hours in methylene chloride (80 ml) at 0 - 5°C. After filtration with a filter aid, the filtrate was evaporated in vacuo. The oily residue was taken up in acetone (75 mL) and the zwitterion was precipitated by addition of p-toluenesulfonic acid monohydrate
(3,8 g) . (3.8g) .
2,8 g av det rå produktet ble opplost i varm 60%'ig etanol (30 ml). Tilsetning av aceton (60 ml) ga den analytisk rene forbindelsen med et smeltepunkt på 165 - 167°c (spaltning). 2.8 g of the crude product was dissolved in hot 60% ethanol (30 ml). Addition of acetone (60 ml) gave the analytically pure compound with a melting point of 165 - 167°C (decomposition).
[aj^°: +280° (c = 1, 0,1-n HCl). U: 83% [αj^°: +280° (c = 1, 0.1-n HCl). U: 83%
EKSEMPEL 24 EXAMPLE 24
6-( N- pyrrolidinoformamidino- N')- penicillansyre En blanding av 6-aminopenicillansyre (4,96 g), trietylamin (3,24 ml), og 1-dimetoksymetyl-pyrrolidin (3,78 g ) i metylenklorid (80 ml) ble omrort i 4,75 timer ved - 5°C. Etter filtrering ble filtratet inndampet i vakuum for å gi 6-(N-pyrrolidinoformamidino-N')-penicillanic acid A mixture of 6-aminopenicillanic acid (4.96 g), triethylamine (3.24 ml), and 1-dimethoxymethylpyrrolidine (3.78 g) in methylene chloride (80 ml ) was stirred for 4.75 hours at - 5°C. After filtration, the filtrate was evaporated in vacuo to give
en olje som ble opplost i aceton (100 ml). Ved tilsetning av p-toluensulfonsyre (3,8 g) ved romtemperatur ble tittel-forbindelsen utfelt. Etter en halv time ved 0 - 5°c ble bunnfallet filtrert fra og omkrystallisert fra vann-aceton an oil which was dissolved in acetone (100 ml). On addition of p-toluenesulfonic acid (3.8 g) at room temperature, the title compound was precipitated. After half an hour at 0 - 5°c, the precipitate was filtered off and recrystallized from water-acetone
og 90%'ig isopropanol-aceton for å gi den analytisk rene forbindelsen med et smeltepunkt på 172,5 - 173,5°C (spaltning). and 90% isopropanol-acetone to give the analytically pure compound with a melting point of 172.5 - 173.5°C (decomposition).
[cc]£°: + 306° (c = 1, H20). U: 76% [cc]£°: + 306° (c = 1, H 2 O). U: 76%
EKSEMPEL 25 EXAMPLE 25
6-[ ( heksahydro- 1 ( 2H)- azocinyl)]- metylenamino- penicillansyre 6-aminopenicillansyre (7,44 g), trietylamin (4,86 ml) og 1-heptametyleniminkarboksaldehyd-dimetylacetal (9,7 g) ble omrort i metylenklorid (120 ml) i 2,5'timer ved 0 - 5°c. 6-[(hexahydro-1(2H)- azocinyl)]-methyleneaminopenicillanic acid 6-aminopenicillanic acid (7.44 g), triethylamine (4.86 ml) and 1-heptamethyleneimine carboxaldehyde dimethyl acetal (9.7 g) were stirred in methylene chloride (120 ml) for 2.5 hours at 0 - 5°C.
Etter filtrering ble filtratet inndampet i vakuum og resten ble opptatt i aceton (150 ml). Losningen ble nøytralisert ved tilsetning av p-toluensulfonsyre-monohydrat (5,2 g) After filtration, the filtrate was evaporated in vacuo and the residue was taken up in acetone (150 ml). The solution was neutralized by the addition of p-toluenesulfonic acid monohydrate (5.2 g)
i aceton (75 ml) med omroring ved 0 - 5°C i 1,5 timer. Bunnfallet ble filtrert fra, vasket med aceton og omkrystallisert fra vann-aceton for å gi den analytisk rene forbindelsen med et smeltepunkt på 169 - 170°C (spaltning). in acetone (75 ml) with stirring at 0 - 5°C for 1.5 hours. The precipitate was filtered off, washed with acetone and recrystallized from water-acetone to give the analytically pure compound with a melting point of 169-170°C (decomposition).
[a]p°: + 309° (c=l, H20). U:73% [α]p°: + 309° (c=1, H 2 O). U:73%
EKSEMPEL 26 EXAMPLE 26
6-( N- morfolinoformamidino- N')- penicillansyre 6-(N-morpholinoformamidino-N')-penicillanic acid
6-aminopenicillansyre (2,48 g), trietylamin (1,62 ml) og 4-morfolinkarboksaldehyd-dimetylacetal (2,10 g) ble omrort i 4 timer i metylenklorid (40 ml) ved 0 - 5°C Etter inndampning i vakuum av filtratet ble resten opptatt i aceton (75 ml). 6-Aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 4-morpholinecarboxaldehyde-dimethyl acetal (2.10 g) were stirred for 4 hours in methylene chloride (40 ml) at 0 - 5°C. After evaporation in vacuo of the filtrate, the residue was taken up in acetone (75 ml).
Tilsetning av p-toluensulfonsyre-monohydrat (2,14 g) forårsaket utfelling av et fast stoff som ble krystallisert fra aceton-vann-aceton (5- 3.5- 15 ml) for å gi den analytisk rene forbindelsen med et smeltepunkt på 172,5 - 174°C. (spaltning). Addition of p-toluenesulfonic acid monohydrate (2.14 g) caused precipitation of a solid which was crystallized from acetone-water-acetone (5-3.5-15 ml) to give the analytically pure compound with a melting point of 172.5 - 174°C. (fission).
[<x]£°: +275° (c = 1, H20). U: 69,5% [<x]£°: +275° (c = 1, H 2 O). U: 69.5%
EKSEMPEL 27 EXAMPLE 27
6-( N, N- dimetylbenzamidino- N')- penicillansyre 6-(N,N-dimethylbenzamidino-N')-penicillanic acid
Ved å folge fremgangsmåten som er beskrevet i eksempel 7 By following the procedure described in example 7
og ved å erstatte 1-heksametyleniminkarboksaldehyd-dimetylacetal med N,N-dimetylbenzamid-dimetylacetal, fremstilles 6-(N,N-dimetylbenzamidino-N')-penicillansyre som et hvitt amorft pulver, loselig i vann. Tynnsjiktskromatografi (Merck silikagel HF2^) ble utfort i de folgende losningsmiddel-systemer: n-butanol-etanol-vann (8:2:2), Rf = 0,10 og n-propanol-vann (7:3), R = 0,24. U: 87% and by replacing 1-hexamethyleneimine carboxaldehyde dimethylacetal with N,N-dimethylbenzamide dimethylacetal, 6-(N,N-dimethylbenzamidino-N')-penicillanic acid is prepared as a white amorphous powder, soluble in water. Thin-layer chromatography (Merck silica gel HF2^) was carried out in the following solvent systems: n-butanol-ethanol-water (8:2:2), Rf = 0.10 and n-propanol-water (7:3), R = 0.24. U: 87%
NMR-spektrum (10% vekt/volum D2°) NMR spectrum (10% w/v D2°)
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB541473A GB1417099A (en) | 1973-02-02 | 1973-02-02 | Method for the production of derivatives of 6-aminopenicillanic acid |
Publications (3)
Publication Number | Publication Date |
---|---|
NO740341L NO740341L (en) | 1974-08-05 |
NO147565B true NO147565B (en) | 1983-01-24 |
NO147565C NO147565C (en) | 1983-05-04 |
Family
ID=9795736
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO740341A NO147565C (en) | 1973-02-02 | 1974-02-01 | PROCEDURE FOR PREPARING DERIVATIVES OF 6-AMINOPENICILLANIC ACID |
Country Status (21)
Country | Link |
---|---|
JP (1) | JPS6037117B2 (en) |
AR (1) | AR202703A1 (en) |
AT (1) | AT329178B (en) |
AU (1) | AU475538B2 (en) |
BG (1) | BG21033A3 (en) |
CA (1) | CA1014549A (en) |
CH (1) | CH593979A5 (en) |
CS (1) | CS182807B2 (en) |
DD (1) | DD109636A5 (en) |
DE (1) | DE2404587C2 (en) |
DK (1) | DK141754B (en) |
ES (1) | ES422873A1 (en) |
FI (1) | FI60017C (en) |
GB (1) | GB1417099A (en) |
HU (1) | HU167788B (en) |
NL (1) | NL7400972A (en) |
NO (1) | NO147565C (en) |
PL (1) | PL88593B1 (en) |
SE (1) | SE412392B (en) |
SU (1) | SU553935A3 (en) |
YU (1) | YU39649B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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SU566843A1 (en) * | 1975-01-06 | 1977-07-30 | Ордена Трудового Красного Знамени Институт Органической Синтеза Ан Латвийской Сср | Method of preparing derivatives of 6- -amidino penicillanic acid |
LU77362A1 (en) * | 1977-05-17 | 1979-01-19 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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BE758782A (en) * | 1969-11-11 | 1971-05-10 | Leo Pharm Prod Ltd | NEW DERIVATIVES OF 6-AMIDINO PENICILLANIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS AS ANTIBIOTICS |
GB1293590A (en) * | 1969-11-11 | 1972-10-18 | Leo Pharm Prod Ltd | New penicillanic acid derivatives |
GB1315566A (en) * | 1970-11-06 | 1973-05-02 | Leo Pharm Prod Ltd | Penicillanic acid derivatives |
-
1973
- 1973-02-02 GB GB541473A patent/GB1417099A/en not_active Expired
-
1974
- 1974-01-16 AT AT33074*#A patent/AT329178B/en not_active IP Right Cessation
- 1974-01-22 AR AR252017A patent/AR202703A1/en active
- 1974-01-24 NL NL7400972A patent/NL7400972A/xx not_active Application Discontinuation
- 1974-01-25 HU HULE732A patent/HU167788B/hu not_active IP Right Cessation
- 1974-01-28 FI FI224/74A patent/FI60017C/en active
- 1974-01-28 CS CS7400000539A patent/CS182807B2/en unknown
- 1974-01-29 DK DK44474AA patent/DK141754B/en not_active IP Right Cessation
- 1974-01-29 YU YU203/74A patent/YU39649B/en unknown
- 1974-01-29 CA CA191,180A patent/CA1014549A/en not_active Expired
- 1974-01-31 DD DD176296A patent/DD109636A5/xx unknown
- 1974-01-31 AU AU65055/74A patent/AU475538B2/en not_active Expired
- 1974-01-31 PL PL1974168467A patent/PL88593B1/pl unknown
- 1974-01-31 DE DE2404587A patent/DE2404587C2/en not_active Expired
- 1974-02-01 CH CH143674A patent/CH593979A5/xx not_active IP Right Cessation
- 1974-02-01 SE SE7401380A patent/SE412392B/en not_active IP Right Cessation
- 1974-02-01 JP JP49012889A patent/JPS6037117B2/en not_active Expired
- 1974-02-01 SU SU1993873A patent/SU553935A3/en active
- 1974-02-01 NO NO740341A patent/NO147565C/en unknown
- 1974-02-01 BG BG25676A patent/BG21033A3/xx unknown
- 1974-02-02 ES ES422873A patent/ES422873A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1417099A (en) | 1975-12-10 |
DE2404587C2 (en) | 1982-12-23 |
SE412392B (en) | 1980-03-03 |
BG21033A3 (en) | 1976-01-20 |
AU6505574A (en) | 1975-07-31 |
CH593979A5 (en) | 1977-12-30 |
NL7400972A (en) | 1974-08-06 |
ATA33074A (en) | 1975-07-15 |
DD109636A5 (en) | 1974-11-12 |
NO740341L (en) | 1974-08-05 |
NO147565C (en) | 1983-05-04 |
AT329178B (en) | 1976-04-26 |
JPS6037117B2 (en) | 1985-08-24 |
DK141754C (en) | 1980-11-03 |
SU553935A3 (en) | 1977-04-05 |
YU20374A (en) | 1982-02-28 |
CA1014549A (en) | 1977-07-26 |
FI60017B (en) | 1981-07-31 |
AU475538B2 (en) | 1976-08-26 |
YU39649B (en) | 1985-03-20 |
ES422873A1 (en) | 1976-05-01 |
JPS49102690A (en) | 1974-09-27 |
DK141754B (en) | 1980-06-09 |
HU167788B (en) | 1975-12-25 |
FI60017C (en) | 1981-11-10 |
DE2404587A1 (en) | 1974-08-15 |
CS182807B2 (en) | 1978-05-31 |
PL88593B1 (en) | 1976-09-30 |
AR202703A1 (en) | 1975-07-15 |
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