NO871763L - CRYSTALLIC MONOHYDRATE. - Google Patents
CRYSTALLIC MONOHYDRATE.Info
- Publication number
- NO871763L NO871763L NO871763A NO871763A NO871763L NO 871763 L NO871763 L NO 871763L NO 871763 A NO871763 A NO 871763A NO 871763 A NO871763 A NO 871763A NO 871763 L NO871763 L NO 871763L
- Authority
- NO
- Norway
- Prior art keywords
- penem
- aminomethyl
- hydroxyethyl
- carboxylic acid
- ether
- Prior art date
Links
- 150000004682 monohydrates Chemical class 0.000 title claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 24
- HOKYYMNHLDIDGI-HIQLJADVSA-N (5R,6S)-3-(aminomethyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate Chemical compound O.NCC=1S[C@H]2N(C1C(=O)O)C([C@@H]2[C@@H](C)O)=O HOKYYMNHLDIDGI-HIQLJADVSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000010586 diagram Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 15
- RXCNILVLOHRALM-UWBRJAPDSA-N (5r,6s)-3-(aminomethyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1C(CN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 RXCNILVLOHRALM-UWBRJAPDSA-N 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 14
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 13
- -1 penem compound Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- DVLVAQTZPDPDQR-MAYQPMADSA-N O1CCCC1.O.NCC=1S[C@H]2N(C1C(=O)O)C([C@@H]2[C@@H](C)O)=O Chemical compound O1CCCC1.O.NCC=1S[C@H]2N(C1C(=O)O)C([C@@H]2[C@@H](C)O)=O DVLVAQTZPDPDQR-MAYQPMADSA-N 0.000 claims description 8
- 238000004279 X-ray Guinier Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 230000005855 radiation Effects 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 125000001477 organic nitrogen group Chemical group 0.000 claims description 6
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 6
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FLMSRLQIPUJJMN-HIQLJADVSA-N CS(=O)(=O)O.NCC=1S[C@H]2N(C1C(=O)O)C([C@@H]2[C@@H](C)O)=O Chemical compound CS(=O)(=O)O.NCC=1S[C@H]2N(C1C(=O)O)C([C@@H]2[C@@H](C)O)=O FLMSRLQIPUJJMN-HIQLJADVSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 150000003871 sulfonates Chemical class 0.000 claims description 4
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000725 suspension Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000370 acceptor Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RXCNILVLOHRALM-LSNRDSIRSA-N (5r)-3-(aminomethyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1C(CN)=C(C(O)=O)N2C(=O)C([C@H](O)C)[C@H]21 RXCNILVLOHRALM-LSNRDSIRSA-N 0.000 description 1
- KSKHAQMLLDVBIQ-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxane-4,5-dione Chemical compound CC1(C)OCC(=O)C(=O)O1 KSKHAQMLLDVBIQ-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- LAOZSCRCYVBSJA-UHFFFAOYSA-N 5,5-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CC1(C)C(=O)NC(=O)NC1=O LAOZSCRCYVBSJA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 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
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 239000000872 buffer Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000012297 crystallization seed Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 244000000058 gram-negative pathogen Species 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-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
- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
-
- 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
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
1 1
Foreliggende oppfinnelse vedrører^det krystallinske monohydratet av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre„te>g (fremgangsmåte ~f or frem sti. lling~ av| dette ^_ The present invention relates to the crystalline monohydrate of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid (method of preparation ~ of| this ^_
I det tyske utlegningsskrift nr. 3431980 er (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre, fremgangsmåte til fremstilling av forbindelsen og anvendelsen av denne som antibakterielt middel beskrevet. Oppfinnelsen oppviser et uvanlig bredt antibakterielt virkningsspektrum, som omfatter de kjente grampositive og gramnegative sykdomsfrem-kallerne, innbefattet problemkim, som meticillin-resistente stafylokokker og Pseudomonas aeruginosa, og kan følgelig anvendes som et parenteralt administrerbart bredspektret-antibiotikum. Ved fremgangsmåten beskrevet i det nevnte tyske utlegningsskriftet oppnås forbindelsen i amorf form. In the German explanatory document no. 3431980 (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid, method for the preparation of the compound and its use as an antibacterial agent described. The invention exhibits an unusually broad spectrum of antibacterial action, which includes the known gram-positive and gram-negative pathogens, including problem germs, such as methicillin-resistant staphylococci and Pseudomonas aeruginosa, and can consequently be used as a parenterally administrable broad-spectrum antibiotic. By the method described in the aforementioned German explanatory document, the compound is obtained in amorphous form.
Amorfe stoffer er beheftet med forskjellige ulemper som gjør Amorphous substances are afflicted with various disadvantages that make
dem lite egnet eller uegnet for anvendelse, spesielt for fremstilling av farmasøytiske preparater. En ulempe ligger i den relativt store overflaten for amorfe stoffer sammenlignet med krystallinske stoffer, dette er, sammen med den uregel-messige, termodynamisk ugunstige: anordningen av molekylene i det faste stoffet, ansvarlig for en betydelig større påvirk-barhet av ytre påvirkninger, som luftoksygen, lys og forhøyet temperatur. Videre viser amorfe stoffer i lang6større grad enn krystallinske forbindelser en tendens til å inneslutte oppløs-ningsmidler og til å motsette seg avgivelse av disse forurens-ningene, eksempelvis ved tørking. Preparater som inneholder slike forurensninger, spesielt skadelige oppløsningsmidler, them not suitable or unsuitable for use, especially for the production of pharmaceutical preparations. A disadvantage lies in the relatively large surface area for amorphous substances compared to crystalline substances, this, together with the irregular, thermodynamically unfavorable: arrangement of the molecules in the solid substance, responsible for a significantly greater susceptibility to external influences, which atmospheric oxygen, light and elevated temperature. Furthermore, to a far greater extent than crystalline compounds, amorphous substances show a tendency to contain solvents and to resist the release of these pollutants, for example during drying. Preparations containing such contaminants, especially harmful solvents,
som acetonitril og klorerte hydrokarboner, er ikke egnet for medisinsk anvendelse, spesielt ved parenteral administrering. such as acetonitrile and chlorinated hydrocarbons, are not suitable for medical use, especially for parenteral administration.
En ytterligere ulempe ved amorfe produkter består i at luftfuktighet opptas i betydelig større grad enn tilfellet er for krystallinske produkter. Det økende vanninnholdet i slike produkter vanskeliggjør på den ene siden fremstillingen av farmasøytiske preparater med et konstant innhold av virksomt stoff og har videre en negativ innvirkning på produktets flytevne. Amorfe produkter har et relativt stort fyllvolum, hvilket A further disadvantage of amorphous products is that humidity is absorbed to a significantly greater extent than is the case for crystalline products. The increasing water content in such products makes it difficult, on the one hand, to manufacture pharmaceutical preparations with a constant content of active substance and also has a negative impact on the product's flowability. Amorphous products have a relatively large filling volume, which
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kan nødvendiggjøre.anvendelse av større beholdere ved lagring og ved fremstilling av legemiddelpreparater. Den ofte util-fredsstillende oppløsningsevnen for amorfe produkter (disse "forklistres" eller kleber lett sammen, hvorved oppløsnings-hastigheten nedsettes) skal også nevnes i denne sammenheng. may necessitate the use of larger containers for storage and for the manufacture of medicinal preparations. The often unsatisfactory dissolution ability of amorphous products (these "stick" or easily stick together, whereby the dissolution rate is reduced) should also be mentioned in this context.
De nevnte ulempene ved amorfe produkter, spesielt den dårlige lagringsstabiliteten, gjør det ønskelig å komme frem til en annen aggregatform enn den amorfe formen, som oppviser de egenskapene som kreves for et legemiddel, som spesielt god lagringsstabilitet. The aforementioned disadvantages of amorphous products, especially the poor storage stability, make it desirable to arrive at a different aggregate form than the amorphous form, which exhibits the properties required for a drug, such as particularly good storage stability.
Det er nå funnet at det krystallinske monohydratet av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre oppfyller de kravene som stilles til et legemiddel, spesielt når det gjelder lagringsstabilitet og bearbeidbarhet, på utmerket måte. 1 mol av det krystallinske produktet inneholder konstant 1 mol vann. Det dreier seg følgelig om et definert monohydrat. It has now been found that the crystalline monohydrate of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid meets the requirements for a drug, especially when applies to storage stability and processability, excellently. 1 mol of the crystalline product constantly contains 1 mol of water. It is therefore a defined monohydrate.
Under betegnelsen "krystallinsk" forstås at produktet er i det vesentlige fritt for amorfe bestanddeler. The term "crystalline" means that the product is essentially free of amorphous components.
Spesielt vedrører oppfinnelsen det krystallinske monohydratet In particular, the invention relates to the crystalline monohydrate
av (5R,6S)-2-aminometyl-6-[(IR)-hydroksyetyl]-2-penem-3-karboksylsyre, som er kjennetegnet ved de etterfølgende gitteravstandene (d-verdier) over 2,8 Ångstrøm og de relative linjeintensitetene for røntgenpulverdiagrammet (Guinier-kamera, strålingskilde kobber-K^): of (5R,6S)-2-aminomethyl-6-[(IR)-hydroxyethyl]-2-penem-3-carboxylic acid, which is characterized by the subsequent lattice spacings (d values) above 2.8 Angstroms and the relative line intensities for the X-ray powder diagram (Guinier camera, radiation source copper-K^):
Produktet oppviser en meget god krystallinitet, er godt filtrerbart, er meget stabilt også ved lengre innvirkning av lys, varme (40°C) og luftoksygen, og viser ved tilnærmet normale omgivelsesbetingelser ingen tendens til å oppta større mengder vann fra luften. Lagringsstabiliteten må følgelig betegnes som god. Sammenlignet med den tidligere kjente amorfe 2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre oppviser produktet ifølge oppfinnelsen en høyere renhetsgrad og må videre ikke lyofiliseres for adskillelse av oppløsnings-middelrester, men kan videre bearbeides etter vanlig tørking i vakuum. Produktet har god flytevne, lar seg lett fylle maskinelt og kan bearbeides til parenteralt administrerbare legemiddelpreparater i ønsket mengde uten vanskelighet. The product exhibits very good crystallinity, is easily filterable, is very stable even when exposed to light, heat (40°C) and atmospheric oxygen for a longer period of time, and shows no tendency to absorb large amounts of water from the air under almost normal ambient conditions. The storage stability must therefore be described as good. Compared to the previously known amorphous 2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid, the product according to the invention exhibits a higher degree of purity and furthermore does not have to be lyophilized to separate solvent residues, but can further processed after normal drying in a vacuum. The product has good fluidity, can be easily filled by machine and can be processed into parenterally administrable pharmaceutical preparations in the desired quantity without difficulty.
/Oppfinnelsen vedrører W-de-r-e| en fremgangsmåte for fremstilling \ /The invention relates to W-de-r-e| a method of manufacturing
av det krystallinske monohydratet av (5R,6S)-2-aminometyl-6-\[ (IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre. Overraskende er det funnet at det krystallinske monohydratet kan oppnås ved at det fremstilles en overmettet oppløsning av et (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre- of the crystalline monohydrate of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid. Surprisingly, it has been found that the crystalline monohydrate can be obtained by preparing a supersaturated solution of a (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid
monohydrat-etersolvat i en vannholdig C-^-C^-alkanol, eller et (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karbok-sylsyre-monohydrat-etersolvat i vann eller en blanding bestående av vann og en C-^-C^-alkanol, oppløsningen behandles med en sulfonsyre, oppløsningen av det dannede sulfonatsaltet overføres, eventuelt etter foregående isolering av sulfonatet var reaksjonsblandingen og etterfølgende gjenoppløsning av det isolerte produktet i vann eller i en blanding bestående av vann og en C-^-C^-alkanol, ved tilsats av ekvimolare mengder av en organisk nitrogenbase og en C^-C^-alkanol til en overmettet oppløsning av den frie penemforbindelsen, produktet bringes til krystallisasjon, og krystallene isoleres og tørkes. monohydrate ether solvate in an aqueous C-^-C^-alkanol, or a (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate -ether solvate in water or a mixture consisting of water and a C-^-C^-alkanol, the solution is treated with a sulphonic acid, the solution of the sulphonate salt formed is transferred, possibly after previous isolation of the sulphonate, the reaction mixture and subsequent redissolution of the isolated product in water or in a mixture consisting of water and a C-^-C^-alkanol, by adding equimolar amounts of an organic nitrogen base and a C^-C^-alkanol to a supersaturated solution of the free penem compound, the product is brought to crystallization , and the crystals are isolated and dried.
Med et (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvat forstås spesielt et slikt estersolvat med en vannoppløslig lavalifatisk eller 5- eller 6-leddet cykloalifatisk eter. Slike etere er eksempelvis 1,2-dimetoksyetan, dioksan og tetrahydrofuran. Foretrukket som utgangsstoff er monohydrat-tetrahydrofuran-hemisolvatet av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-kårbok-sylsyre. By a (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvate is meant in particular such an ester solvate with a water-soluble low aliphatic or 5- or 6- linked cycloaliphatic ether. Such ethers are, for example, 1,2-dimethoxyethane, dioxane and tetrahydrofuran. Preferred starting material is the monohydrate tetrahydrofuran hemisolvate of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid.
Med en oppløsning av et (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl ]-2-penem-3-karboksylsyre-monohydrat-etersolvat i en vannholdig C-^-C^-alkanol forstås eksempelvis en oppløsning i en oppløsningsmiddelblanding, bestående av vann og metanol, vann og etanol, vann og n-propanol samt vann og isopropanol. Foretrukket som alkanolkomponenter er isopropanol og spesielt etanol. Vanninnholdet av en slik vannholdig C-^-C^-alkanol ut-gjør f.eks. 5-30 volum-%, fortrinnsvis 9-20 volum-%. En overmettet oppløsning ifølge den første fremgangsmåtevarianten kan fremstilles ved at man oppløser til metning en hvilken som helst form av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvatet, f.eks. den amorfe formen eller den krystallinske formen, i vann ved romtemperatur eller fortrinnsvis ved forhøyet temperatur, f.eks. inntil kokepunktet for det anvendte oppløsningsmidlet, men fortrinnsvis til maksimalt 50°C, under unngåelse eller fjernelse av tilstedeværende.krystallisasjonsk kim, og den oppnådde rene oppløsningen bringes til overmetning. For dette formålet blandes den mettede oppløsningen, som oppviser en temperatur på s>eT. 20 til&af 50°C, fortrinnsvis fra G-fiT 40° til 50°C, med et overskudd av av C^-C^-alkanolen, spesielt med et 4-10 gangers overskudd av C^-C^-alkanolen beregnet på basis av den anvendte vannmengden, og avkjøles langsomt, eksempelvis til en temperatur mellom 0° ogj3^T^30°C, fortrinnsvis til ca.^25°C. Krystalldannelsen kan foregå spontant, eksempelvis på overflaten av reaksjonsbeholderen, hhv. rørerinnretningen, men kan også utløses ved poding, dvs. innføring av podekrystaller. Dersom ingen podekrystaller står til disposisjon kan disse fremstilles, fortrinnsvis i en del av oppløsningen, på vanlig måte, f.eks. ved kraftig risting, innføring av glasstøv eller rissing i beholderveggen. I en foretrukket utførelsesform av den første fremgangsmåtevarianten podes den overmettede oppløs-ningen med podekrystaller. Før fremstilling av den overmettede oppløsningen kan det innføres et eller flere rensetrinn, f.eks. behandling med aktivt kull og/eller filtrering, spesielt steril filtrering. By a solution of a (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvate in an aqueous C-^-C^-alkanol is understood for example a solution in a solvent mixture, consisting of water and methanol, water and ethanol, water and n-propanol as well as water and isopropanol. Preferred alkanol components are isopropanol and especially ethanol. The water content of such a water-containing C-^-C^-alkanol is e.g. 5-30% by volume, preferably 9-20% by volume. A supersaturated solution according to the first method variant can be prepared by dissolving to saturation any form of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid -monohydrate ether solvate, e.g. the amorphous form or the crystalline form, in water at room temperature or preferably at elevated temperature, e.g. up to the boiling point of the solvent used, but preferably to a maximum of 50°C, while avoiding or removing any crystallization seed present, and the pure solution obtained is brought to supersaturation. For this purpose, the saturated solution, which exhibits a temperature of s>eT, is mixed. 20 to&of 50°C, preferably from G-fiT 40° to 50°C, with an excess of of the C^-C^-alkanol, in particular with a 4-10 times excess of the C^-C^-alkanol calculated on the basis of the amount of water used, and is cooled slowly, for example to a temperature between 0° and j3^T^30°C, preferably to approx.^25°C. The crystal formation can take place spontaneously, for example on the surface of the reaction vessel, or the stirring device, but can also be triggered by grafting, i.e. introduction of grafting crystals. If no seed crystals are available, these can be prepared, preferably in part of the solution, in the usual way, e.g. by vigorous shaking, introduction of glass dust or scratching in the container wall. In a preferred embodiment of the first method variant, the supersaturated solution is seeded with seed crystals. Before producing the supersaturated solution, one or more purification steps can be introduced, e.g. treatment with activated carbon and/or filtration, especially sterile filtration.
I en £a»dx-@j fremgangsmåtevariant av fremgangmåten ifølge oppfinnelsen fremstilles det et sulfonat med utgangspunkt i (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karbok-sylsyre-monohydrat-etersolvat,som eventuelt kan isoleres, In a process variant of the process according to the invention, a sulfonate is prepared starting from (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carbox -silicic acid monohydrate ether solvate, which can possibly be isolated,
og dette overføres i et etterfølgende trinn til monohydratet ifølge oppfinnelsen. Sammenlignet med den ovenfor nevnte første fremgangsmåtevarianten har "sulfonatvarianten" den store fordelen at (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-sulfonatet oppviser en meget god vann-oppløslighet, slik at den mengden vann som kreves som oppløs-ningsmiddel kan reduseres i betydelig grad. Ved siden av de fremgangsmåteøkonomiske fordelene som derved oppnås (lavere væskevolum, mindre dimensjonerte reaksjonsbeholdere, lavere energikostnader ved avkjøling for utkrystallisering av slutt-produktet) opptrer også en utbytteøkning, i det produkttap går tilbake i moderluten p.g.a. det lavere oppløsningsmiddelvolumet. Videre består den muligheten å isolere det intermediært dannede and this is transferred in a subsequent step to the monohydrate according to the invention. Compared to the above-mentioned first process variant, the "sulfonate variant" has the great advantage that the (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid sulfonate exhibits a very good water solubility, so that the amount of water required as a solvent can be reduced to a considerable extent. Alongside the economic benefits of the process that are thereby achieved (lower liquid volume, smaller sized reaction vessels, lower energy costs during cooling for crystallization of the final product) there is also an increase in yield, as product loss returns to the mother liquor due to the lower solvent volume. Furthermore, it remains possible to isolate the intermediately formed
sulfonatet, fordelen med et ekstra rensetrinn. Fremgangsmåten the sulfonate, the advantage of an additional purification step. The procedure
v/v^\^—■ ' s - -'"—" v/v^\^—■ ' s - -'"—"
er følgelig egnet for gjennomføring i industriell målestokk. is therefore suitable for implementation on an industrial scale.
Med en sulfonsyre forstås ^fjarjst^jsg^J^ eventuelt, f.eks. med halogen, som fluor, substituert C^-C^-alkansulfon-syre, f.eks. metansulfonsyre, eller en eventuelt, f.eks. med C^-C^-alkyl, som metyl, eller halogen, som brom, substituert benzensulfonsyre, f.eks. benzensulfonsyre, p-toluensulfonsyre eller p-brombenzensulfonsyre. Foretrukket som sulfonsyre er metansulfonsyre. By a sulphonic acid is understood possibly, e.g. with halogen, such as fluorine, substituted C 1 -C 4 -alkanesulfonic acid, e.g. methanesulfonic acid, or an optional, e.g. with C 1 -C 4 -alkyl, such as methyl, or halogen, such as bromine, substituted benzenesulfonic acid, e.g. benzenesulfonic acid, p-toluenesulfonic acid or p-bromobenzenesulfonic acid. Preferred as sulfonic acid is methanesulfonic acid.
En organisk nitrogenbase er spesielt et eventuelt substituert, lavere alifatisk primært, sekundært eller tertiært amin, som spesielt et eventuelt med hydroksy substituert mono-, di- An organic nitrogen base is in particular an optionally substituted, lower aliphatic primary, secondary or tertiary amine, such as in particular an optionally hydroxy substituted mono-, di-
eller tri-C-^-C^-alkylamin, f.eks. trietylamin, diisopropylamin, etanolamin, dietanolamin eller trietanolamin, et cyklo-C^-Cg-alkylamin, f.eks. cykloheksylamin, eller et cyklisk amin med 4 eller 5 karbonatomer, f.eks. pyrrolidin, piperidin eller morfolin. Foretrukket som nitrogenbase er de nevnte lavali-fatiske aminene, spesielt trietylamin. or tri-C 1 -C 4 -alkylamine, e.g. triethylamine, diisopropylamine, ethanolamine, diethanolamine or triethanolamine, a cyclo-C 1 -C 8 -alkylamine, e.g. cyclohexylamine, or a cyclic amine with 4 or 5 carbon atoms, e.g. pyrrolidine, piperidine or morpholine. Preferred as nitrogen base are the aforementioned lavaliphatic amines, especially triethylamine.
For fremgangsmåten suspenderes utgangsmaterialet, (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvatet i en liten mengde vann eller i en blanding bestående av vann og en C-^-C^-alkanol, f.eks. en av de ovenfor nevnte, spesielt etanol eller isopropanol. Det er ikke nødvendig å fremstille en oppløsning, i det oppløsning inntrer ved den etterfølgende dannelsen av sulfonatet. Fortrinnsvis foregår reaksjonen med en ekvimolar mengde av sulfon-syren i vann eller i en blanding bestående av vann og C^-C^-alkanolen med et vanninnhold på *e-a". 25-75%, ved romtemperatur eller svakt redusert temperatur, f.eks. i et temperaturområde fra 0°C til -e-aT 20°C. Ekvimolare mengder av den organiske nitrogenbasen, spesielt trietylamin, tilsettes ved den samme temperaturen i form av en oppløsning i den samme C-^-C^-alkanolen, hvorved etter avsluttet tilsats det samlede volumforholdet vann-C-^-C^-alkanol for oppnåelse av overmetningstilstanden bør ligge i et område mellom 1:3 og 1:10, fortrinnsvis ved js-a- 1:3 til c-a-. 1:5. Den overmettede oppløsningen avkjøles deretter langsomt til en temperatur mellom 0° og jz& C -5-30°C, fortrinnsvis til ca. •f25°C. Krystalldannelsen kan foregå spontant eller kan utløses ved poding, f.eks. som beskrevet ovenfor. For the process, the starting material, (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvate is suspended in a small amount of water or in a mixture consisting of water and a C 1 -C 4 alkanol, e.g. one of those mentioned above, especially ethanol or isopropanol. It is not necessary to prepare a solution, since dissolution occurs with the subsequent formation of the sulfonate. Preferably, the reaction takes place with an equimolar amount of the sulfonic acid in water or in a mixture consisting of water and the C₁-C₂ alkanol with a water content of *e-a". 25-75%, at room temperature or slightly reduced temperature, e.g. eg in a temperature range from 0° C to -e-aT 20° C. Equimolar amounts of the organic nitrogen base, especially triethylamine, are added at the same temperature in the form of a solution in the same C-^-C^-alkanol, whereby, after the addition has been completed, the total volume ratio of water-C-^-C^-alkanol to achieve the supersaturation state should lie in a range between 1:3 and 1:10, preferably at js-a- 1:3 to c-a-. 1: 5. The supersaturated solution is then cooled slowly to a temperature between 0° and jz& C -5-30° C, preferably to about •f25° C. The crystal formation can take place spontaneously or can be triggered by grafting, for example as described above .
Fortrinnsvis innføres før tilsatsen av den organiske nitrogenbasen, et eller flere rensetrinn. Eksempelvis kan sulfonat-oppløsningen underkastes en behandling med aktivt kull og/eller filtrering, som spesielt en steril filtrering. Preferably, one or more purification steps are introduced before the addition of the organic nitrogen base. For example, the sulphonate solution can be subjected to treatment with activated carbon and/or filtration, such as sterile filtration in particular.
For å oppnå en ytterligere renseeffekt kan det intermediært dannede sulfonatet isoleres fra reaksjonsblandingen. Overraskende er det funnet at sulfonatet oppnås i krystalinsk form når den vandige eller vandig-C-^-C^-alkanoliske oppløsningen av sulfonatet i et temperaturområde f ra _c.a-r— 0° til ■ e- arr" 20°C blandes med et overskudd av C-^-C^-alkanolen inntil et volum-forhold vann-C-^-C^-alkanol på ca. 1:3 til 1:10, fortrinnsvis fra ca. 1:5 til ca. 1:8. Sulfonatet oppstår i meget ren krystallinsk form, slik at forurensninger uten problemer kan fraskilles med moderluten. Det krystallinske sulfonatet fraskilles på vanlig måte, ved romtemperatur eller noe redu-serte temperatur, f.eks. ved <e-a-r~ 0 0 til-ear. 20°C, oppløst i litt vann eller i en blanding bestående av vann og en C-^-C^-alkanol, og blandes ved den samme temperaturen med ekvimolare mengder av den organiske nitrogenbasen, oppløst i den samme C-^-C^-alkanolen, hvorved det samlede volumforholdet vann-C^-C^-alkanol, etter avsluttet basetilsats, fortrinnsvis bør ligge i et område mellom 1:3 og 1:10 for å oppnå overmetningstilstanden. Den overmettede oppløsningen avkjøles deretter langsomt til en temperatur mellom 0° og Usa». -r30°C, spesielt til ca.^25°C. Krystalldannelsen kan foregå spontant eller kan utløses ved poding, f.eks. som beskrevet ovenfor. To achieve a further cleaning effect, the intermediately formed sulfonate can be isolated from the reaction mixture. Surprisingly, it has been found that the sulfonate is obtained in crystalline form when the aqueous or aqueous C-^-C^-alkanolic solution of the sulfonate in a temperature range from _c.a-r— 0° to ■ e- arr" 20°C is mixed with a excess of the C 1 -C 2 alkanol until a volume ratio of water to C 2 -C 3 alkanol of about 1:3 to 1:10, preferably from about 1:5 to about 1:8. The sulphonate occurs in a very pure crystalline form, so that impurities can be separated without problems with the mother liquor. The crystalline sulphonate is separated in the usual way, at room temperature or a slightly reduced temperature, for example at <e-a-r~ 0 0 to-ear. 20 °C, dissolved in a little water or in a mixture consisting of water and a C-^-C^-alkanol, and mixed at the same temperature with equimolar amounts of the organic nitrogen base, dissolved in the same C-^-C^- the alkanol, whereby the total volume ratio of water-C^-C^-alkanol, after the base addition has ended, should preferably lie in a range between 1:3 and 1:10 in order to achieve the supersaturation state. the supersaturated solution is then cooled slowly to a temperature between 0° and Usa'. -r30°C, especially to approx.^25°C. The crystal formation can take place spontaneously or can be triggered by grafting, e.g. as described above.
De dannede nye krystallinske forbindelsene, spesielt (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydratet, kan isoleres og samles ved hjelp av en hvilken som helst av de fremgangsmåtene som står til disposisjon for adskillelse av binære fast/flytende systemer, f.eks. ved filtre ring, trykkfiltrering ("avnutsjing"), sentrifugering eller dekantering. For fjernelse av forurensninger som finnes igjen i moderlutrestene kan det ettervaskes med den C2-C4~alkanolen som er anvendt for krystallisasjon som inneholder små mengder (e-a-. 2-10%) vann. The new crystalline compounds formed, especially the (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate, can be isolated and collected by any of the methods available for the separation of binary solid/liquid systems, e.g. by filtering, pressure filtration ("squeezing"), centrifugation or decantation. To remove impurities remaining in the mother liquor residues, it can be washed with the C2-C4 alkanol used for crystallization which contains small amounts (e-a-. 2-10%) of water.
Tørkingen gjennomføres ved normal eller svakt forhøyet temperatur, f.eks. i temperaturområdet fra -ear- 15°C til-es. 40°C, fortrinnsvis ved e^rr 20° til -e-a-. 25°C (romtemperatur), og fortsettes inntil tilnærmet konstant vekt er oppnådd. For å akselerere tørkingen kan det arbeides underjredusert trykk, hvorved f.eks. såkalt vannstrålevakuum (ca. 650 til ca. 3 300 Pa) eller høyvakuum (&éh? 5 til e-a. 100 Pa) kan anvendes. The drying is carried out at a normal or slightly elevated temperature, e.g. in the temperature range from -ear- 15°C to-es. 40°C, preferably at e^rr 20° to -e-a-. 25°C (room temperature), and continue until approximately constant weight is achieved. To accelerate drying, work can be done under reduced pressure, whereby e.g. so-called water jet vacuum (approx. 650 to approx. 3,300 Pa) or high vacuum (&éh? 5 to e-a. 100 Pa) can be used.
Oppfinnelsen vedrører veidere de som mellomprodukter oppnådde sulfonatene av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyren i amorf og i krystallinsk form, og fremgangsmåte for fremstilling av disse. The invention also relates to the sulfonates obtained as intermediates of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid in amorphous and in crystalline form, and to a method for producing these.
Spesielt vedrører oppfinnelsen (5R,6S)-2-aminometyl-6-[ (IR)-1-hydroksyetyl]-2-penem-karboksylsyre-metansulfonat i amorf og i krystallinsk form. Den krystallinske formen av metansulfonatet er kjennetegnet ved følgende gitteravstander (d-verdier) over 3,0 Ångstrøm og de relative linjeintensitetene i røntgenpulverdiagrammer (Guinier-kamera, strålingskilde kobber-K ,): In particular, the invention relates to (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem carboxylic acid methanesulfonate in amorphous and crystalline form. The crystalline form of the methanesulfonate is characterized by the following lattice spacings (d-values) above 3.0 Angstroms and the relative line intensities in X-ray powder diagrams (Guinier camera, radiation source copper-K,):
a 1 a 1
Fremgangsmåten for fremstilling av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-sulfonatet er kjennetegnet ved at man behandler et (5R,6S)-2-amino€tyl-6-[(1R)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvat i vann eller i en blanding bestående av vann og en C^-C^-alkanol, med en sulfonsyre, fremstiller en overmettet oppløsning ved tilsats av et overskudd av C-^-C^-alkanolen, bringer produktet til krystallisasjon og isolerer og tørker krystallene. The method for the preparation of the (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid sulfonate is characterized by treating a (5R,6S)-2- amino€tyl-6-[(1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvate in water or in a mixture consisting of water and a C 1 -C 4 -alkanol, with a sulphonic acid, prepares a supersaturated solution by adding an excess of the C-^-C^-alkanol, brings the product to crystallization, and isolates and dries the crystals.
De ifølge oppfinnelsen som utgangsstoffer anvendte (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvatene er nye og utgjør også gjenstand for foreliggende oppfinnelse. De kan fremstilles ved at man om-setter en forbindelse av formelen hvori R' står for eventuelt substituert allyl, i en blanding bestående av en vannoppløslig, lavalifatisk eller 5- eller 6-leddet cykloalifatisk eter, med en allylgruppeakseptor i nærvær av en egnet palladium (0)-katalysator, og eventuelt i nærvær av trifenylfosfin. The (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvates used according to the invention as starting materials are new and also form the subject of the present invention. They can be prepared by reacting a compound of the formula in which R' stands for optionally substituted allyl, in a mixture consisting of a water-soluble, low-aliphatic or 5- or 6-membered cycloaliphatic ether, with an allyl group acceptor in the presence of a suitable palladium (0)-catalyst, and optionally in the presence of triphenylphosphine.
Eventuelt substituert allyl er eksempelvis metallyl, cinnamyl eller spesielt allyl. Optionally substituted allyl is, for example, metallyl, cinnamyl or especially allyl.
En vannoppløslig, lavalifatisk eller 5- eller 6-leddet cyklo-alif atisk eter er eksempelvis 1,2-dimetoksyetan, dioksan eller spesielt tetrahydrofuran. A water-soluble, low-aliphatic or 5- or 6-membered cyclo-aliphatic ether is, for example, 1,2-dimethoxyethane, dioxane or especially tetrahydrofuran.
Egnede allylgruppeakseptorer er eksempelvis cykliske6-dikarbo-nylforbindelser med en pK a-verdi på 5 eller mindre enn 5, Suitable allyl group acceptors are, for example, cyclic 6-dicarbonyl compounds with a pK a value of 5 or less than 5,
f.eks. dimedon, meldrum's syre (2,2-dimetyl-l,3-dioksan-4,5-dion) samt barbitursyre og dens N-mono- og N,N'-di-substituerte derivater, som barbitursyre og N,N<1->dimetylbarbitursyre. Foretrukne som allylgruppeakseptorer er dimedon og N,N'-dime-tylbarbitursyre . e.g. dimedone, meldrum's acid (2,2-dimethyl-1,3-dioxane-4,5-dione) as well as barbituric acid and its N-mono- and N,N'-di-substituted derivatives, such as barbituric acid and N,N<1 ->dimethylbarbituric acid. Preferred as allyl group acceptors are dimedone and N,N'-dimethylbarbituric acid.
En egnfedlet palladium(0) -katalysator er eksempelvis bis-(di-benzylidenacetonato)-palladium eller tetrakis-(trifenylfosfin)-palladium. An appropriate palladium(0) catalyst is, for example, bis-(di-benzylideneacetonato)-palladium or tetrakis-(triphenylphosphine)-palladium.
Omsetningen gjennomføres i en av de nevnte vannoppløslige eterne, som inneholder - er£~. 2-15 volum-%, spesielt re-a-. 3-8 volum-% The reaction is carried out in one of the mentioned water-soluble ethers, which contain - er£~. 2-15% by volume, especially re-a-. 3-8% by volume
vann, ved romtemperatur eller svakt redusert eller forhøyet temperatur, f.eks. ved-era". 0° til e-a- 30°C, fortrinnsvis ved 0° tilScT. 20°C. Reaksjonen gjennomføres med 1,5-3 mol water, at room temperature or slightly reduced or elevated temperature, e.g. ved-era". 0° to e-a- 30°C, preferably at 0° to ScT. 20°C. The reaction is carried out with 1.5-3 mol
ekvivalenter, spesielt 1,8-2,4 molekvivalenter av allylgruppe-akseptoren i nærvær av ca. 1-5 mol-%, spesielt 1-3 mol-% palladium (0)-katalysator og fortrinnsvis i nærvær av 10-50 mol-%, spesielt 15-30 mol-%, trifenylfosfin, om nødvendig i en inertgassatmosfære, f.eks. i en nitrogen- eller argonatmosfære. equivalents, especially 1.8-2.4 molar equivalents of the allyl group acceptor in the presence of approx. 1-5 mol-%, especially 1-3 mol-% palladium (0) catalyst and preferably in the presence of 10-50 mol-%, especially 15-30 mol-%, triphenylphosphine, if necessary in an inert gas atmosphere, e.g. e.g. in a nitrogen or argon atmosphere.
Overraskende ble det funnet at reaksjonsproduktet, (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre, utfelles som krystallinsk monohydrat-etersolvat, uavhengig av typen av den anvendte vannoppløslige eteren, ved anvendelse av tetrahydrofuran som eterkomponent i oppløsningsmidlet eksempelvis som godt filtrerbart krystallinsk monohydrat-tetrahydrofuran-hemisolvat. Solvatene oppstår i tilnærmet kvantitativt utbytte og er analyserene. P.g.a. den høye renheten for monohydratet er solvatene , spesielt monohydrat-tetrahydrofuran-hemisolvåtet, er ytterligere rensetrinn unødvendige, og disse mellomproduktene kan anvendes direkte i fremgangsmåten ifølge oppfinnelsen for fremstilling av (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-metansulfonat og (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat. Følgelig oppnås ved anvendelsen av monohydrat-tetrahydrofuran-hemisolvatet som utgangsforbindelse (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydratet i meget gode utbytter og i høy renhet (for fremstilling av en farmasøytisk form er bare få uproblematiske rensetrinn påkrevet, som f.eks. behandling med aktiv kull og steril filtrering. Surprisingly, it was found that the reaction product, (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid, precipitates as a crystalline monohydrate ether solvate, regardless of the type of solvent used the water-soluble ether, using tetrahydrofuran as the ether component in the solvent, for example as a well-filterable crystalline monohydrate tetrahydrofuran hemisolvate. The solvates occur in almost quantitative yield and are the analytes. Because of. the high purity of the monohydrate is the solvates, especially the monohydrate-tetrahydrofuran-hemisolvate, further purification steps are unnecessary, and these intermediate products can be used directly in the process according to the invention for the production of (5R,6S)-2-aminomethyl-6-[(IR)- 1-hydroxyethyl]-2-penem-3-carboxylic acid methanesulfonate and (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate. Consequently, by using the monohydrate tetrahydrofuran hemisolvate as starting compound (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate is obtained in very good yields and in high purity (for the production of a pharmaceutical form only a few unproblematic purification steps are required, such as treatment with activated charcoal and sterile filtration.
Oppfinnelsen vedrører videre spesielt (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-tetra-hydrof uran-hemisolvat i amorf og krystallinsk form. Den krystallinske formen av solvatet er kjennetegnet ved de etter-følgende gitteravstandene (d-verdiene) over 2,9 Ångstrøm og de relative linjeintensitetene i røntgenpulverdiagrammet (Guinier-kamera, strålinqskilde kobber-K , ) : The invention further relates in particular to (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate in amorphous and crystalline form. The crystalline form of the solvate is characterized by the following lattice spacings (d-values) above 2.9 Angstroms and the relative line intensities in the X-ray powder diagram (Guinier camera, radiation source copper-K , ):
al eel
Utgangsforbindelsene av formel I er kjente, eksempelvis fra det tyske utlegningsskrift nr. 3431980, eller kan fremstilles analogt de der angitte frem^Tagsmåtene. The starting compounds of formula I are known, for example from the German specification no. 3431980, or can be prepared analogously to the methods of preparation indicated there.
Oppfinnelsen vedrører også fremgangsmåten for fremstilling av det krystallinske monohydratet av (5R,6S)-2-aminometyl-6-[(IR)-1- hydroksyetyl]-2-penem-3-karboksylsyre, som er kjennetegnet ved at man overfører en forbindelse av formel I til et (5R,6S)-2- aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-etersolvat, en oppløsning av dette overføres som angitt, f.eks. via et sulfonat-mellomprodukt, til en overmettet oppløsning av den frie penem-forbindelsen og produktet bringes til krystallisasjon. The invention also relates to the process for producing the crystalline monohydrate of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid, which is characterized by transferring a compound of formula I to a (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate ether solvate, a solution of which is transferred as indicated, e.g. . via a sulfonate intermediate, to a supersaturated solution of the free penem compound and the product is brought to crystallization.
Oppfinnelsen vedrører videre farmasøytiske preparater som inne holder en terapeutisk virksom mengde av det krystallinske (5R,6S)-2-aminometyl-6-[(IR)-l-hydDoksyetyl]-2-penem-3-karboksylsyre-monohydratet sammen med eller i blanding med uorganiske eller organiske, faste^eller flytende, farmasøytisk anvendelige bærerstoffer, som egner seg for parenteral, dvs. f.eks. intramuskulær, intravenøs./ subkutan eller intraperi-toneal administrering. The invention further relates to pharmaceutical preparations containing a therapeutically effective amount of the crystalline (5R,6S)-2-aminomethyl-6-[(IR)-1-hydoxyethyl]-2-penem-3-carboxylic acid monohydrate together with or in mixture with inorganic or organic, solid^or liquid, pharmaceutically usable carriers, which are suitable for parenteral use, i.e. e.g. intramuscular, intravenous./ subcutaneous or intraperitoneal administration.
For parenteral administrering egner seg først og fremst infu-sjonsoppløsninger, fortrinnsvis^ isotoniske vandige oppløs-ninger eller suspensjoner, hvorved disse f.eks. kan fremstilles før bruk fra preparater som inneholder det virksomme stoffet alene eller sammen med et bærJrmateriale, f. eks. mannit. For parenteral administration, infusion solutions are primarily suitable, preferably isotonic aqueous solutions or suspensions, whereby these e.g. can be prepared before use from preparations containing the active substance alone or together with a carrier material, e.g. mannite.
Slike preparater kan være steriliserte og/eller inneholde hjelpestoffer, f.eks. konserverings-, stabiliserings-, fukte-og/eller emulgeringsmidler, oppløslighetsformidlere, salter for regulering av det osmotiske trykket og/eller buffere. Such preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers.
De foreliggende farmasøytiske preparatene som, om ønsket, kan inneholde andre farmakologisk verdifulle stoffer, fremstilles på i og for seg kjent måte,| f.eks. ved hjelpe av konvensjonelle blande- og oppløsningsfremgangsmåter. Det ifølge oppfinnelsen oppnådde krystallinske ( 5R,'6S)-2-aminometyl-6-[ (IR)-1-hydroksyetyl [-2-penem-3-karboksylsyre-monohydratet er godt flytbart og kan som sådant, eller etter tilsats av ytterligere bærerstoffer, som mannit, avfyljles i flasker eller ampuller maskinelt under aseptiske betingelser i ønsket mengde. Preparatene ifølge foreliggende oppfinnelse inneholder fra ca. 0,1% til 100%, preparater i ampuller fra ca. 50% til ca. 100% av det aktive stoffet. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are produced in a manner known per se, e.g. using conventional mixing and dissolving methods. The crystalline (5R,'6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl [-2-penem-3-carboxylic acid monohydrate obtained according to the invention is well flowable and can as such, or after the addition of additional carrier substances, such as mannitol, are filled into bottles or ampoules mechanically under aseptic conditions in the desired quantity. The preparations according to the present invention contain from approx. 0.1% to 100%, preparations in ampoules from approx. 50% to approx. 100% of the active substance.
Avhengig av typen infeksjon og den individuelle tilstanden Depending on the type of infection and the individual condition
for den infiserte organismen anvendes det daglig parenterale doser fra ca. 100 mg til jca. 5 g av det virksomme stoffet for behandling av varmblodige pattedyr (mennesker og dyr) av vekt ca. 70 kg. for the infected organism, daily parenteral doses of approx. 100 mg to approx. 5 g of the active substance for the treatment of warm-blooded mammals (humans and animals) weighing approx. 70 kg.
Anvendelsen av den krystallinske penemforbindelsen ifølge opp-/ finnelsen til terapeutisk /behandling av mennesker og dyr, spesielt som antibakterielt antibiotikum, utgjør også gjenstand for foreliggende oppfinnelse. The use of the crystalline penem compound according to the invention for the therapeutic treatment of humans and animals, especially as an antibacterial antibiotic, is also the subject of the present invention.
De følgende eksemplene tjener som illustrasjon på oppfinnelsen. The following examples serve to illustrate the invention.
Eksperimentell del Experimental part
Beskrivelse av røntgenpulverdiagrammene: Description of the X-ray powder diagrams:
For bestemmelse av nettplanavstandene (d-verdier) ble det frak-sjonsbildet registrert på film. Opptaket foregikk i transmisjon med et Guinier-kamera ("Enraf-Nonius FR 552") og Kobber-K ,-stråling (bølgelengde = 1,54050 Å). Som kalibreringsstoff ble det anvendt kvarts, hvis d-verdier ble beregnet fra a = 4,913 Å og c = 5,405 Å (PDF 5-490). De angitte tabellene inneholder d-verdiene for de sterkeste linjene, sammen med relative linje-intensiteter observert ved hjelp av øyet. To determine the grid plane distances (d-values), the fraction image was recorded on film. The recording took place in transmission with a Guinier camera ("Enraf-Nonius FR 552") and Kobber-K , radiation (wavelength = 1.54050 Å). Quartz was used as a calibration substance, whose d-values were calculated from a = 4.913 Å and c = 5.405 Å (PDF 5-490). The tables provided contain the d-values for the strongest lines, together with relative line intensities observed by eye.
( /wiiXi3n^p. ) ( /wiiXi3n^p. )
Eksempel 1: ( 5R, 6S)- 2- aminometyl- 6-[( IR)- 1- hydroksyetyl]- 2-penem- 3- karboksylsyre- monohydrat- tetrahydrofuran-hemisolvat Example 1: (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate
45,2 g (100 mMol) (5R,6S)-2-allyloksykarbonylaminometyl-6-[(IR)-1-allyloksykarbonyloksyetyl]-2-penem-3-karboksylsyreallylester, 28,0 g (180 mMol) N,N'-dimetylbarbitursyre og 5,2 g (20 mMol) trifenylfosfin oppløses i en blanding av 500 ml tetrahydrofuran og 25 ml vann. Oppløsningen spyles i 15 minutter med argon, blandes deretter ved 0-5°C med 1,6 g (1,4 mMol) tetrakis-(trifenylfosfin)-palladium og utrøres i 2,5 timer, hvorved tempera turen langsomt økes til romtemperatur. Det krystallinske bunnfallet frafiltreres, vaskes med tetrahydrofuran og tørkes i høyvakuum. DC (H20, OPTI-UP C12), Rf = 0,48. Smeltepunkt 12 7°C (dekomp.). 45.2 g (100 mmol) (5R,6S)-2-allyloxycarbonylaminomethyl-6-[(IR)-1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester, 28.0 g (180 mmol) N,N' -dimethylbarbituric acid and 5.2 g (20 mmol) of triphenylphosphine are dissolved in a mixture of 500 ml of tetrahydrofuran and 25 ml of water. The solution is flushed for 15 minutes with argon, then mixed at 0-5°C with 1.6 g (1.4 mmol) of tetrakis-(triphenylphosphine)-palladium and stirred for 2.5 hours, whereby the temperature is slowly raised to room temperature. The crystalline precipitate is filtered off, washed with tetrahydrofuran and dried under high vacuum. DC (H2O, OPTI-UP C12), Rf = 0.48. Melting point 12 7°C (decomp.).
<C>9<H>12<N>2°4S"H2° " 0,5 C4H8° (molekYlvekt 298,3) <C>9<H>12<N>2°4S"H2° " 0.5 C4H8° (molecular weight 298.3)
De 21 sterkeste linjene i røntgenpulverdiagrammene med d-verdier over 2,9 Ångstrøm tilsvarer følgende nettplanavstander og relative intensiteter: The 21 strongest lines in the X-ray powder diagrams with d-values above 2.9 Angstroms correspond to the following grid plane distances and relative intensities:
Eksempel 2: ( 5R, 6S)- 2- aminometyl- 6-[( IR)- 1- hydroksyetyl]-2- penem- 3- karboksylsyre- metansulfonat Example 2: (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid methanesulfonate
22,3 g (75 mMol) (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-tetrahydrofuran-hemisolvat suspenderes i en blanding av 20 ml vann og 60 ml absolutt etanol ved 5-10°C og oppløses ved langsom tilsats av en opp-løsning av 5 ml (77 mMol) metansulfonsyre i 10 ml vann. Den lett uklare oppløsningen filtreres. Filtratet blandes med 150 ml absolutt etanol og omrøres ved 0-5°C, hvorved krystalli-sasjonen inntrer, denne fullføres ved flere timers omrøring ved -25°C. Produktet frafiltreres, vaskes med kald absolutt etanol og tørkes i høyvakuum; voluminøst, hvitt krystallisat, smeltepunkt 129-131°C (under dekomponering). 22.3 g (75 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate is suspended in a mixture of 20 ml water and 60 ml absolute ethanol at 5-10°C and dissolved by slow addition of a solution of 5 ml (77 mmol) methanesulfonic acid in 10 ml water. The slightly cloudy solution is filtered. The filtrate is mixed with 150 ml of absolute ethanol and stirred at 0-5°C, whereby crystallization occurs, this is completed by stirring for several hours at -25°C. The product is filtered off, washed with cold absolute ethanol and dried in high vacuum; voluminous, white crystal, melting point 129-131°C (during decomposition).
C9<H>12<N>2°4<S>" CH4°3S (molekylvekt: 340,4) C9<H>12<N>2°4<S>" CH4°3S (molecular weight: 340.4)
De 32 sterkeste linjene i røntgenpulverdiagrammet med d-verdier over 3,0 Ångstrøm tilsvarer følgende nettplanavstander og relative intensiteter: The 32 strongest lines in the X-ray powder diagram with d-values above 3.0 Angstroms correspond to the following grid plane distances and relative intensities:
Eksempel 3: ( 5R, 6S)- 2- aminometyl- 6-[( IR)- 1- hydroksyetyl]- 2-penem- 3- karboksylsyre- monohydrat ( fremstilling Example 3: (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate (preparation
via sulfonatet) via the sulfonate)
a. Fra monohydrat- tetrahydrofuran- hemisolvate t ( i vandig etanol) a. From monohydrate tetrahydrofuran hemisolvate (in aqueous ethanol)
En suspensjon av 29,8 g (100 mMol) (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-tetrahydrofuran-hemisolvat i 60 ml vann oppløses ved 10°C ved langsom tilsats av 32 ml vandig (3M) metansulfonsyre (96 mMol). Oppløsningen omrøres i 15 minutter med 3 g aktivt kull og filtreres. Filtratet (innbefattet 20 ml vaskeoppløsning) fortynnes ved 5-10°C med 120 ml absolutt etanol, blandes deretter med en oppløsning av 3,47 ml (25 mMol) trietylamin i 60 ml absolutt etanol, podes eventuelt og omrøres i 30 minutter, hvorved det dannes.en suspensjon. Deretter tilsettes dråpevis ved den samme temperaturen, i løpet av 90 minutter, en oppløs-ning av 9,3 ml (66 mMol) trietylamin i 158 ml etanol. Suspensjonen avkjøles til -25°C, omrøres i 2 timer og filtreres deretter, vaskes med kald etanol (96%) og tørkes i høyvakuum ved 30°C. Forbindelsen i overskriften oppstår som fargeløs og grov krystallinsk. Smeltepunkt 133°C (dekomponering). A suspension of 29.8 g (100 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate in 60 ml of water dissolve at 10°C by slow addition of 32 ml of aqueous (3M) methanesulfonic acid (96 mmol). The solution is stirred for 15 minutes with 3 g of activated charcoal and filtered. The filtrate (including 20 ml washing solution) is diluted at 5-10°C with 120 ml absolute ethanol, then mixed with a solution of 3.47 ml (25 mmol) triethylamine in 60 ml absolute ethanol, inoculated if necessary and stirred for 30 minutes, whereby it is formed.a suspension. A solution of 9.3 ml (66 mmol) of triethylamine in 158 ml of ethanol is then added dropwise at the same temperature over the course of 90 minutes. The suspension is cooled to -25°C, stirred for 2 hours and then filtered, washed with cold ethanol (96%) and dried in high vacuum at 30°C. The title compound occurs as colorless and coarsely crystalline. Melting point 133°C (decomposition).
DC (H20, OPTI-UP C12), Rf = 0,48. DC (H2O, OPTI-UP C12), Rf = 0.48.
<C>9<H>12N2°4S'H2° (Molekylvekt: 262,3) <C>9<H>12N2°4S'H2° (Molecular weight: 262.3)
De 23 sterkeste linjene i røntgenpulverdiagrammet med d-verdier over 2,8 Ångstrøm tilsvarer følgende nettplanavstander og relative intensiteter: The 23 strongest lines in the X-ray powder diagram with d-values above 2.8 Angstroms correspond to the following grid plane distances and relative intensities:
b. Fra monohydrat- tetrahydrofuran- hemisolvatet ( i vandig isopropanol ) b. From the monohydrate tetrahydrofuran hemisolvate (in aqueous isopropanol)
En suspensjon av 29,8 g (100 mMol) (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydrat-tetrahydrofuran-hemisolvat i 60 ml vann oppløses ved 10°C ved langsom tilsats av 32 ml vandig (3M) metansulfonsyre (96 mMol). Oppløs-ningen omrøres i 15 minutter med 3 g aktiv kull og filtreres. Filtratet (inkludert 20 ml spyleoppløsning) fortynnes ved 5-10°C med 120 ml isopropanol, blandes deretter med en oppløsning av 1,5 ml (25 mMol) etanolamin i 60 ml isopropanol, podes eventuelt og omrøres i 30 minutter, hvorved det dannes en suspensjon. Deretter tilsettes det dråpevis, ved den samme temperaturen, A suspension of 29.8 g (100 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate in 60 ml of water dissolve at 10°C by slow addition of 32 ml of aqueous (3M) methanesulfonic acid (96 mmol). The solution is stirred for 15 minutes with 3 g of activated charcoal and filtered. The filtrate (including 20 ml flushing solution) is diluted at 5-10°C with 120 ml isopropanol, then mixed with a solution of 1.5 ml (25 mmol) ethanolamine in 60 ml isopropanol, inoculated if necessary and stirred for 30 minutes, thereby forming a suspension. It is then added dropwise, at the same temperature,
i løpet av 90 minutter en oppløsning av 4,0 ml etanolamin (66 mMol) i 160 ml isopropanol. Suspensjonen avkjøles til -25°C, omrøres i 2 timer og filtreres. Monohydratet vaskes med litt kald isopropanol som inneholder 5% vann og tørkes under vakuum ved 30°c. Produktet oppstår i fargeløs, grov krystallinsk form. Smeltepunkt 129°C (dekomponering). DC (H20, OPTI-UP C12), Rf = 0,48. during 90 minutes a solution of 4.0 ml of ethanolamine (66 mmol) in 160 ml of isopropanol. The suspension is cooled to -25°C, stirred for 2 hours and filtered. The monohydrate is washed with a little cold isopropanol containing 5% water and dried under vacuum at 30°c. The product occurs in colorless, coarse crystalline form. Melting point 129°C (decomposition). DC (H2O, OPTI-UP C12), Rf = 0.48.
C9H12<N>2°4<S>" H2° (Molekylvekt: 262,3) C9H12<N>2°4<S>" H2° (Molecular weight: 262.3)
Røntgenpulverdiagrammet for produktet er identisk med det i eksempel 3a angitte røntegenpulverdiagrammet. The X-ray powder diagram for the product is identical to the X-ray powder diagram given in example 3a.
c. Fra metansulfonatet c. From the methanesulfonate
17,1 g (50 mMol) ( 5R, 6S)-2-aminometyl-6- [(lR-l-hydroksyetyl] - 2-penem-3-karboksylsyre-metansulfonat oppløses i en blanding av 40 ml vann og 20 ml absolutt etanol ved 10°C. For oppløsning tilsettes under omrøring straks 30 ml 0,4 M trietylaminoppløs-ning i absolutt etanol ved 5-10°C. Etter poding omrøres det videre ved 5-10°C i 30 minutter, hvorved det dannes en krystall-suspensjon. Deretter tilsettes det dråpevis i løpet av 90 minutter ytterligere ca. 95 ml 0,4 M trietylaminoppløsning i absolutt etanol inntil pH 5 er nådd. Suspensjonen avkjøles til -25°C og omrøres i 2-4 timer ved denne temperaturen. Det krystallinske produktet filtreres, vaskes med kald etanol (96%) og tørkes i høyvakuum. DC: (vann, OPTI-UP C12), Rf = 0,48. Smeltepunktet, krystallformen og røntgenpulverdiagrammet for produktet er identisk med de tilsvarende dataene for produktet beskrevet i eksempel 3a). 17.1 g (50 mmol) (5R, 6S)-2-aminomethyl-6-[(1R-1-hydroxyethyl]-2-penem-3-carboxylic acid methanesulfonate is dissolved in a mixture of 40 ml of water and 20 ml of absolute ethanol at 10° C. For dissolution, 30 ml of 0.4 M triethylamine solution in absolute ethanol is immediately added while stirring at 5-10° C. After inoculation, it is stirred further at 5-10° C for 30 minutes, whereby a crystal suspension. Then, over 90 minutes, a further approx. 95 ml of 0.4 M triethylamine solution in absolute ethanol is added dropwise until pH 5 is reached. The suspension is cooled to -25°C and stirred for 2-4 hours at this temperature. The crystalline product is filtered, washed with cold ethanol (96%) and dried under high vacuum. DC: (water, OPTI-UP C12), Rf = 0.48. The melting point, crystal form and X-ray powder diagram of the product are identical to the corresponding data for the product described in example 3a).
Eksempel 4: ( 5R, 6S)- 2- aminomety1- 6-[( IR)- 1- hydroksyetyl ]- 2-penem- 3- karboksylsyre- monohydrat ( direkte fremstilling fra monohydrat- THF- hemisolvat) Example 4: (5R, 6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate (direct preparation from monohydrate THF hemisolvate)
29,8 g (100 mMol) (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl ] -2-penem-3-karboksylsyre-monohydrat-tetrahydrofuran-hemisolvat oppløses ved 45-50°C i 250 ml vann. Den varme oppløsningen omrøres i 10 minutter med 3 g aktiv kull og filtreres deretter. Det samlede filtratet (inkludert 25 ml spylevann) blandes raskt ved 45-50°c med 1200 ml varm absolutt etanol. Den innlednings-vis fremdeles klare oppløsningen podes og avkjøles i løpet av 2 timer jevnt til -25°C. Krystallsuspensjonen omrøres i ytterligere 2 timer ved -25°C og filtreres deretter. Produktet vaskes med litt kald etanol (96%) og tørkes ved 30°C under vakuum. Det oppnås et voluminøst, fargeløst krystallisat. Smeltepunkt 132°C (under dekomponering). DC (H20, OPTI-UP C12), Rf = 0,48. 29.8 g (100 mmol) (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate tetrahydrofuran hemisolvate is dissolved at 45-50°C in 250 ml of water. The hot solution is stirred for 10 minutes with 3 g of activated carbon and then filtered. The combined filtrate (including 25 ml of rinse water) is quickly mixed at 45-50°C with 1200 ml of hot absolute ethanol. The initially still clear solution is inoculated and cooled evenly to -25°C over the course of 2 hours. The crystal suspension is stirred for a further 2 hours at -25°C and then filtered. The product is washed with a little cold ethanol (96%) and dried at 30°C under vacuum. A voluminous, colorless crystal is obtained. Melting point 132°C (during decomposition). DC (H2O, OPTI-UP C12), Rf = 0.48.
C9H12N2°4<S>"<H>2° (Molekylvekt: 262,3) C9H12N2°4<S>"<H>2° (Molecular weight: 262.3)
Røntgenpulverdiagrammet for produktet er identisk med det i eksempel 3a angitte røntgenpulverdiagrammet. The X-ray powder diagram for the product is identical to the X-ray powder diagram given in example 3a.
Eksempel 5: Bestemmelse av den termiske stabiliteten og Example 5: Determination of the thermal stability and
va nnopptaket fra luft water absorption from air
For bestemmelse av den termiske stabiliteten og vannopptaket fra luft anvendes prøver av det krystallinske (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyre-monohydratet (forbindelse 1) og den fra det tyske utlegningsskrift nr. 3431980 tidligere kjente amorfe (5R,6S)-2-aminometyl-6-[(IR)-1-hydroksyetyl]-2-penem-3-karboksylsyren (forbindelse 2). To determine the thermal stability and water absorption from air, samples of the crystalline (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid monohydrate (compound 1) are used and the previously known amorphous (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid (compound 2) from the German Explanatory Document No. 3431980.
For bestemmelse av den termiske lagringsstabiliteten oppvarmes forsøksforbindelsene i lukkede glassrør, i et termostatregulert oljebad, til 50°C og holdes i 14 dager ved denne temperaturen. Etter 1, 3, 7 og 14 dager tas prøver som undersøkes ved hjelp av væskekromatografi (LC) vedrørende innholdet av ikke-dekompo-nert penem. På de enkelte prøvene måles også ekstinksjonen ved 425 nm (c = 5,0; vann). To determine the thermal storage stability, the test compounds are heated in closed glass tubes, in a thermostatically controlled oil bath, to 50°C and kept for 14 days at this temperature. After 1, 3, 7 and 14 days, samples are taken which are examined using liquid chromatography (LC) regarding the content of non-decomposed penem. The extinction at 425 nm (c = 5.0; water) is also measured on the individual samples.
Videre bestemmes lagringsstabiliteten for forsøksforbindelsene ved 35°C og 95% relativ luftfuktighet i 7 dager. For under-søkelsen anvendes igjen innholdsbestemmelser ved hjelp av væskekromatografi (LC) og ekstinksjonsmålinger ved 425 nm. Videre bestemmes vannopptaket for forsøksforbindelsene i løpet av 7 dager. Vannbestemmelsen foregår ved den kjente fremgangsmåten etter Karl Fischer. Furthermore, the storage stability of the test compounds is determined at 35°C and 95% relative humidity for 7 days. For the investigation, content determinations using liquid chromatography (LC) and extinction measurements at 425 nm are again used. Furthermore, the water absorption of the test compounds is determined during 7 days. The determination of water takes place by the well-known method according to Karl Fischer.
Resultatene er sammenfattet i de følgende tabellene: The results are summarized in the following tables:
a. Stabilitet ved 50°C ( lukkede glassrør) b. Stabilitet ved 35°C og 95% relativ luftfuktighet a. Stability at 50°C (closed glass tubes) b. Stability at 35°C and 95% relative humidity
Disse eksemplene viser at det krystallinske hydratet ifølge oppfinnelsen oppviser en betydelig høyere stabilitet ved varme-og fuktighetsinnvirkning enn det tidligere kjente amorfe produktet. These examples show that the crystalline hydrate according to the invention exhibits a significantly higher stability when exposed to heat and moisture than the previously known amorphous product.
Eksempel 6 : Example 6:
Tørrampuller eller flasker, inneholdende krystallinsk (5R,6S)-2-aminometyl-6- [ (IR) -1-hydrok/syetyl ] -2-penem-3-karboksylsyre-monohydrat som virksomt stoff, fremstilles på følgende måte: Dry ampoules or bottles, containing crystalline (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxy/cyethyl]-2-penem-3-carboxylic acid monohydrate as active substance, are prepared as follows:
Sammensetning (for 1 ampulle/ eller flaske): Composition (for 1 ampoule/ or bottle):
Det virksomme stoffet og manniten utveies under aseptiske betingelser, fylles i 10 ml ampuller eller 10 ml flasker, og "ne hhv-fiaskene ikes09un~s- The active substance and mannitol are weighed out under aseptic conditions, filled into 10 ml ampoules or 10 ml bottles, and "ne hhv fiaskene ikes09un~s-
Claims (18)
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| CH174786 | 1986-04-29 |
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| EP (1) | EP0243921A3 (en) |
| JP (1) | JPS62258384A (en) |
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| DK (1) | DK216187A (en) |
| FI (1) | FI871835A (en) |
| HU (1) | HU196808B (en) |
| IL (1) | IL82338A0 (en) |
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| US4761408A (en) * | 1984-11-02 | 1988-08-02 | Ciba-Geigy Corporation | Crystalline aminomethyl compound |
-
1987
- 1987-04-27 JP JP62102123A patent/JPS62258384A/en active Pending
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| HUT43852A (en) | 1987-12-28 |
| DD268946A5 (en) | 1989-06-14 |
| AU7212687A (en) | 1987-11-05 |
| NO871763D0 (en) | 1987-04-28 |
| FI871835A (en) | 1987-10-30 |
| IL82338A0 (en) | 1987-10-30 |
| ZA873010B (en) | 1987-12-30 |
| EP0243921A3 (en) | 1987-12-16 |
| NZ220122A (en) | 1989-01-06 |
| JPS62258384A (en) | 1987-11-10 |
| FI871835A0 (en) | 1987-04-27 |
| DK216187D0 (en) | 1987-04-28 |
| PT84767A (en) | 1987-05-01 |
| KR870010059A (en) | 1987-11-30 |
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