NO144153B - PROCEDURE FOR PREPARATION OF DELTA3-7-ACYLAMIDO-3-METHYL-CEFEM-4-CARBOXYLIC ACIDS - Google Patents
PROCEDURE FOR PREPARATION OF DELTA3-7-ACYLAMIDO-3-METHYL-CEFEM-4-CARBOXYLIC ACIDS Download PDFInfo
- Publication number
- NO144153B NO144153B NO2942/72A NO294272A NO144153B NO 144153 B NO144153 B NO 144153B NO 2942/72 A NO2942/72 A NO 2942/72A NO 294272 A NO294272 A NO 294272A NO 144153 B NO144153 B NO 144153B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- mmol
- trimethylsilyl
- sulfoxide
- yield
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000002253 acid Substances 0.000 claims description 69
- -1 phenylacetamido- Chemical class 0.000 claims description 62
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 49
- 150000003462 sulfoxides Chemical class 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 33
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000008707 rearrangement Effects 0.000 claims description 5
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 4
- FVVXWRGARUACNW-UHFFFAOYSA-N 3-methylisoquinoline Chemical compound C1=CC=C2C=NC(C)=CC2=C1 FVVXWRGARUACNW-UHFFFAOYSA-N 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- QHUOBLDKFGCVCG-UHFFFAOYSA-N n-methyl-n-trimethylsilylacetamide Chemical compound CC(=O)N(C)[Si](C)(C)C QHUOBLDKFGCVCG-UHFFFAOYSA-N 0.000 claims description 3
- OIALIKXMLIAOSN-UHFFFAOYSA-N 2-Propylpyridine Chemical compound CCCC1=CC=CC=N1 OIALIKXMLIAOSN-UHFFFAOYSA-N 0.000 claims description 2
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 claims description 2
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 claims description 2
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims 1
- DBOLXXRVIFGDTI-UHFFFAOYSA-N 4-benzylpyridine Chemical compound C=1C=NC=CC=1CC1=CC=CC=C1 DBOLXXRVIFGDTI-UHFFFAOYSA-N 0.000 claims 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004437 phosphorous atom Chemical group 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims 1
- 229910052721 tungsten Inorganic materials 0.000 claims 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical group [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 74
- 229940056360 penicillin g Drugs 0.000 description 65
- 235000019371 penicillin G benzathine Nutrition 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 45
- 239000000243 solution Substances 0.000 description 44
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 38
- 238000012360 testing method Methods 0.000 description 38
- 238000011065 in-situ storage Methods 0.000 description 34
- 230000002906 microbiologic effect Effects 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 20
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 17
- 238000006049 ring expansion reaction Methods 0.000 description 17
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 13
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- BKFNEOXRGFXAML-UHFFFAOYSA-N 2-methylpyridin-1-ium;bromide Chemical compound Br.CC1=CC=CC=N1 BKFNEOXRGFXAML-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 description 11
- 150000008064 anhydrides Chemical class 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 150000003961 organosilicon compounds Chemical class 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 8
- 229910000160 potassium phosphate Inorganic materials 0.000 description 8
- 235000011009 potassium phosphates Nutrition 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 7
- DNPOVSLJNLLGMA-SJUANORRSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenoxyacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical class N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)COC1=CC=CC=C1 DNPOVSLJNLLGMA-SJUANORRSA-N 0.000 description 6
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical class N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- OMSBSIXAZZRIRW-UHFFFAOYSA-N 2-methylpyridine;hydrochloride Chemical compound Cl.CC1=CC=CC=N1 OMSBSIXAZZRIRW-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000012009 microbiological test Methods 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- XRVPSMBZQKYMGA-WDOBJEIGSA-N (6r,7r)-3-(acetyloxymethyl)-7-[(2-acetyloxy-2-phenylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)C(OC(C)=O)C1=CC=CC=C1 XRVPSMBZQKYMGA-WDOBJEIGSA-N 0.000 description 4
- HYBDSXBLGCQKRE-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)ethanone Chemical compound CC(=O)C1=C(Cl)C=CC=C1Cl HYBDSXBLGCQKRE-UHFFFAOYSA-N 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 208000010668 atopic eczema Diseases 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229930195708 Penicillin V Natural products 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 229940056367 penicillin v Drugs 0.000 description 3
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 3
- 238000006884 silylation reaction Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 description 2
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DXVYLFHTJZWTRF-UHFFFAOYSA-N Ethyl isobutyl ketone Chemical compound CCC(=O)CC(C)C DXVYLFHTJZWTRF-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- QMSVNDSDEZTYAS-UHFFFAOYSA-N 1-bromo-1-chloroethane Chemical compound CC(Cl)Br QMSVNDSDEZTYAS-UHFFFAOYSA-N 0.000 description 1
- KIAMPLQEZAMORJ-UHFFFAOYSA-N 1-ethoxy-2-[2-(2-ethoxyethoxy)ethoxy]ethane Chemical compound CCOCCOCCOCCOCC KIAMPLQEZAMORJ-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- HYDWALOBQJFOMS-UHFFFAOYSA-N 3,6,9,12,15-pentaoxaheptadecane Chemical compound CCOCCOCCOCCOCCOCC HYDWALOBQJFOMS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- 241001233242 Lontra Species 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- TVJPBVNWVPUZBM-UHFFFAOYSA-N [diacetyloxy(methyl)silyl] acetate Chemical compound CC(=O)O[Si](C)(OC(C)=O)OC(C)=O TVJPBVNWVPUZBM-UHFFFAOYSA-N 0.000 description 1
- VLFKGWCMFMCFRM-UHFFFAOYSA-N [diacetyloxy(phenyl)silyl] acetate Chemical compound CC(=O)O[Si](OC(C)=O)(OC(C)=O)C1=CC=CC=C1 VLFKGWCMFMCFRM-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- UCKORWKZRPKRQE-UHFFFAOYSA-N bromo(triethyl)silane Chemical compound CC[Si](Br)(CC)CC UCKORWKZRPKRQE-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000004426 flaxseed Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- KSEMETYAQIUBQB-UHFFFAOYSA-N n,n-diethylmethanesulfonamide Chemical compound CCN(CC)S(C)(=O)=O KSEMETYAQIUBQB-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical class [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003860 tertiary carboxamides Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- DENFJSAFJTVPJR-UHFFFAOYSA-N triethoxy(ethyl)silane Chemical compound CCO[Si](CC)(OCC)OCC DENFJSAFJTVPJR-UHFFFAOYSA-N 0.000 description 1
- JCVQKRGIASEUKR-UHFFFAOYSA-N triethoxy(phenyl)silane Chemical compound CCO[Si](OCC)(OCC)C1=CC=CC=C1 JCVQKRGIASEUKR-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
- C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
-
- 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
Description
Foreliggende oppfinnelse angår en fremgangsmåte The present invention relates to a method
for fremstilling av A^7-acylamido-3-métyl-cefem-4-karpoks,ylsyrer ved omleiring av de tilsvarende 6-acylamidopenicillansyre- for the production of Δ7-acylamido-3-methyl-cephem-4-carboxylic acids by rearrangement of the corresponding 6-acylamidopenicillanic acids
sulfoksyder hvis karboksylgruppe er beskyttet, ved forhøyd temperatur og under sure betingelser, med derpå følgende avspaltning av karboksylbeskyttelsesgruppen. sulfoxides whose carboxyl group is protected, at elevated temperature and under acidic conditions, with subsequent cleavage of the carboxyl protecting group.
Fra CA 817883 er det kjent at man kan forbedre From CA 817883 it is known that one can improve
den av R.B. Morin et al. ibeskrevne omleiring av penicillin- that of R.B. Morin et al. undescribed rearrangement of penicillin-
sulfoksyder til desacetoksyeefalosporiner (se U.S. patent nr. 3275626) ved at man omleirer esteren i nærvær av 5% eddiksyréanhydrid i dimetylformamid: sammenlign også E.H. sulfoxides to desacetoxycephalosporins (see U.S. Patent No. 3,275,626) by rearranging the ester in the presence of 5% acetic anhydride in dimethylformamide: compare also E.H.
Flynn, "Cephalosporins and Penicillins", 1972, side 185. Flynn, "Cephalosporins and Penicillins", 1972, page 185.
I DE-OS 2006689 er det beskrevet en ytterligere DE-OS 2006689 describes a further one
forbedring av fremgangsmåten for fremstilling av desacetoksycefalosporansyreestere ved oppvarming av penicillin-sulfoksydestere, spesielt penicillin-V-sulfoksydestere, i et tertiært karboksamid, fortrinnsvis dimetylacetamid, improvement of the process for the preparation of desacetoxycephalosporanic acid esters by heating penicillin sulfoxide esters, especially penicillin V sulfoxide esters, in a tertiary carboxamide, preferably dimethylacetamide,
dimetylformamid eller N-metyl-2-pyrrolidon, i nærvær av en sulfonsyre samt et vannbindende middel. Med penicillin-V-sulfoksydmetylesteren som eksempel forløper reaksjonen dimethylformamide or N-methyl-2-pyrrolidone, in the presence of a sulphonic acid and a water binding agent. With the penicillin V-sulfoxide methyl ester as an example, the reaction proceeds
skjematisk som følger: schematically as follows:
Ytterligere fremgangsmåter for fremstilling Additional methods of manufacture
av desacetoksycefalosporansyreestere ved omleiring av de tilsvarende 6-acylamidopenicillansyresulfoksydestere er beskrevet i DE-OS 2011351 og 2011376. For fremstill- of desacetoxycephalosporanic acid esters by rearrangement of the corresponding 6-acylamidopenicillanic acid sulfoxide esters is described in DE-OS 2011351 and 2011376. For producing
ing av de frie syrer eller disses salter må estergruppen spaltes av i et ytterligere trinn. Dette fører nødven- ing of the free acids or their salts, the ester group must be split off in a further step. This necessarily leads to
digvis til tap av utbytte. sometimes to a loss of profit.
Ved anvendelse av den av eddiksyréanhydrid eller When using that of acetic anhydride or
-syre katalyserte omleiring på penicillin-V-sulfoksyd fant Morin et al., "J. Am Chem. Soc", bind 91 (1969), side 1401, det dekårboksylerte fenoksyacetamidocefalosporin som hoved-produkt : Foreliggende oppfinnelse har til oppgave ut fra 6-acylamidopenicillansyresulfoksyder i fri syreform med formel umiddelbart å fremstille de tilsvarende desacetoksycefalospo-ransyrer med formel -acid catalyzed rearrangement of penicillin-V-sulfoxide found Morin et al., "J. Am Chem. Soc", volume 91 (1969), page 1401, the decarboxylated phenoxyacetamidosporin as the main product: The present invention has the task of 6-acylamidopenicillanic acid sulfoxides in free acid form with formula immediately to prepare the corresponding desacetoxycephalosporan acids with formula
der -NR.^2 nar den i ingressen til krav 1 angitte betydning, som sådanne eller i form av alkalimetall- eller aminsalter derav, ved en "enkolbe" metode som på enkel måte kan gjennom-føres og som forløper med gode utbytter. Denne oppgave løses ved foreliggende oppfinnelse. Fremgangsmåten ifølge oppfinnelsen fremgår av kravets karakteriserende del. where -NR.^2 has the meaning given in the preamble to claim 1, as such or in the form of alkali metal or amine salts thereof, by a "one-flask" method which can be carried out in a simple way and which proceeds with good yields. This task is solved by the present invention. The method according to the invention appears from the characterizing part of the claim.
Nedenfor sammenlignes ved hjelp av en tabell fremgangsmåten i henhold til den kjente teknikk og fremgangsmåten ifølge foreliggende oppfinnelse. Below, a table compares the method according to the known technique and the method according to the present invention.
Bemerkninger: Remarks:
Al: Dette reaksjonstrinn er i DE-OS 2011351 og 2011376 kun beskrevet i generell form. Foretrukket er i disse DE-OS 2,2,2-trikloretylester. Derfor ble som kjent teknikk BE-PS 71^748 nevnt, der fremstillingen av 2,2,2-trikloretyl-esteren av penicillin G er beskrevet med et utbytte på 65$. Ved denne kjente fremgangsmåte har man altså Al: This reaction step is in DE-OS 2011351 and 2011376 only described in general form. Preferred in these DE-OS is 2,2,2-trichloroethyl ester. Therefore, as prior art, BE-PS 71^748 was mentioned, in which the preparation of the 2,2,2-trichloroethyl ester of penicillin G is described with a yield of 65$. With this known method, one thus has
allerede før ringutvidelsen et tap på 35$, beregnet på even before the ring expansion a loss of 35$, calculated on
utgangsmaterialet. the starting material.
A2: Fremstillingen av sulfoksydet forløper ikke i 100 55-ig utbytte. Derfor er denne verdi satt i parentes. Dette ' trinn har dog ingen innflytelse på sammenligningen mellom de to fremgangsmåter, da det samme trinn i fremgangsmåten ifølge oppfinnelsen gjennomføres under tilsvarende betingelser, og det ikke kunne fastslås vesent-lige forskjeller. A2: The production of the sulfoxide does not proceed in 100 55-ig yield. Therefore, this value is set in parentheses. However, this step has no influence on the comparison between the two methods, as the same step in the method according to the invention is carried out under similar conditions, and no significant differences could be determined.
A3: Trinnet med omdanning av penSO-esteren til cefesteren ble angitt med et utbytte på 80%. Denne verdi er. basert på det utbytte av urent sluttprodukt som ble oppnådd umiddelbart fra reaksjonsblandingen. Man skal påpeke dette da utbyttene i eksempel 6 i DE-OS 2011351 og eksempel 68 i DE-OS 2011376 er eksepsjonelt høye og dermed ikke uttrykk for en generell regel. I DE-OS 2011351 beskriver 17 av 21 eksempler og i DE-OS 2011376 66 av 73 eksempler omsetting med 2,2,2-tri-kloretylestere. I DE-OS 2011351 er det i 4 av de 17 eksempler og i DE-OS 2011376 i 5 av 66 eksempler angitt ukorrigerte utbytter på over 805?. Herved skal man passe på at det av og til er to fraksjoner som bidrar til utbytteverdien. Da det kun i 9 eksempler av til sammen 83 (17+66) er angitt et utbytte på A3: The step of conversion of the penSO ester to the cepester was indicated in 80% yield. This value is based on the yield of impure final product obtained immediately from the reaction mixture. This should be pointed out as the yields in example 6 in DE-OS 2011351 and example 68 in DE-OS 2011376 are exceptionally high and thus not an expression of a general rule. In DE-OS 2011351 17 out of 21 examples and in DE-OS 2011376 66 out of 73 examples describe reaction with 2,2,2-trichloroethyl esters. In DE-OS 2011351, in 4 of the 17 examples and in DE-OS 2011376 in 5 of 66 examples, uncorrected yields of over 805? Hereby, care must be taken that there are occasionally two fractions that contribute to the dividend value. Since in only 9 examples out of a total of 83 (17+66) is a dividend of
over 8052, synes det rettferdiggjort å fastsette den nedre verdi for utbyttene i de kjente fremgangsmåter above 8052, it seems justified to determine the lower value for the yields in the known methods
til 8052. to 8052.
A4: De utbytter som er angitt i de nevnte DE-OS må korri-geres. Av praktiske grunner synes det rettferdiggjort å innføre en renhetskorreksjonsfaktor på 0,90 A4: The dividends stated in the aforementioned DE-OS must be corrected. For practical reasons, it seems justified to introduce a purity correction factor of 0.90
med hvilken man må multiplisere de angitte utbytter. with which one must multiply the specified dividends.
A5: Dette trinn- er i de anførte DE-OS kun beskrevet i generell form. Det er ikke kjent noen litteratur der dette trinn spesielt er beskrevet. Litteraturen som foreligger hva angår dette trinn, gir grunn til å anta at karboksylbeskyttelsesgruppen vanligvis forblir uangrepet inntil de etterfølgende reaksjoner, nemlig avspaltingen av sidekjeden, er gjennomført. Erfaringsmessig synes et utbytte på 81% ved avspalting av trikloretylestergruppen ytterst usannsynlig. Det er mer realistisk å sette denne verdi til ca. 70%. A5: In the listed DE-OS, this step is only described in general form. No literature is known in which this step is specifically described. The literature available regarding this step gives reason to assume that the carboxyl protecting group usually remains unattacked until the subsequent reactions, namely the cleavage of the side chain, are completed. In terms of experience, a yield of 81% when splitting off the trichloroethyl ester group seems extremely unlikely. It is more realistic to set this value to approx. 70%.
Fra de i de kjente fremgangsmåter angitte utbytter for de enkelte trinn oppnår man et totalutbytte på From the yields specified in the known methods for the individual steps, a total yield of
37, H% rent sluttprodukt. 37, H% pure end product.
Bl: Her gjelder de samme betraktninger som anført ovenfor Bl: The same considerations apply here as stated above
for A2. for A2.
B2: Ved dette trinnet dreier det seg om fshemgangsmåten B2: At this step, it is about the procedure
ifølge oppfinnelsen. Utbyttet er:beregnet på den rene forbindelse. Utbyttet ble bestemt mikrobiologisk. • Utbytteverdien på 39,^% ble beregnet ut fra reaksjons-skj emaet. according to the invention. The yield is: calculated on the pure compound. The yield was determined microbiologically. • The dividend value of 39.^% was calculated based on the reaction scheme.
B3: Isoleringen er beskrevet spesielt i eksempel 1. Det mikrobiologisk bestemte utbytte utgjør 83??, mens utbyttet av effektivt isolert forbindelse utgjør 78%. B3: The isolation is described in particular in example 1. The microbiologically determined yield amounts to 83??, while the yield of effectively isolated compound amounts to 78%.
Ved isoleringen opptrer et tap av utbytte på høyst In the case of isolation, a loss of yield occurs at most
5%. 5%.
Fra det ovenfor anførte reaksjonsskjema kan From the above-mentioned reaction scheme can
man slutte følgende. one concludes the following.
Hvis fremgangsmåten ifølge oppfinnelsen skulle skje ved et totalutbytte på J>7»^%, ville den være den kjente fremgangsmåte overlegen kun med henblikk på utbytte. Fremgangsmåten medfører dog også et betydelig teknisk fremskritt. If the method according to the invention were to take place with a total yield of J>7%, it would be superior to the known method only with regard to yield. However, the procedure also entails significant technical progress.
Fra DE-OS 2006689 er det kjent at reaksjons-vannet må separeres ved ringutvidelse. Ved fremgangs- From DE-OS 2006689 it is known that the reaction water must be separated by ring expansion. In case of progress
måten ifølge oppfinnelsen er dette spesielt nødvendig in the manner according to the invention, this is particularly necessary
fordi syreanhydridfunksjonen i de forbindelser som anvendes ifølge oppfinnelsen er vannømfindtelige. Anvendelsen av slike funksjonelle grupper har på den annen side spesielle fordeler, idet de etter ferdig reaksjon lett lar seg spalte av. Også dette er kjent f.eks. fra den i AT 279803 beskrevne omsetting. Anvendelsen av spesielle organosilisiumforbindelser av den because the acid anhydride function in the compounds used according to the invention are water sensitive. The use of such functional groups, on the other hand, has particular advantages, as they can easily be split off after the reaction is complete. This is also known, e.g. from the turnover described in AT 279803. The application of special organosilicon compounds of it
i kravet nevnte type for vannseparering under ringutvidelsen, kan dog ikke ansees som nærliggende. Ved ringutvidelse av penicillinsulfoksyder med anhydrid-karboksylbeskyttelses-grupper ble det i omfangsrike forsøk undersøkt et stort antall forbindelser som binder vann, enten kjemisk eller fysikalsk. Eksempler på undersøkte forbindelser er: etoksyacetylen, molekylsikter, in the requirement, the type mentioned for water separation during the ring expansion cannot, however, be regarded as imminent. By ring expansion of penicillin sulfoxides with anhydride-carboxyl protecting groups, a large number of compounds that bind water, either chemically or physically, were investigated in extensive experiments. Examples of investigated compounds are: ethoxyacetylene, molecular sieves,
dicykloheksylkarbodiimid, dicyclohexylcarbodiimide,
fosforpentoksyd, fenyltrietoksysilan, tetraetoksysilan, etyltrietoksysilan, metyltriacetoksysilan, phosphorus pentoxide, phenyltriethoxysilane, tetraethoxysilane, ethyltriethoxysilane, methyltriacetoxysilane,
fenyltriacetoksysilan, phenyltriacetoxysilane,
ortomaursyretrietylester, orthoformic acid triethyl ester,
dimetoksypropan, vinyletyleter, dimethoxypropane, vinyl ethyl ether,
2,3-dihydro-4H-pyran og eddiksyréanhydrid. 2,3-dihydro-4H-pyran and acetic anhydride.
Ikke med noen av forbindelsene skjedde en ringutvidelse. Derav må man slutte at enten er reaksjonsevnen for de anvendte anhydrider overfor vann for høy slik at det vannbindende middel er uvirksomt, eller at det vannbindende middel forstyrrer ringutvidelsen. Ring expansion did not occur with any of the compounds. From this it must be concluded that either the reactivity of the anhydrides used towards water is too high so that the water-binding agent is ineffective, or that the water-binding agent interferes with the ring expansion.
På den annen side er et vanlig silylerings-middel slik som trimetylklorsilan som kommer i betraktning som utvalgt middel for silyleringsfremgangsmåter, uegnet for løsning av oppgaven ifølge oppfinnelsen, i det minste hvis det ikke tas ytterligere forhåndsregler. Heller ikke ved anvendelse av overskuddsmengder av denne forbindelse både til beskyttelse av karboksylgruppen og til separering av vannet, skjer det noen ringutvidelse hvis det ikke tilsettes bestemte baser i stort overskudd til reaksjonsblandingen. Denne utførelsesform er foreslått i DE-OS 2107650. Ringutvidelsen skjer her, dog er utbyttene lavere On the other hand, a common silylation agent such as trimethylchlorosilane which comes into consideration as the agent of choice for silylation processes is unsuitable for solving the task according to the invention, at least if no further precautions are taken. Even when excess amounts of this compound are used both to protect the carboxyl group and to separate the water, no ring expansion occurs if certain bases are not added in large excess to the reaction mixture. This embodiment is proposed in DE-OS 2107650. The ring expansion takes place here, but the yields are lower
enn i foreliggende fremgangsmåte. than in the present method.
To ytterligere sterke fordommer mot anvendelse av andre kjente silyleringsmidler som bis-(trimetylsilyl)-acetamid (BSA) og beslektede forbindelser måtte overvinnes. Two further strong prejudices against the use of other known silylating agents such as bis-(trimethylsilyl)acetamide (BSA) and related compounds had to be overcome.
a) Disse ytterst aktive silyleringsmidler silylerer og des-aktiverer syrer som er egnet som katalysatorer ved de a) These extremely active silylating agents silylate and deactivate acids which are suitable as catalysts in the
kjente fremgangsmåter, f.eks. den som er beskrevet i DE-OS 2011376. Ved omsetting av penicillin G-sulfoksyd known methods, e.g. the one described in DE-OS 2011376. When converting penicillin G-sulfoxide
i dioksan med BSA i overskudd og den vanlige mengde fosforsyremonofenylester (en av de foretrukne katalysatorer) kunne det ikke fastslås spor av benzyldesacetoksy-eefalosporin i reaksjonsblandingen. b) En ytterligere sterk fordom mot anvendelse av BSA og beslektede silyleringsmidler for ringutvidelse av forbindelser som penicillin G-sulfoksyd kan man finne i publikasjoner av G.E. Gutowski i "Tetrahedron Letters", 1970, sidene 1779-1782, og_i tilsvarende U.S. patent nr. 3719667. Era disse publikasjoner fremgår det at penicillinsulfoksyder isomeriseres til 6a-epimeren av silylamider slik som BSA. Ved ringutvidelsen av disse 6a-epimerer oppnås de uønskede epimerer av cefalo-sporinene. Reaksjonstiden for epimeriseringen utgjør ved romtemperatur riktignok 168 timer. Reaksjons-hastigheten tiltar dog med en faktor 2-3 når reaksjonstemperaturen heves 10°C. Således forløper epimeriseringen ved 80°C i løpet av 15-150 minutter. in dioxane with BSA in excess and the usual amount of phosphoric acid monophenyl ester (one of the preferred catalysts), no trace of benzyldesacetoxy-cephalosporin could be determined in the reaction mixture. b) A further strong bias against the use of BSA and related silylating agents for the ring expansion of compounds such as penicillin G sulfoxide can be found in publications by G.E. Gutowski in "Tetrahedron Letters", 1970, pages 1779-1782, and_in corresponding U.S. patent no. 3719667. In these publications it appears that penicillin sulfoxides are isomerized to the 6a-epimer of silylamides such as BSA. By the ring expansion of these 6a-epimers, the unwanted epimers of the cephalosporins are obtained. Admittedly, the reaction time for the epimerization at room temperature is 168 hours. However, the reaction rate increases by a factor of 2-3 when the reaction temperature is raised by 10°C. Thus, the epimerization proceeds at 80°C within 15-150 minutes.
De ovenfor anførte betraktninger viser at de utmerkede resultater som oppnås ved fremgangsmåten for ringutvidelsen ifølge oppfinnelsen "ikke er nærliggende på bakgrunn av den kjente teknikk. The above-mentioned considerations show that the excellent results obtained by the method for the ring expansion according to the invention "are not obvious on the basis of the known technique.
Noen av de syreanhydrider som dannes i trinn a) Some of the acid anhydrides formed in step a)
er nye forbindelser. Hvis ønskelig, kan disse isoleres are new connections. If desired, these can be insulated
fra reaksjonsblandingen før den virkelige ringutvidelses-reaksjonen i trinn b) utføres. Disse nye forbindelser er beskrevet i norsk patentsøknad nr. 22b2-73. from the reaction mixture before the actual ring expansion reaction in step b) is carried out. These new compounds are described in Norwegian patent application no. 22b2-73.
De i trinn b) anvendte organosilisiumforbindelser gir ved reaksjon med vann nøytrale forbindelser som ikke påvirker reaksjonsforløpet og som ikke hindrer isoleringen av A^-7-acylamido-3-nietylcefem-4-karboksylsyre. The organosilicon compounds used in step b) give, by reaction with water, neutral compounds which do not affect the course of the reaction and which do not prevent the isolation of N-7-acylamido-3-niethylcephem-4-carboxylic acid.
Spesielt foretrukne organosilisiumforbindelser Particularly preferred organosilicon compounds
er NjO-bis-(trimetylsilyl)-acetamid og N,N'-bis-(trimetylsilyl)-urinstoff som begge reagerer meget raskt med vann som oppstår under ringutvidelsen og danner heksametyldisiloksan og acetamid eller urinstoff, og således forhindrer avspalting av syreanhydridfunksjonen under ringutvidelsen på grunn av det oppståtte vann. are NjO-bis-(trimethylsilyl)-acetamide and N,N'-bis-(trimethylsilyl)-urea which both react very rapidly with water produced during ring expansion to form hexamethyldisiloxane and acetamide or urea, thus preventing cleavage of the anhydride function during ring expansion due to the resulting water.
Mengden av organosilisiumforbindelse som tilsettes til reaksjonsblandingen i trinn b) må være så stor at alt vann som dannes under omsettingen fjernes fullstendig og slik at alle frie karboksylgrupper i det anvendte 6-acylamidopenicillansyresulfoksyd silyleres. Det er nødven- The amount of organosilicon compound added to the reaction mixture in step b) must be so large that all water formed during the reaction is completely removed and so that all free carboxyl groups in the 6-acylamidopenicillanic acid sulfoxide used are silylated. It is necessary
dig med minst lg molekvivalent av organosilisiumforbindelsen pr. mol 6-acylamidopenicillansyresulfoksyd, nemlig 11 molekvivalent for silylering av karboksylgruppen og resten for å fjerne det dannede vann. Fortrinnsvis anvendes minst 2-4 molekvivalenter av organosilisiumforbindelsen pr. mol 6-acylamidopenicillansyresulfoksyd. with at least lg molar equivalent of the organosilicon compound per moles of 6-acylamidopenicillanic acid sulfoxide, namely 11 mole equivalents for silylation of the carboxyl group and the rest to remove the water formed. Preferably, at least 2-4 molar equivalents of the organosilicon compound are used per moles of 6-acylamidopenicillanic acid sulfoxide.
I trinn b) kan syren settes direkte til reak-sj onsblandingen. Fortrinnsvis overføres syren til et salt ved hjelp av et alifatisk, cykloalifatisk, aromatisk eller heterocyklisk amin, fortrinnsvis heksametylentetramin, In step b), the acid can be added directly to the reaction mixture. Preferably, the acid is transferred to a salt by means of an aliphatic, cycloaliphatic, aromatic or heterocyclic amine, preferably hexamethylenetetramine,
anilin, difenylamin, N-metylanilin, dimetylanilin, pyridin, aniline, diphenylamine, N-methylaniline, dimethylaniline, pyridine,
et substituert pyridin, kinolin, et substituert kinolin, isokinolin eller er substituert isokinolin, pyrazol, imi- a substituted pyridine, quinoline, a substituted quinoline, isoquinoline or is substituted isoquinoline, pyrazole, imi-
dazol eller et substituert imidazol. Som substituenter kommer i betraktning f.eks. lavere alkyl-, aralkyl-, aryl-eller mono- eller di-(lavere)-alkylaminorester. Spesielle eksempler for substituerte pyridiner, kinoliner, isokino- dazole or a substituted imidazole. As substituents come into consideration e.g. lower alkyl, aralkyl, aryl or mono- or di-(lower) alkylamino residues. Special examples for substituted pyridines, quinolines, isoquino-
liner og imidazoler er de forskjellige pikoliner, 2-etylpyridin, 2-propylpyridin, 2,3~dimetylpyridin, 2,5-dimetyl-' pyridin, 2,6-dimetylpyridin, de forskjellige kollidiner, 2-dimetylaminopyridin, 3_metylisokinolin og N-metylimida- lines and imidazoles are the various picolines, 2-ethylpyridine, 2-propylpyridine, 2,3-dimethylpyridine, 2,5-dimethyl-' pyridine, 2,6-dimethylpyridine, the various collidines, 2-dimethylaminopyridine, 3-methylisoquinoline and N-methylimida -
zol. Fortrinnsvis anvendte baser er pyridin, kinolin og imidazol samt derivater derav. Fortrinnsvis anvendes sol. Preferably used bases are pyridine, quinoline and imidazole and derivatives thereof. Preferably used
basen i overskudd beregnet på syren. the base in excess calculated for the acid.
Saltet som dannes fra syren og basen kan dannes in situ i reaksjonsblandingen,-idet det i et vannfritt inert organisk oppløsningsmiddel oppløste 6-acylamidopenicillansyresulfoksyd først omsettes med et halogenid med den generelle formel R -hal, der R har den i krav 1 angitte betydning. Det derved dannede halogenhydrogen bindes deretter av basen. Dette er fordelaktig fordi syreanh<y>driddannelsen derved forløper lettere og fordi penicillinsulfoksydringen er The salt formed from the acid and the base can be formed in situ in the reaction mixture, where the 6-acylamidopenicillanic acid sulfoxide dissolved in an anhydrous inert organic solvent is first reacted with a halide of the general formula R -hal, where R has the meaning stated in claim 1. The resulting halogen hydrogen is then bound by the base. This is advantageous because the acid anhydride formation thereby proceeds more easily and because the penicillin sulfoxide ring is
•meget ømfindtelig overfor frie sterke syrer. •very sensitive to free strong acids.
Det i trinn a) dannede halogenhydrogen The halogen hydrogen formed in step a).
kan utgjøre syren som er nødvendig for ringutvidelsen av penicillinsulfoksydet eller kan supplere denne. Foretrukne molforhold for de i reaksjonsblandingen foreliggende forbindelser er pr. mol 6-acylaminopenicillansyresulfoksyd 1-4 mol syre, 1/4-4 ekvivalenter, og fortrinnsvis 1/3-1 ekvivalent R -hal og minst 2 ekvivalenter, og fortrinnsvis 3~7 ekvivalenter organosilisiumforbindelse; når syren anvendes sammen med basen, 1/10-10 mol, og fortrinnsvis 1/4-4 mol syre-basekompleks, 1/4-2 ekvivalenter, og fortrinnsvis 1/3-1 ekvivalent R -hal, minst 2 ekvivalenter, can constitute the acid necessary for the ring expansion of the penicillin sulfoxide or can supplement this. Preferred molar ratios for the compounds present in the reaction mixture are per mol of 6-acylaminopenicillanic acid sulfoxide 1-4 mol of acid, 1/4-4 equivalents, and preferably 1/3-1 equivalent of R -hal and at least 2 equivalents, and preferably 3-7 equivalents of organosilicon compound; when the acid is used together with the base, 1/10-10 mol, and preferably 1/4-4 mol acid-base complex, 1/4-2 equivalents, and preferably 1/3-1 equivalent R -hal, at least 2 equivalents,
og fortrinnsvis 3-7 ekvivalenter organosilisiumforbindelse, og fortrinnsvis en ytterligere mengde av basen;selv, and preferably 3-7 equivalents of organosilicon compound, and preferably a further amount of the base; itself,
f.eks. 1-10 mol, hvorved fortrinnsvis mengden av ytterligere base tiltar i direkte forhold til den anvendte mengde syre-basekompleks. Med uttrykket "en ekvivalent" menes det antall mol R -hal eller organosilisiumforbind- e.g. 1-10 mol, whereby preferably the amount of additional base increases in direct proportion to the amount of acid-base complex used. By the expression "one equivalent" is meant the number of moles of R -hal or organosilicon compound
else som teoretisk er nødvendig for omsetting med 1 mol 6-acylaminopenicillansyresulfoksyd. else which is theoretically necessary for reaction with 1 mol of 6-acylaminopenicillanic acid sulphoxide.
Syreanhydriddannelsen og ringutvidelsesreak-sjonen gjennomføres i et vannfritt organisk oppløsnings-middel, og eksempler på slike oppløsningsmidler er The acid anhydride formation and the ring expansion reaction are carried out in an anhydrous organic solvent, and examples of such solvents are
acetonitril, klorbenzen, toluen, dietylmetylsulfonamid, dimetylformamid, N,N-dimetylacetamid, 1,2-dimetoksyetan, acetonitrile, chlorobenzene, toluene, diethylmethylsulfonamide, dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane,
dioksan, trietylenglykoldietyleter, dioxane, triethylene glycol diethyl ether,
tetraetylenglykoldietyleter, tetraethylene glycol diethyl ether,
nitrobenzen, benzylcyanid, nitrobenzene, benzyl cyanide,
eddiksyrebutylester, acetic acid butyl ester,
eddiksyreisoaraylester, acetic acid isoarayl ester,
oksalsyredietylester, anisol, benzen, karbontetraklorid, dimetylsulfoksyd, metyletylketon, metyl- eller etylisobutylketon og halogenalkaner, slik som 1,2-dikloretan, 1,1-dikloretan, 1-brom-l-kloretan, 1,2,3-triklorpropan, metylenklorid og kloroform. oxalic acid diethyl ester, anisole, benzene, carbon tetrachloride, dimethyl sulfoxide, methyl ethyl ketone, methyl or ethyl isobutyl ketone and haloalkanes, such as 1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1-chloroethane, 1,2,3-trichloropropane, methylene chloride and chloroform.
Fortrinnsvis anvendes dioksan. Preferably, dioxane is used.
Ringutvidelsen gjennomføres ved temperaturer fra 50-l6o°C, og fortrinnsvis 60-130°C, og aller helst fra 70-110°C. Reaksjonstemperaturen holdes under l60°C for å holde dannelsen av spaltingsprodukter lavest mulig. Vanligvis avstemmes reaksjonstemperatur og -tid mot hverandre for å oppnå gode utbytter av A^-7-acylamido-3-metylcefem-4-karboksylsyre. Ved lave temperaturer trenger man lengere reaksjonstider og ved høyere temperaturer kortere reaksjonstider. F.eks. utgjør reaksjonstiden ved 80, 90 hhv. 100°C omtrent 24, 10 hhv. 6 timer. The ring expansion is carried out at temperatures from 50-160°C, and preferably 60-130°C, and most preferably from 70-110°C. The reaction temperature is kept below 160°C to keep the formation of cleavage products as low as possible. Usually, reaction temperature and time are coordinated to achieve good yields of N-7-acylamido-3-methylcephem-4-carboxylic acid. At low temperatures longer reaction times are needed and at higher temperatures shorter reaction times. E.g. constitutes the reaction time at 80, 90 respectively. 100°C approximately 24, 10 or 6 hours.
I en foretrukken utførelsesform av fremgangsmåten ifølge oppfinnelsen anvendes pr. mol 6-acylamidopenicillansyresulfoksyd, f.eks. benzylpenicillinsulfoksyd, 1-4 mol syre, og fortrinnsvis bromhydrogensyre eller saltsyre, 1,5-15 mol base, og fortrinnsvis a-pikolin, hvorved basemengden alltid er større enn syremengden, og 2-4 mol N,0-bis-(trimetylsilyl)-acetamid. I dette tilfellet gjennomføres omsettingen ved temperaturer fra 80-110°C In a preferred embodiment of the method according to the invention, pr. mol 6-acylamidopenicillanic acid sulfoxide, e.g. benzylpenicillin sulfoxide, 1-4 mol of acid, and preferably hydrobromic acid or hydrochloric acid, 1.5-15 mol of base, and preferably α-picoline, whereby the amount of base is always greater than the amount of acid, and 2-4 mol of N,0-bis-(trimethylsilyl) -acetamide. In this case, the reaction is carried out at temperatures from 80-110°C
i et vannfritt inert oppløsningsmiddel, fortrinnsvis dioksan. in an anhydrous inert solvent, preferably dioxane.
I en annen foretrukken utførelsesform av oppfinnelsen benyttes det pr. mol 6-acylamidopenicillansyresulfoksyd 1/3-1 ekvivalent acetylbromid, 1,5-15 mol base, fortrinnsvis a-pikolin, hvorved mengden av basen alltid er større enn mengden av syre som dannes, og l,5-3 mol N,0-bis-(trimetylsilyl)-acetamid eller N,N'-bis-(trimetylsilyl)-urinstoff * In another preferred embodiment of the invention, it is used per mol of 6-acylamidopenicillanic acid sulfoxide 1/3-1 equivalent of acetyl bromide, 1.5-15 mol of base, preferably a-picoline, whereby the amount of base is always greater than the amount of acid formed, and 1.5-3 mol of N,0- bis-(trimethylsilyl)-acetamide or N,N'-bis-(trimethylsilyl)-urea *
Por hydrolysen i trinn c) kan reaksjonsblandingen etter avkjøling ekstraheres med vann som f.eks. ved hjelp av fortynnet vandig kaliumhydroksydoppløsning er innstilt til pH 7» Fra den vandige oppløsningen kan man etter vask-ing med et organisk oppløsningsmiddel slik som eddiksyrebutylester oppnå A~<*->7-acylamido-3-metylcefem-4-karboksyl-syre (f.eks. 7_fenylacetamidoderivatét) eller dennes salt: (a) ved tilsetting av en vandig oppløsning av en syre og fra-filtrering av den utfe-lte desacetoksycefalosporansyre; (b) ved ekstrahering med et organisk oppløsningsmiddel ved en pH-verdi under 4,5 og inndamping av ekstrakten, hvorved syren krystalliserer ut; (c) ved tilsetting av n-butanol, fjerning av. vannet og utkrystallisering av kaliumsaltet av syren fra butanol-oppløsningen; (d) ved ekstraksjon med et organisk oppløsningsmiddel ved en pH-verdi under 4,5> derpå følgende tilsetting av et alkalimetallsalt slik som kaliumacetat, eller en oppløsning av et alkalimetallsalt, f.eks. kalium-2-etylheksanoat, eller av et amin, f.eks. trietvlamin eller cykloheksylamin, i et organisk oppløsningsmiddel og avfiltrering av det utfelte alkalimetall- eller aminsalt av syren; eller (e) ved ektraksjon med et organisk oppløsningsmiddel 'ved en pH-verdi under 4,5 og utfelling av desacetoksycefalosporansyre 'ved tilsetting av et apolart organisk oppløsningsmiddel slik som dietyleter eller cyklo-heksan. After the hydrolysis in step c), the reaction mixture can be extracted after cooling with water such as e.g. with the help of dilute aqueous potassium hydroxide solution is adjusted to pH 7". From the aqueous solution, after washing with an organic solvent such as acetic acid butyl ester, A~<*->7-acylamido-3-methylcephem-4-carboxylic acid ( e.g. the 7-phenylacetamido derivative) or its salt: (a) by adding an aqueous solution of an acid and filtering off the precipitated desacetoxycephalosporanic acid; (b) by extracting with an organic solvent at a pH below 4.5 and evaporating the extract, whereby the acid crystallizes out; (c) by addition of n-butanol, removal of. the water and crystallization of the potassium salt of the acid from the butanol solution; (d) by extraction with an organic solvent at a pH value below 4.5> followed by the addition of an alkali metal salt such as potassium acetate, or a solution of an alkali metal salt, e.g. potassium 2-ethylhexanoate, or of an amine, e.g. triethylamine or cyclohexylamine, in an organic solvent and filtering off the precipitated alkali metal or amine salt of the acid; or (e) by extraction with an organic solvent 'at a pH value below 4.5 and precipitation of desacetoxycephalosporanic acid' by addition of an apolar organic solvent such as diethyl ether or cyclohexane.
Ved gjennomføring av omsettingen i et med vann blandbart organisk oppløsningsmiddel kan A^-7-acylamido-3_ metylcefem-4-karboksylsyren separeres ved å helle reaksjonsblandingen i vann og å tilsette et organisk oppløsnings-middel. Det må tilsettes en tilstrekkelig mengde vann og organisk oppløsningsmiddel for å oppnå separering av blandingen i to faser. Den organiske fase reekstraheres med vann ved en pH-verdi lik 7 og de forenede vandige faser vaskes med et organisk oppløsningsmiddel slik som eddiksyrebutylester og behandles deretter som angitt ovenfor under punktene (a)-(e) for å oppnå A^-desacetoksycefalosporansyren eller salter derav. En annen mulighet for å avslutte reaksjonen består i å dampe av det organiske oppløsningsmiddel und- When carrying out the reaction in a water-miscible organic solvent, the N-7-acylamido-3-methylcephem-4-carboxylic acid can be separated by pouring the reaction mixture into water and adding an organic solvent. A sufficient amount of water and organic solvent must be added to achieve separation of the mixture into two phases. The organic phase is re-extracted with water at a pH equal to 7 and the combined aqueous phases are washed with an organic solvent such as acetic acid butyl ester and then treated as indicated above under items (a)-(e) to obtain the A^-desacetoxycephalosporanic acid or salts hence. Another possibility for terminating the reaction consists in evaporating off the organic solvent und-
er redusert trykk, oppløse den amorfe rest i et med vann ublandbart oppløsningsmiddel og å tilsette vann. Etter inn-stilling av pH-verdien til 7 kastes den organiske fasen. is reduced pressure, dissolving the amorphous residue in a water-immiscible solvent and adding water. After setting the pH value to 7, the organic phase is discarded.
Den vandige oppløsning vaskes med et organisk oppløsnings-middel og behandles deretter som angitt ovenfor under punktene (a)-(e). Reaksjonsblandingen kan også opparbeides ved å helle den i en vandig syreoppløsning med en pH-verdi på The aqueous solution is washed with an organic solvent and then treated as indicated above under points (a)-(e). The reaction mixture can also be worked up by pouring it into an aqueous acid solution with a pH value of
ca. 2 under omrøring og med etterfølgende avfiltrering av desacetoksycefalosporansyren. about. 2 with stirring and with subsequent filtration of the desacetoxycephalosporanic acid.
Utbyttet av A"^-7-acylamido-3-metylcefem-4-karboksylsyre avhenger ved fremgangsmåten ifølge oppfinnelsen av de anvendte reagenser og reaksjonsbetingelser. Generelt oppnår man imidlertid utbytter på mer enn 45-70, The yield of A"^-7-acylamido-3-methylcephem-4-carboxylic acid in the process according to the invention depends on the reagents and reaction conditions used. In general, however, yields of more than 45-70,
og sågar over 90%, beregnet på 6-acylamidopenicillansulf-oksyd. and even over 90%, calculated on 6-acylamidopenicillan sulphoxide.
Ved fremgangsmåten ifølge oppfinnelsen anvendes som utgangsforbindelser fortrinnsvis slike 6-acylamidopenicillansyresulfoksyder som er oppnådd ved fermentering slik som benzylpenicillin eller fenoksymetylpenicillin.In the method according to the invention, starting compounds are preferably used as 6-acylamidopenicillanic acid sulphoxides which have been obtained by fermentation, such as benzylpenicillin or phenoxymethylpenicillin.
Eksemplene skal forklare oppfinnelsen nærmere. I de eksempler hvor utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre er bestemt ved en mikrobiologisk prøve, kan syren oppnås ved behandling av reaksjonsblandingen i henhold til det følgende eksempel 1. The examples shall explain the invention in more detail. In the examples where the yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid is determined by a microbiological test, the acid can be obtained by treating the reaction mixture according to the following example 1.
EkseniDel_I ExeniDel_I
Til 10,5 g (30 mmol) benzylpenicillinsulfok- To 10.5 g (30 mmol) of benzylpenicillin sulfoc-
syd ble det etter hverandre tilsatt 195 ml dioksan, 25 ml 195 ml dioxane, 25 ml
(102 mmol) N,0-bis(trimetylsilyl)acetamid, 6 ml (61 mmol) a-pikolin og en 5>8-molar oppløsning av .a-pikolinhydrobromid i diklormetan (5,2 ml, 30 mmol a-pikolinhydrobromid). Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Etter koking under tilbakeløp av reaksjonsblandingen i 6 timer ved en temperatur på 102°C, ble den avkjølt til 20°C og-helt opp i 1500 ml isvann. Deretter ble 650 ml etylacetat og 50 ml butylacetat tilsatt og under omrøring ble pH-verdien justert til 7,0 med HN-kaliumhydroksydopp-løsning. Blandingen ble tillatt å skille seg og det organiske sjikt ble satt tilside. Det vandige sjikt ble vasket med 300 ml etylacetat og 50 ml butylacetat. Det resulter-ende organiske sjikt ble kombinert med det andre som var oppnådd på forhånd og de kombinerte sjikt ble omekstrahert med 200 ml av en 0,75-molar vandig kaliumfosfatoppløsning som var bufret til pH 7. Ekstraktet ble tilsatt til den vandige hovedoppløsning. Denne kombinerte vandige :blanding mneholdt9>2 g av kaliumsaltet av A3^~7~fenylacetamido-desacetoksycefalosporansyre, dvs. A^-benzyldesacetoksy-cefalosporin i et utbytte på 83%, bestemt ved mikrobiologisk prøving ved bruk av Escherichia coli som forsøksmikro-organisme. (102 mmol) N,0-bis(trimethylsilyl)acetamide, 6 ml (61 mmol) α-picoline and a 5>8 molar solution of α-picoline hydrobromide in dichloromethane (5.2 ml, 30 mmol α-picoline hydrobromide) . The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After refluxing the reaction mixture for 6 hours at a temperature of 102°C, it was cooled to 20°C and poured into 1500 ml of ice water. Then 650 ml of ethyl acetate and 50 ml of butyl acetate were added and, with stirring, the pH value was adjusted to 7.0 with HN potassium hydroxide solution. The mixture was allowed to separate and the organic layer was set aside. The aqueous layer was washed with 300 ml of ethyl acetate and 50 ml of butyl acetate. The resulting organic layer was combined with the second previously obtained and the combined layers were re-extracted with 200 ml of a 0.75 molar aqueous potassium phosphate solution buffered to pH 7. The extract was added to the main aqueous solution. This combined aqueous mixture contained 9>2 g of the potassium salt of A3^~7~phenylacetamido-desacetoxycephalosporanic acid, i.e. A^-benzyldesacetoxy-cephalosporin in a yield of 83%, determined by microbiological testing using Escherichia coli as the test microorganism.
Etter tilsetting av 500 ml butylacetat til den vandige oppløsning ble blandingen omrørt og pH-verdien ble justert til 2 med 4N-svovelsyre. Blandingen ble satt hen og den organiske ekstrakt ble separert. Det vandige sjikt ble omekstrahert med 250 ml butylacetat. De kombinerte butylacetatekstrakter ble filtrert ;med et vannav-støtende filter. Det vandige sjikt, som fremdeles inneholdt noe A^-7-fenylacetamidodesacetoksycefalosporansyre ble kassert. Til butylacetatoppløsningen ble det deretter under heftig omrøring tilsatt 2,65 g (27 mmol) vannfritt, finpulverisert kaliumacetat. Etter omrøring i 3 timer ved romtemperatur, ble bunnfallet isolert ved filtrering, vasket med noe butylacetat og tørket i vakuum ved 30°C, noe som ga 10,2 g av kaliumsaltet av a3~7-fenylacetamido-desacetoksyciefalosporansyre med en renhet på 85%, bestemt ved mikrobiologisk prøving (utbytte 23,5 mmol, 78%). After adding 500 ml of butyl acetate to the aqueous solution, the mixture was stirred and the pH was adjusted to 2 with 4N sulfuric acid. The mixture was set aside and the organic extract was separated. The aqueous layer was re-extracted with 250 ml of butyl acetate. The combined butyl acetate extracts were filtered with a water-repellent filter. The aqueous layer, which still contained some N-7-phenylacetamidodesacetoxycephalosporanic acid was discarded. 2.65 g (27 mmol) of anhydrous, finely powdered potassium acetate was then added to the butyl acetate solution with vigorous stirring. After stirring for 3 hours at room temperature, the precipitate was isolated by filtration, washed with some butyl acetate and dried in vacuo at 30°C, yielding 10.2 g of the potassium salt of α3~7-phenylacetamido-desacetoxycephalosporanic acid with a purity of 85% , determined by microbiological testing (yield 23.5 mmol, 78%).
X maks. (H20): 262 nm. (E^ cm : 175). X max. (H 2 O): 262 nm. (E^ cm : 175).
Strukturen ble bestemt ved IR- og PMR-spektra. Analysen av PMR-spektret var som følger: The structure was determined by IR and PMR spectra. The analysis of the PMR spectrum was as follows:
PMR (som kaliumsaltet i D20, verdier i ppm) PMR (as the potassium salt in D20, values in ppm)
<5 : 1,94 (s,3); 2,99 (d,J = l8 Hz,l); 3,44 (d,J = 18 Hz,l); 3,62 (s,2); 4,97 (d,J=4,5 Hz,l)j 5,58 <5 : 1.94 (p,3); 2.99 (d,J = 18 Hz,1); 3.44 (d,J = 18 Hz,l); 3.62 (p.2); 4.97 (d,J=4.5 Hz,l)j 5.58
(d,J=4,5 Hz,i); 7,27 (s,5). (d, J=4.5 Hz, i); 7.27 (p. 5).
Natriumsaltet av 2,2-dimetyl-2-silapentyl-5-sulfo-nat ble benyttet som intern referanse. The sodium salt of 2,2-dimethyl-2-silapentyl-5-sulfonate was used as an internal reference.
Eksemgel_II Eczema gel_II
(a) 1,05 g (3 mmol) benzylpenicillinsulfoksyd ble tilsatt til en blanding av 20 ml av en oppløsning av 3,0 (a) 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added to a mixture of 20 ml of a solution of 3.0
mmol hydrogenbromid i dioksan og 2,5 ml (10 mmol) N,0-bis-(trimetylsilyl)acetamid. Trimetylsilylderivatet av benzyl-penicillinsulf oksyd ble dannet in situ. Reaksjonsblandingen ble oppvarmet til 102°C. Reaksjonen ble fulgt av tynnsj iktkromatografi. mmol of hydrogen bromide in dioxane and 2.5 ml (10 mmol) of N,0-bis-(trimethylsilyl)acetamide. The trimethylsilyl derivative of benzyl penicillin sulfoxide was formed in situ. The reaction mixture was heated to 102°C. The reaction was followed by thin-layer chromatography.
Etter 6 timer var det intet penicillinsulfok- After 6 hours there was no penicillin sulfoc-
syd tilbake i reaksjonsblandingen. Prøver på 5 ml ble tatt og helt opp i 35 ml av en 0,75~molar vandig kalium-fosfatoppløsning som var bufret til pH 7. Den vandige oppløsning ble vasket med 10 ml etylacetat og fortynnet med vann til 50 ml. Mengden av kaliumsaltet av A^-7-fenylacetamido-desacetoksycefalosporansyre i den vandige oppløsning ble anslått ved en direkte mikrobiologisk prøve ved bruk av Escherichia coli som forsøksmikro-organisme. Etter 6 timer var utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre 47%• (b) Forsøket som er beskrevet under (a) ble gjentatt med den forskjell at 18 ml toluen og 2 ml av en 1,5-molar oppløsning av hydrogenbromid i dioksan ble benyttet i stedet for 20 ml dioksan. Utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre var 46%, syd back into the reaction mixture. Samples of 5 ml were taken and poured into 35 ml of a 0.75-molar aqueous potassium phosphate solution buffered to pH 7. The aqueous solution was washed with 10 ml of ethyl acetate and diluted with water to 50 ml. The amount of the potassium salt of ?-7-phenylacetamido-desacetoxycephalosporanic acid in the aqueous solution was estimated by a direct microbiological test using Escherichia coli as the test microorganism. After 6 hours the yield of A^-7-phenylacetamido-desacetoxycephalosporanic acid was 47%• (b) The experiment described under (a) was repeated with the difference that 18 ml of toluene and 2 ml of a 1.5-molar solution of hydrogen bromide in dioxane was used instead of 20 ml of dioxane. The yield of A^-7-phenylacetamido-desacetoxycephalosporanic acid was 46%,
bestemt ved mikrobiologisk prøving. determined by microbiological testing.
(c) Forsøket som er beskrevet under (a) ble (c) The experiment described under (a) was
gjentatt med den forskjell at en ytterligere mengde på 0,9 ml .(9 mmol) a-pikolin ble benyttet. Utbyttet av A -7-fenylacetamido-desacetoksycefalosporansyre var 82%, bestemt ved mikrobiologisk prøving. repeated with the difference that a further amount of 0.9 ml (9 mmol) of α-picoline was used. The yield of A -7-phenylacetamido-desacetoxycephalosporanic acid was 82%, determined by microbiological testing.
Eksemgel_III Eczema gel_III
Til 1,05 g (3 mmol) benzylpenicillinsulfoksyd To 1.05 g (3 mmol) of benzylpenicillin sulfoxide
ble det etter hverandre tilsatt 20 ml dioksan, 3,2 ml (13 mmol) N,0-bis(trimetylsilyl)acetamid og 0,57 g (3 mmol) p_-toluensulfonsyre. Trimetylsilylderivatet av benzylpenicillinsulfoksydet ble dannet in situ. Etter oppvarming av reaksjonsblandingen i 6 timer til 101°C, var det intet sulfok- 20 ml of dioxane, 3.2 ml (13 mmol) of N,0-bis(trimethylsilyl)acetamide and 0.57 g (3 mmol) of p-toluenesulfonic acid were added one after the other. The trimethylsilyl derivative of the benzylpenicillin sulfoxide was formed in situ. After heating the reaction mixture for 6 hours at 101°C, there was no sulfoc-
syd tilbake. Etter opparbeidelse av reaksjonsblandingen slik som i eksempel II, var utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyren 41%, bestemt ved mikrobiologisk prøving. south back. After work-up of the reaction mixture as in Example II, the yield of the ?-7-phenylacetamido-desacetoxycephalosporanic acid was 41%, determined by microbiological testing.
Eksempel_IV Example_IV
En blanding av 2,1 g (6 mmol) benzylpenicillinsulfoksyd, 20 ml kloroform, 5 ml (20 mmol) N,0-bis(trimetylsilyl)-acetamid og 2 ml av en 3,3-ni oppløsning av a-pikolinhydroklorid (6,6 mmol) i dikloretan oppvarmes 24 timer til.84°C. Utbyttet av A^-7-fenylacetamidodesacetoksycefalo-sporansyre var 53% av det teoretiske slik det i henhold til eksempel II kan bestemmes ved mikrobiologisk prøving. A mixture of 2.1 g (6 mmol) of benzylpenicillin sulfoxide, 20 ml of chloroform, 5 ml (20 mmol) of N,0-bis(trimethylsilyl)-acetamide and 2 ml of a 3,3-ni solution of α-picoline hydrochloride (6 .6 mmol) in dichloroethane is heated to 84°C for 24 hours. The yield of ?-7-phenylacetamidodesacetoxycephalo-sporanoic acid was 53% of the theoretical as can be determined by microbiological testing according to example II.
Eksempel_V Example_V
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 10 ml benzylcyanid, 10 ml (100 mmol) a-pikolin, A mixture of 1.05 g (3 mmol) benzyl penicillin sulfoxide, 10 ml benzyl cyanide, 10 ml (100 mmol) α-picoline,
3 ml 3,3-molar oppløsning av a-pikolinhydroklorid (10 3 ml of 3.3-molar solution of α-picoline hydrochloride (10
mmol) i 1,2-dikloretan og 2,5 ml (10 mmol) N,0-bis(trimetyl-silyl)-acetamid ble oppvarmet til 95°C Trimetylsilylderivatet av benzylpenicillinsulfoksydet ble dannet in situ. Etter 6 timer var utbyttet av A^-7-fenylacetamido-desacetoksyeefalosporansyre 48%, bestemt ved mikrobiolog- mmol) in 1,2-dichloroethane and 2.5 ml (10 mmol) of N,0-bis(trimethylsilyl)-acetamide was heated to 95°C. The trimethylsilyl derivative of the benzylpenicillin sulfoxide was formed in situ. After 6 hours, the yield of A^-7-phenylacetamido-desacetoxycephalosporanic acid was 48%, determined by microbiological
isk prøving ved bruk av den fremgangsmåte som er beskrevet i eksempel II. ical testing using the method described in example II.
Eksem<De>l_VI Eczema<De>l_VI
Forsøket som er beskrevet i eksempel V ble gjentatt, bortsett fra at 15 ml benzylcyanid og 5 ml (50 mmol) a-pikolin ble benyttet. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A 3- J-fenylacetamido-desacetoksycefalosporansyre var etter 6 timers oppvarming til 95°C 48%, bedømt ved den mikrobiologiske prøve som er beskrevet i eksempel II. The experiment described in Example V was repeated, except that 15 ml of benzyl cyanide and 5 ml (50 mmol) of α-picoline were used. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of A 3-J-phenylacetamido-desacetoxycephalosporanic acid after 6 hours of heating to 95°C was 48%, judged by the microbiological test described in example II.
<Eksemp>_<el>_<VII><Example>_<el>_<VII>
Forsøket som er beskrevet i eksempel V ble gjentatt, bortsett fra at 17>5 ml benzylcyanid, 2,5 ml (25 mmol) a-pikolin og 2 ml av en 3,3-molar oppløsning av a-pikolinhydroklorid (6,6 mmol) i 1,2-dikloretan, ble benyttet. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre var etter 6 timers oppvarming til 95°C 48%, bedømt ved mikrobiologisk prøving ved bruk av den fremgangsmåte som er beskrevet i eksempel II. The experiment described in Example V was repeated, except that 17>5 ml of benzyl cyanide, 2.5 ml (25 mmol) of α-picoline and 2 ml of a 3.3-molar solution of α-picoline hydrochloride (6.6 mmol ) in 1,2-dichloroethane, was used. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid after 6 hours of heating to 95°C was 48%, judged by microbiological testing using the method described in example II.
Eksemgel_VIII Eczema_VIII
En blanding av 1 g (3 mmol) benzylpenicillinsulfoksyd, 15 ml benzylcyanid, 7,2 ml (72 mmol) pyridin, A mixture of 1 g (3 mmol) benzylpenicillin sulfoxide, 15 ml benzyl cyanide, 7.2 ml (72 mmol) pyridine,
2,5 ml (10 mmol) N,C—bis(trimetylsilyl)-acetamid og 0,27 ml (1 mmol) av en 3,3-molar oppløsning av a-pikolinhydroklorid ble oppvarmet til 90°C. Trimetylsilylderi- 2.5 ml (10 mmol) of N,C-bis(trimethylsilyl)-acetamide and 0.27 ml (1 mmol) of a 3.3 molar solution of α-picoline hydrochloride were heated to 90°C. trimethylsilyl deri-
vatet av benzylpenicillinsulfoksyd ble dannet in situ. the vat of benzylpenicillin sulfoxide was formed in situ.
Etter 6 timer var utbyttet av A^~7~fenylacetamidodesacet-oksycefalosporansyre 38%, bedømt ved mikrobiologisk prøving ved bruk av den fremgangsmåte som er beskrevet i eksempel After 6 hours, the yield of A^~7~phenylacetamidodesacetoxycephalosporanic acid was 38%, as judged by microbiological testing using the method described in Example
II. II.
_Eks_emp_e_l _ IX _Ex_emp_e_l _ IX
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 20 ml benzylcyanid, 2,5 ml (10 mmol) N,0-bis-(trimetylsilyl)-acetamid og 0,24 g (1,5 mmol) pyridinhydrobromid ble oppvarmet til 90°C. Trimetylsilylderi- A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 20 ml benzyl cyanide, 2.5 ml (10 mmol) N,0-bis-(trimethylsilyl)-acetamide and 0.24 g (1.5 mmol) pyridine hydrobromide was heated to 90°C. trimethylsilyl deri-
vatet av benzylpenicillinsulfoksyd ble dannet in situ. the vat of benzylpenicillin sulfoxide was formed in situ.
Etter 10 timer var utbyttet av A^-fenylacetamidodesacet-oksyCefalosporansyre 54%, bedømt ved mikrobilogisk prøving. After 10 hours, the yield of ?-phenylacetamidodesacet-oxycephalosporanic acid was 54%, as judged by microbiological testing.
Eksem<p>.el_<X>Eczema<p>.el_<X>
Forsøket som er beskrevet i eksempel IX ble gjentatt -ved bruk av 0,48 g (3 mmol) i stedet for 0,24 g pyridinhydrobromid og med tilsetting av 0,3 ml (3 mmol) a-pikolin. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Etter oppvarming i 10 timer til 90°C var utbyttet av A~<*->7-fenylacetamidodesacetoksycefalosporansyre 59%, bedømt ved mikrobiologisk prøving. The experiment described in Example IX was repeated using 0.48 g (3 mmol) instead of 0.24 g of pyridine hydrobromide and with the addition of 0.3 ml (3 mmol) of α-picoline. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating for 10 hours at 90°C, the yield of A~<*->7-phenylacetamidodesacetoxycephalosporanic acid was 59%, judged by microbiological testing.
Eksemgel_XI Exemgel_XI
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 20 ml dioksan, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)acetamid, 0,48 g (3 mmol) pyridinhydrobromid og 0,3 ml (3 mmol) a-pikolin ble oppvarmet til 85°C. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Etter 22 timer ble reaksjonsblandingen helt opp i 150 ml av en 0,75-molar kaliumfosfatoppløsning (vandig) som var bufret til pH 7 og vasket med 50 ml kloroform. pH-verdien i det vandige lag ble justert til 2 i nærvær av 50 ml etylacetat. Etylacetatsjiktet ble vasket med vann og tørket over vannfri natriumsulfat. Ved fordamping av etylacetatet ble det oppnådd 1 g A^-7-fenylacetamido-desacetoksycefalosporansyre med en renhet på 56%, bedømt ved PMR, ved bruk av 2,6-dikloracetofenon som intern referanse. A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 20 mL dioxane, 2.5 mL (10 mmol) N,0-bis(trimethylsilyl)acetamide, 0.48 g (3 mmol) pyridine hydrobromide and 0.3 mL ( 3 mmol) of α-picoline was heated to 85°C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 22 hours, the reaction mixture was poured into 150 ml of a 0.75 M potassium phosphate solution (aqueous) buffered to pH 7 and washed with 50 ml of chloroform. The pH of the aqueous layer was adjusted to 2 in the presence of 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of the ethyl acetate yielded 1 g of N-7-phenylacetamido-desacetoxycephalosporanic acid with a purity of 56%, judged by PMR, using 2,6-dichloroacetophenone as an internal reference.
EksemB<el_X>II EczemaB<el_X>II
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 20 ml dioksan, 2,5 ml (10 mmol) N,0-bis-(trimetylsilyl)acetamid, 0,5 ml (3 mmol) av en 6-molar oppløsning av a-pikolinhydrobromid i diklormetan og 0,6 ml (6 mmol) a-pikolin ble oppvarmet til 102°C, under oppvarming. Trimetylsilylderivatet av benzylpenicillinsulfoksydet ble dannet in situ. Etter 6 timer ble reaksjonsblandingen helt opp i en blanding av 200 ml av en 0,75-molar vandig kaliumfosfatoppløsning som var bufret til A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 20 mL dioxane, 2.5 mL (10 mmol) N,0-bis-(trimethylsilyl)acetamide, 0.5 mL (3 mmol) of a 6-molar solution of α-picoline hydrobromide in dichloromethane and 0.6 ml (6 mmol) of α-picoline was heated to 102°C, with heating. The trimethylsilyl derivative of the benzylpenicillin sulfoxide was formed in situ. After 6 hours, the reaction mixture was poured into a mixture of 200 ml of a 0.75 M aqueous potassium phosphate solution buffered to
pH 7 og 50 ml etylacetat. Det bufrede vandige sjikt ble vasket med 50 ml etylacetat og, etter justering av pH- pH 7 and 50 ml ethyl acetate. The buffered aqueous layer was washed with 50 ml of ethyl acetate and, after adjusting the pH
verdien til 2, ble det vandige sjikt ekstrahert to ganger med 100 ml etylacetat. Etter tørking over magnesiumsulfat ble etylacetatet fordampet under redusert trykk. Resten (1,07 g) inneholdt 70% A^-7-fenylacetamidodesacetoksycéfalo-sporansyre, bedømt ved ultraviolett- og PMR-spektra. value of 2, the aqueous layer was extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The residue (1.07 g) contained 70% N-7-phenylacetamidodesacetoxycephalosporanic acid as judged by ultraviolet and PMR spectra.
(Utbytte 2,25 mmol; 75%). (Yield 2.25 mmol; 75%).
Eksempel_XIII Example_XIII
0,64 g (3,3 mmol) trietylbromsilan ble tilsatt 0.64 g (3.3 mmol) of triethylbromosilane was added
til en blanding av 1,05 g (3 mmol) benzylpenicillinsulfok- to a mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoc-
syd, 20 ml dioksan og 0,9 ml (9 mmol) a-pikolin. Etter omrøring i en halv time ble trietylsilylderivatet av ben-zylpenicillinsulf oksyd dannet in situ, noe som ble bekreftet ved PMR. Deretter ble 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)acetamid tilsatt, og blandingen som inneholdt a-piko- syd, 20 ml dioxane and 0.9 ml (9 mmol) α-picoline. After stirring for half an hour, the triethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ, which was confirmed by PMR. Then 2.5 ml (10 mmol) of N,0-bis(trimethylsilyl)acetamide was added, and the mixture containing α-pico-
o o
linhydrobromid ble oppvarmet i 4 timer til 102 C. Etter behandling av reaksjonsblandingen slik som beskrevet i eksempel II var utbyttet av A^~7-fenylacetamidodesacetoksy-cefalosporansyren 73%, bedømt ved mikrobiologisk prøving. linseed hydrobromide was heated for 4 hours to 102° C. After treatment of the reaction mixture as described in Example II, the yield of the .alpha.-7-phenylacetamidodesacetoxy-cephalosporanic acid was 73%, as judged by microbiological testing.
Eksemgel_XIV Exemgel_XIV
Til en blanding av 2 ml (3 mmol) av en 1,5- To a mixture of 2 ml (3 mmol) of a 1.5-
molar oppløsning av hydrogenklorid i benzylcyanid, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)acetamid og 0,9 ml (9 mmol) a-pikolin i 19 ml benzylcyanid ble det tilsatt 1,05 g (3 mmol) benzylpenicillinsulfoksyd. Blandingen ble opp- molar solution of hydrogen chloride in benzyl cyanide, 2.5 ml (10 mmol) N,0-bis(trimethylsilyl)acetamide and 0.9 ml (9 mmol) α-picoline in 19 ml benzyl cyanide, 1.05 g (3 mmol ) benzylpenicillin sulfoxide. The mixture was up-
varmet til 95°C i 6 timer, og utbyttet av A^-7~fenylacet-amidodesacetoksycefalosporansyre som var dannet ble bedømt ved den fremgangsmåte som er beskrevet i eksempel II og utgjorde 48%. heated to 95°C for 6 hours, and the yield of N-7-phenylacetamidodesacetoxycephalosporanic acid which was formed was judged by the method described in Example II and was 48%.
Eksempel_XV Example_XV
(a) Til 1,05 g (3 mmol) benzylpenicillinsulfoksyd ble det tilsatt 18 ml dioksan, 2,5 ml N,O-bis-(trimetylsilyl )acetamid, (10 mmol), og 0,9 ml a-pikolin (9 mmol). (a) To 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added 18 ml of dioxane, 2.5 ml of N,O-bis-(trimethylsilyl)acetamide, (10 mmol), and 0.9 ml of α-picoline (9 mmol).
Etter få minutter ble 2 ml av en 1,5-molar oppløsning av hydrogenbromid (3 mmol) i dioksan tilsatt, og den resul-terende blanding ble oppvarmet i 6 timer til 101°C. Trimetylsilylderivatet av benzylpenicillinsulfoksydet After a few minutes, 2 ml of a 1.5 molar solution of hydrogen bromide (3 mmol) in dioxane was added and the resulting mixture was heated for 6 hours at 101°C. The trimethylsilyl derivative of benzylpenicillin sulfoxide
ble dannet in situ. Behandlingen av reaksjonsblandingen, was formed in situ. The treatment of the reaction mixture,
slik som beskrevet -i eksempel II ga et utbytte av en A -7-fenylacetamido-desacetoksycefalosporansyre på 97%, bedømt ved mikrobiologisk prøving. (b) En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)-acetamid, as described - in Example II gave a yield of A -7-phenylacetamido-desacetoxycephalosporanic acid of 97%, judged by microbiological testing. (b) A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 2.5 ml (10 mmol) N,0-bis(trimethylsilyl)-acetamide,
0,3 ml (3 mmol) a-pikolin og 0,25 ml (1,5 mmol) av en 6- 0.3 ml (3 mmol) of α-picoline and 0.25 ml (1.5 mmol) of a 6-
molar oppløsning av a-pikolinhydrogenbromid i 20 ml dioksan ble kokt under tilbakeløp i 4,5 timer. Trimetylsilylderi- molar solution of α-picoline hydrogen bromide in 20 ml of dioxane was refluxed for 4.5 hours. trimethylsilyl deri-
vatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A"^-7-fenylacetamido-desacetoksycefalosporansyre var 82%, bedømt ved mikrobiologisk prøving. the vat of benzylpenicillin sulfoxide was formed in situ. The yield of N-7-phenylacetamido-desacetoxycephalosporanic acid was 82%, as judged by microbiological testing.
(c) Man går fram som under (b), anvender imidlertid 700 mg (3 mmol) pikrinsyre i stedet for a-pikolinhydrobromid. Trimetylsilylderivatet av benzylpenicillinsulfoksyd oppstår in situ. Utbyttet av A^~7~fenylacetamido-desacet-oksyeefalosporansyre utgjorde 4755 av det teoretiske, be- (c) Proceed as under (b), but use 700 mg (3 mmol) picric acid instead of α-picoline hydrobromide. The trimethylsilyl derivative of benzylpenicillin sulfoxide occurs in situ. The yield of A^~7~phenylacetamido-desacet-oxycephalosporanic acid amounted to 4755 of the theoretical, be-
stemt ved mikrobilogisk prøving.'approved by microbiological testing.'
Eksempel_XVI Example_XVI
(a) 530 g (1,5 mmol) benzylpenicillinsulfoksyd ble suspendert i 10 ml dioksan. Etter tilsetting av 0,45 (a) 530 g (1.5 mmol) of benzyl penicillin sulfoxide was suspended in 10 ml of dioxane. After adding 0.45
ml (4,5 mmol) a-pikolin, ble den klare oppløsning avkjølt til 0°C. Under heftig omrøring ble 0,05 ml (0,5 mmol) fosfortribromid tilsatt. Blandingen ble omrørt i 30 min- ml (4.5 mmol) α-picoline, the clear solution was cooled to 0°C. With vigorous stirring, 0.05 ml (0.5 mmol) of phosphorus tribromide was added. The mixture was stirred for 30 min-
utter ved 0°C. Anhydridet av benzylpenicillinsulfoksyd og fosfortribromid ble dannet in situ. Deretter ble 0,9 ml (3,5 mmol) N,0-bis(trimetylsilyl)acetamid til- otter at 0°C. The anhydride of benzylpenicillin sulfoxide and phosphorus tribromide was formed in situ. Then 0.9 ml (3.5 mmol) of N,0-bis(trimethylsilyl)acetamide was added to
satt. Etter 4,5 timers koking under tilbakeløp var mengden t?- l- fenylacetamido-desacetoksycefalosporansyre som var dannet 85%, bedømt ved mikrobiologisk prøving. sat. After 4.5 hours of boiling under reflux, the amount of t?-l-phenylacetamido-desacetoxycephalosporanic acid that had been formed was 85%, judged by microbiological testing.
(b) Forsøket som er beskrevet under-(a) ble (b) The experiment described under (a) was
gjentatt med den forskjell at det ble benyttet 0,05 ml repeated with the difference that 0.05 ml was used
(0,5 mmol) acetylbromid i stedet for fosfortribromid. Mellomproduktet som ble dannet i dette tilfellet var acetylanhydridet av benzylpenicillinsulfoksyd. Utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre var 87%, bedømt ved mikrobiologisk prøving. (0.5 mmol) acetyl bromide instead of phosphorus tribromide. The intermediate formed in this case was the acetyl anhydride of benzylpenicillin sulfoxide. The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was 87%, as judged by microbiological testing.
(c) Forsøket som er beskrevet under (b) ble gjentatt med den forskjell at acetylbromidet ble tilsatt mens blandingen hådde romtemperatur. Utbyttet var 83% av A^-7-fenylacetamido-desacetoksycefalosporansyre, bedømt ved mikrobiologisk prøving. (d) Forsøket som er beskrevet under (b) ble gjentatt med den forskjell at det ble benyttet 0,36 ml (4,5 mmol) pyridin i stedet for a-pikolin. Utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre var SH%. (e) Forsøket som er beskrevet under (d) ble gjentatt med den forskjell at det ble benyttet 0,07 ml (1>0 mmol) i stedet for 0,05 ml acetylbromid. Utbyttet av A^-7-fenyl-. acetamido-desacetoksycefalosporansyre var 92%. (f) Forsøket som er beskrevet under (d) ble gjentatt med den forskjell at det ble benyttet 0,14 ml (2,0 mmol) i stedet for 0,05 ml acetylbromid. Utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre var 93%. (g) Forsøket som er beskrevet under (d) ble gjentatt med den forskjell at 0,05 ml oksalylbromid ble benyttet i stedet for acetylbromid. Mellomproduktet som ble dannet var i dette tilfellet oksalylanhydridet av benzylpenicillinsulfoksyd. Utbyttet av A^-7-fenylacetamido-desacetoksyce-'falosporansyre var 69%. (h) Forsøket som er beskrevet under (e) ble gjentatt med den forskjell at 10 ml toluen ble benyttet som oppløs-ningsmiddel i stedet for dioksan. Acetylanhydridet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A^-7-fenylacetamidp-desacetoksycefalosporansyre var 76%. (i) Forsøket som er beskrevet under (e) ble gjentatt med den forskjell at 10 ml butylacetat ble benyttet i stedet for dioksan. Utbyttet av A^~7_fenylacetamido-desacetoksycefalosporansyre var 78%. (c) The experiment described under (b) was repeated with the difference that the acetyl bromide was added while the mixture was at room temperature. The yield was 83% of N-7-phenylacetamido-desacetoxycephalosporanic acid, as judged by microbiological testing. (d) The experiment described under (b) was repeated with the difference that 0.36 ml (4.5 mmol) of pyridine was used instead of α-picoline. The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was SH%. (e) The experiment described under (d) was repeated with the difference that 0.07 ml (1>0 mmol) was used instead of 0.05 ml of acetyl bromide. The yield of A^-7-phenyl-. acetamido-desacetoxycephalosporanic acid was 92%. (f) The experiment described under (d) was repeated with the difference that 0.14 ml (2.0 mmol) was used instead of 0.05 ml of acetyl bromide. The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was 93%. (g) The experiment described under (d) was repeated with the difference that 0.05 ml of oxalyl bromide was used instead of acetyl bromide. The intermediate that was formed in this case was the oxalylan anhydride of benzylpenicillin sulfoxide. The yield of N-7-phenylacetamido-desacetoxyce-phalosporanic acid was 69%. (h) The experiment described under (e) was repeated with the difference that 10 ml of toluene was used as solvent instead of dioxane. The acetylanhydride of benzylpenicillin sulfoxide was formed in situ. The yield of N-7-phenylacetamide-desacetoxycephalosporanic acid was 76%. (i) The experiment described under (e) was repeated with the difference that 10 ml of butyl acetate was used in instead of dioxane. The yield of A^~7_phenylacetamido-desacetoxycephalosporanic acid was 78%.
Eksempel_XVII Example_XVII
En oppløsning av 10,5 g (30 mmol) benzylpenicillinsulfoksyd i 150 ml dioksan og 7>2 ml (90 mmol) pyridin ble avkjølt til 6°C. Etter tilsetting av en oppløs-ning av 1,4 ml (18,5 mmol) acetylbromid i 50 ml dioksan, ble blandingen omrørt i 30 minutter ved 5°C. Acetylanhydridet av benzylpenicillinsulfoksyd ble dannet in situ. Deretter ble l8 ml (70 mmol) N,0-bis(trimetylsilyl)acetamid tilsatt og reaksjonsblandingen ble kokt under tilbakeløp i 4,5 timer. Etter avkjøling ble blandingen helt opp i 1 liter.av en 0,2-molar vandig kaliumfosfatoppløsning som var bufret til pH 7> Etter justering av pH-verdien til 7 med 4 N kaliumhydroksyd-oppløsning, ble 600 ml butylacetat tilsatt. Blandingen ble rystet og etterpå ble de to sjikt tillatt å skille seg i en skilletrakt. Det vandige sjikt ble vasket med 400 ml butylacetat. De kombinerte butylacetatsjikt ble ekstrahert med 500 ml av en 0,75-molar vandig kaliumfosfatoppløsning som var bufret til pH 7 og ekstraktet ble tilsatt til den vandige hovedoppløsning. A solution of 10.5 g (30 mmol) of benzylpenicillin sulfoxide in 150 ml of dioxane and 7>2 ml (90 mmol) of pyridine was cooled to 6°C. After addition of a solution of 1.4 ml (18.5 mmol) of acetyl bromide in 50 ml of dioxane, the mixture was stirred for 30 minutes at 5°C. The acetylanhydride of benzylpenicillin sulfoxide was formed in situ. Then 18 ml (70 mmol) of N,0-bis(trimethylsilyl)acetamide was added and the reaction mixture was refluxed for 4.5 hours. After cooling, the mixture was poured into 1 liter of a 0.2 molar aqueous potassium phosphate solution buffered to pH 7. After adjusting the pH to 7 with 4 N potassium hydroxide solution, 600 ml of butyl acetate was added. The mixture was shaken and afterwards the two layers were allowed to separate in a separatory funnel. The aqueous layer was washed with 400 ml of butyl acetate. The combined butyl acetate layers were extracted with 500 ml of a 0.75 molar aqueous potassium phosphate solution buffered to pH 7 and the extract added to the main aqueous solution.
De kombinerte vandige oppløsninger inneholdt The combined aqueous solutions contained
9,1 g av kaliumsaltet av A^-7-fenylacetamido-desacetoksy-cef alosporansyre i et utbytte på 82%, bedømt ved ultraviolett spektroskopi og ved mikrobiologisk prøving ved bruk av Escherichia coli som forsøksmikroorganisme. 9.1 g of the potassium salt of ?-7-phenylacetamido-desacetoxy-cephalosporanic acid in a yield of 82%, judged by ultraviolet spectroscopy and by microbiological testing using Escherichia coli as the test microorganism.
Kaliumsaltet av A^-7-fenylacetamido-desacetoksycefalosporansyre ble isolert slik som i eksempel I The potassium salt of N-7-phenylacetamido-desacetoxycephalosporanic acid was isolated as in Example I
og ga 11,1 g med en renhet på 67%, bedømt ved mikrobiologisk, prøving (utbytte 757°)- and gave 11.1 g with a purity of 67%, judged by microbiological testing (yield 757°)-
Eksem<p>el_<XV>III Example<p>el_<XV>III
(a) 530 mg (1,5 mmol) benzylpenicillinsulfoksyd ble' suspendert i 10 ml dioksan. Etter tilsetting av 0,45 ml (4,5 mmol) a-pikolin ble den klare oppløsning avkjølt til 0°C_. Under heftig omrøring ble 0,05 ml (0,7 mmol) acetylbromid tilsatt og blandingen ble om- (a) 530 mg (1.5 mmol) of benzyl penicillin sulfoxide was suspended in 10 ml of dioxane. After addition of 0.45 ml (4.5 mmol) of α-picoline, the clear solution was cooled to 0°C. With vigorous stirring, 0.05 ml (0.7 mmol) of acetyl bromide was added and the mixture was re-
rørt i 30 minutter ved 0°C. Acetylanhydridet av benzylpenicillinsulfoksyd ble dannet in situ. Deretter ble 1,35 g (6,6 mmol) N,N'-bis(trimetylsilyl)urea tilsatt, stirred for 30 minutes at 0°C. The acetylanhydride of benzylpenicillin sulfoxide was formed in situ. Then 1.35 g (6.6 mmol) of N,N'-bis(trimethylsilyl)urea was added,
og etter koking under tilbakeløp i 4,5 timer, ble mengden av A^-fenylacetamido-desacetoksycefalosporansyre bedømt ved mikrobiologisk prøving. Utbyttet var 54%. and after refluxing for 4.5 hours, the amount of N-phenylacetamido-desacetoxycephalosporanic acid was assessed by microbiological testing. The yield was 54%.
(b) Forsøket som er beskrevet under (a) ble gjentatt med den forskjell at det ble benyttet 0,05 ml (b) The experiment described under (a) was repeated with the difference that 0.05 ml was used
(0,5 mmol) fosfortribromid i stedet for acetylbromid. Mellomproduktet som ble dannet var i dette tilfellet anhydridet av benzylpenicillinsulfoksyd og fosfortribromid. Utbyttet av A^~7_fenylacetamido-desacetoksycefalosporansyre var 33%, bedømt ved mikrobiologisk prøving. (c) Forsøket som er beskrevet under (a) ble gjentatt med den forskjell at det ble benyttet 10 ml butylacetat i stedet for dioksan og 0,12 ml (1,5 mmol) acetylbromid i stedet for 0,7 mmol. Utbyttet av A^- J- fenylacetamido-desacet-oksyoefalosporasyre var 5^%. (d) Forsøket som er beskrevet under (a) ble gjentatt med den forskjell at 0,36 ml (4,5 mmol) pyridin i stedet for a-pikolin og 0,22 ml (2,5 mmol) trimetylbromsilan i stedet for acetylbromid ble benyttet. (0.5 mmol) of phosphorus tribromide instead of acetyl bromide. The intermediate product formed in this case was the anhydride of benzylpenicillin sulfoxide and phosphorus tribromide. The yield of ??7-phenylacetamido-desacetoxycephalosporanic acid was 33%, judged by microbiological testing. (c) The experiment described under (a) was repeated with the difference that 10 ml of butyl acetate was used instead of dioxane and 0.12 ml (1.5 mmol) of acetyl bromide instead of 0.7 mmol. The yield of A^-J-phenylacetamido-desacet-oxyoephalosporic acid was 5^%. (d) The experiment described under (a) was repeated with the difference that 0.36 ml (4.5 mmol) pyridine instead of α-picoline and 0.22 ml (2.5 mmol) trimethylbromosilane instead of acetyl bromide was used.
Det dannede mellomprodukt var trimetylsilylderivatet av benzylpenicillinsulfoksyd. Utbyttet av A^-fenylacetamido-desacetoksycefalosporansyre var 80%. (e) 525 mg (1,5 mmol) benzylpenicillinsulfoksyd og 76O mg (3,7 mmol) N,N'-bis(trimetylsilyl)urea ble suspendert i 10 ml toluen. Deretter ble 0,12 ml (1,5 mmol) pyridin og 0,12 ml (1,0 mmol) benzoylbromid tilsatt og blandingen ble oppvarmet til 100°C i 5 timer. Benzoyl-anhydridet av benzylpenicillinsulfoksyd ble dannet som mellomprodukt. Utbyttet av A^-7~fenylacetamido-desacet-oksyeefalosporansyre var 57%, bedømt ved mikrobiologisk prøving. (f) Forsøket som er beskrevet under (e) ble gjentatt med den forskjell at forskjellige andre syrederi- The intermediate formed was the trimethylsilyl derivative of benzylpenicillin sulfoxide. The yield of ?-phenylacetamido-desacetoxycephalosporanic acid was 80%. (e) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 760 mg (3.7 mmol) of N,N'-bis(trimethylsilyl)urea were suspended in 10 ml of toluene. Then 0.12 ml (1.5 mmol) of pyridine and 0.12 ml (1.0 mmol) of benzoyl bromide were added and the mixture was heated to 100°C for 5 hours. The benzoyl anhydride of benzylpenicillin sulfoxide was formed as an intermediate. The yield of ?-7-phenylacetamido-desacet-oxycephalosporanic acid was 57%, as judged by microbiological testing. (f) The experiment described under (e) was repeated with the difference that various other acid derivatives
vater ble benyttet i stedet for benzoylbromid. Resul- vater was used instead of benzoyl bromide. Resul-
tatene er angitt i den følgende tabell: tates are indicated in the following table:
EksemDel_XIX_ EczemaDel_XIX_
525 mg (1,5 mmol) benzylpenicillinsulfoksyd og 1,4 g (8 mmol) N,N'-bis(trimetylsilyl)urea ble suspendert i 10 ml dioksan. 0,35 ml (2 mmol) av en 6-molar oppløsning av a-pikolinhydrobromid i diklormetan ble tilsatt og blandingen ble oppvarmet til 100°C i 4 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Mengden av A^- J- fenylacetamido-desacetoksycefalosporansyre som var dannet ble dømt til 80% ved bruk av den fremgangsmåte som er beskrevet i eksempel II. 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.4 g (8 mmol) of N,N'-bis(trimethylsilyl)urea were suspended in 10 ml of dioxane. 0.35 ml (2 mmol) of a 6 molar solution of α-picoline hydrobromide in dichloromethane was added and the mixture was heated to 100°C for 4 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of A^-J-phenylacetamido-desacetoxycephalosporanic acid formed was judged to be 80% using the method described in Example II.
Eksempel_XX Example_XX
(a) 525 mg (1,5 mmol) benzylpenicillinsulfoksyd (a) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide
og 1,05 g (5 mmol) N,N'-bis(trimetylsilyl)urea ble suspendert i 10 ml dioksan. 0,25 ml (3 mmol) pyridin og 0,15 ml (1,6 mmol) trimetylbromsilan ble tilsatt og blandingen ble oppvarmet til 100°C i 4,5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Mengden A^-7-fenylacetamido-desacetoksycefalosporansyre som var dannet var 85%, bedømt ved mikrobiologisk prøving. (b) Forsøket som er, beskrevet under (a) ble gjentatt med den forskjell at det ble benyttet 0,16 ml (1,6 mmol) a-pikolin i stedet for pyridin. Utbyttet var 85%. (c) Forsøket som er beskrevet under (a) ble gjentatt med den forskjell at 0,83 ml (3,^ mmol) N,0-bis-(trimetylsilyl)acétamid ble benyttet i stedet for N,N'-bis(trimetylsilyl)urea. Utbyttet av A^-7~fenylacetamido-desacetoksycefalosporansyre var 69%, bedømt ved mikrobiologisk prøving. and 1.05 g (5 mmol) of N,N'-bis(trimethylsilyl)urea was suspended in 10 ml of dioxane. 0.25 mL (3 mmol) of pyridine and 0.15 mL (1.6 mmol) of trimethylbromosilane were added and the mixture was heated to 100°C for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of ?-7-phenylacetamido-desacetoxycephalosporanic acid formed was 85%, as judged by microbiological testing. (b) The experiment described under (a) was repeated with the difference that 0.16 ml (1.6 mmol) of α-picoline was used instead of pyridine. The yield was 85%. (c) The experiment described under (a) was repeated with the difference that 0.83 ml (3.^ mmol) of N,0-bis-(trimethylsilyl)acetamide was used instead of N,N'-bis(trimethylsilyl )urea. The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was 69%, judged by microbiological testing.
Eksemnel_XXI Example_XXI
525 mg (1,5 mmol) benzylpenicillinsulfoksyd 525 mg (1.5 mmol) benzylpenicillin sulfoxide
og 1,05 g (5 mmol) N,N'-bis(trimetylsilyl)urea ble suspendert i 10 ml butylacetat. 0,23 ml (2,3 mmol) a-pikolin og 0,2 ml (2,2 mmol) trimetylbromsilan ble tilsatt. Trimetylsilylderivatet av benzylpenicillinsulfoksyd and 1.05 g (5 mmol) of N,N'-bis(trimethylsilyl)urea was suspended in 10 ml of butyl acetate. 0.23 ml (2.3 mmol) of α-picoline and 0.2 ml (2.2 mmol) of trimethylbromosilane were added. The trimethylsilyl derivative of benzylpenicillin sulfoxide
ble dannet in situ. Etter oppvarming til 100°C i 4,5 was formed in situ. After heating to 100°C for 4.5
timer var utbyttet av A^-7~fenylacetamido-desacetoksyGefalo-sporansyre 78%j bedømt ved mikrobiologisk prøving. hours, the yield of A^-7~phenylacetamido-desacetoxyGephalo-sporanoic acid was 78%j assessed by microbiological testing.
Eksemp_el_XXII Example_el_XXII
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 3»1 ml (15 mmol) heksametyldisilazan, 6 ml av en 0,5-molar oppløsning av hydrogenbromid i dioksan og 14 ml dioksan ble oppvarmet til 100°C i 4,5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A^_7~fenylacetamido-desacetoksycefalosporansyre ble bedømt ved den fremgangsmåte som er beskrevet i eksempel II og utgjorde 48%. A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 3.1 ml (15 mmol) of hexamethyldisilazane, 6 ml of a 0.5 molar solution of hydrogen bromide in dioxane and 14 ml of dioxane was heated to 100°C for 4, 5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of A^_7~phenylacetamido-desacetoxycephalosporanic acid was assessed by the method described in Example II and amounted to 48%.
Eksempel_XXIII Example_XXIII
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 18 ml dioksan, 0,9 ml (9 mmol) a-pikolin, A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 18 ml dioxane, 0.9 ml (9 mmol) α-picoline,
2,6 g (10 mmol) N,0-bis(trimetylsilyl)-trifluoracetamid og 2 ml av en l,5_molar oppløsning av hydrogenbromid i dioksan ble kokt under tilbakeløp i 4,5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A^-7~fenylacetamido-desacetoksycefalosporansyre som var dannet ble bedømt med mikrobiologisk prøving og utgjorde 73%. 2.6 g (10 mmol) of N,0-bis(trimethylsilyl)-trifluoroacetamide and 2 ml of a 1.5-molar solution of hydrogen bromide in dioxane were refluxed for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of A^-7~phenylacetamido-desacetoxycephalosporanic acid which was formed was judged by microbiological testing and amounted to 73%.
Eksempel_XXIV Example_XXIV
1)05 g (3 mmol) benzylpenicillinsulfoksyd ble suspendert i 15 ml dioksan, 2,5 ml (10 mmol) N,0-bis-(trimetylsilyl)acetamid, 1,2 ml (9 mmol) 2-metylkinolin og 6 ml av en 0,5-molar oppløsning av hydrogenbromid i dioksan ble tilsatt, og blandingen ble oppvarmet til 100°C i 4,5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Mengden A^-7-fenylacetamido-desacetoksycefalosporansyre ble bedømt ved den fremgangsmåte som er beskrevet i eksempel II ved mikrobiologisk prøving ved bruk av Escherichia coli som forsøksmikroorganisme. Utbyttet var 49%. 1) 05 g (3 mmol) of benzylpenicillin sulfoxide was suspended in 15 ml of dioxane, 2.5 ml (10 mmol) of N,0-bis-(trimethylsilyl)acetamide, 1.2 ml (9 mmol) of 2-methylquinoline and 6 ml of a 0.5 molar solution of hydrogen bromide in dioxane was added and the mixture was heated to 100°C for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of ?-7-phenylacetamido-desacetoxycephalosporanic acid was assessed by the method described in example II in microbiological testing using Escherichia coli as the test microorganism. The yield was 49%.
Forsøket ble gjentatt med forskjellige andre baser enn 2-metylkinolin. Resultatene er angitt i følg-ende tabell. The experiment was repeated with various bases other than 2-methylquinoline. The results are shown in the following table.
Eksem£el_XXV Example_XXV
(a) En blanding av 525 mg (1,5 mmol) benzylpenicillinsulfoksyd, 10 ml toluen, 0,12 ml (1,5 mmol) pyridin, 1,45 ml 59 mmol) N-metyl-N-trimetylsilyl-acetamid og 0,35 ml av en 6-molar oppløsning av a-pikolinhydrobromid i diklormetan ble oppvarmet til 100°C i 5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Utbyttet av A ~7~fenylacetamido-desacetoksycefalosporansyre var 58%, bedømt ved mikrobiologisk prøving. (b) Det foregående forsøk ble gjentatt, bortsett fra at 1,7 ml (9,2 mmol) N-metyl-N-trimetylsilyl-trifluor-acetamid ble benyttet i stedet for N-metyl-N-trimetylsilyl-acetamid, Utbyttet av A^~7-fenylacetamido-desacetoksycefalosporansyre var 86%. (a) A mixture of 525 mg (1.5 mmol) benzylpenicillin sulfoxide, 10 mL toluene, 0.12 mL (1.5 mmol) pyridine, 1.45 mL (59 mmol) N-methyl-N-trimethylsilyl-acetamide and 0 .35 ml of a 6-molar solution of α-picoline hydrobromide in dichloromethane was heated to 100°C for 5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of A ~7~phenylacetamido-desacetoxycephalosporanic acid was 58%, judged by microbiological testing. (b) The preceding experiment was repeated, except that 1.7 ml (9.2 mmol) of N-methyl-N-trimethylsilyl-trifluoroacetamide was used instead of N-methyl-N-trimethylsilyl-acetamide, The yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was 86%.
Eksempel_XXVI Example_XXVI
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)-acetamid, 0,6 ml (6 mmol) a-pikolin og 0,5 ml av en 6-molar oppløsning av a-pikolinhydrobromid i metylenklorid i 20 ml dioksan ble kokt under tilbakeløp i 4,5 timer. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. A mixture of 1.05 g (3 mmol) benzylpenicillin sulfoxide, 2.5 ml (10 mmol) N,0-bis(trimethylsilyl)-acetamide, 0.6 ml (6 mmol) α-picoline and 0.5 ml of a A 6-molar solution of α-picoline hydrobromide in methylene chloride in 20 ml of dioxane was refluxed for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.
Mengden A^-7-fenylacetamido-desacetoksycefalosporansyre ble bedømt slik som beskrevet i eksempel II The amount of ?-7-phenylacetamido-desacetoxycephalosporanic acid was assessed as described in Example II
ved mikrobiologisk prøving. Utbyttet var 82%. by microbiological testing. The yield was 82%.
Forsøket ble gjentatt i andre oppløsningsmidler enn dioksan. Resultatene er angitt i den følgende tabell. The experiment was repeated in solvents other than dioxane. The results are shown in the following table.
1 1
Ekjempel_XXVII Example_XXVII
1,3 g (3 mmol) 2-etoksynaftyl-penicillinsulfoksyd, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)acetamid, 0,3 ml (3 mmol) a-pikolin og 0,25 ml (1,5 mmol) av en 6-molar opp-løsning av a-pikolinhydrobromid i metylenklorid ble oppløst 1 20 ml dioksan. Trimetylsilylderivatet av 2-etoksynaftyl-penicillinsulfoksyd ble dannet in situ. Blandingen ble kokt under tilbakeløp i 4,5 timer og deretter helt opp i en kald blanding av 200 ml av en 0,75-molar vandig kalium-fosfatoppløsning som var bufret til pH 7 og 50 ml etylacetat. Etter justering av pH-verdien til 7 med 4N-kaliumhydrdksyd-oppløsning, ble blandingen overført til en skilletrakt, rystet og satt hen. Det vandige sjikt ble vasket med 50 ml etylacetat og, etter justering av pH-verdien til 2 med en 4N-svovelsyreoppløsning, ekstrahert to ganger med 100 ml etylacetat. Etter tørking over magnesiumsulfat, ble etylacetatet fordampet'under redusert trykk. Den tørkede rest (490 mg) inneholdt 80% A<3->7~(2-etoksynaft-amido)-desacetoksycefalosporansyre, bedømt ved PMR-spektroskopi, ved bruk av 2,6-dikloracetofenon som intern referanse. Utbyttet var 31%. 1.3 g (3 mmol) 2-ethoxynaphthyl penicillin sulfoxide, 2.5 ml (10 mmol) N,0-bis(trimethylsilyl)acetamide, 0.3 ml (3 mmol) α-picoline and 0.25 ml (1 .5 mmol) of a 6-molar solution of α-picoline hydrobromide in methylene chloride was dissolved in 20 ml of dioxane. The trimethylsilyl derivative of 2-ethoxynaphthyl penicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and then poured into a cold mixture of 200 mL of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and 50 mL of ethyl acetate. After adjusting the pH to 7 with 4N potassium hydroxide solution, the mixture was transferred to a separatory funnel, shaken and set aside. The aqueous layer was washed with 50 ml of ethyl acetate and, after adjusting the pH to 2 with a 4N sulfuric acid solution, extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The dried residue (490 mg) contained 80% A<3->7~(2-ethoxynaphthamido)-desacetoxycephalosporanic acid, as judged by PMR spectroscopy, using 2,6-dichloroacetophenone as an internal reference. The yield was 31%.
Eksempel^ XXVIII Example^ XXVIII
Eksperimentet som er beskrevet i eksempel The experiment described in Example
XXVII ble gjentatt med 1,1 g (3 mmol) ftalimidopenicillinsulfoksyd med den forskjell at 0,25 ml a-pikolinhydro-bromidoppløsning og 0,3 ml a-pikolin ble erstattet av 0,5 ml (3 mmol) av en. 6-molar oppløsning av a-pikolinhydrobromid i metylenklorid. Trimetylsilylderivatet av ftalimidopenicillinsulfoksyd ble dannet in situ. Reaksjonsblandingen ble behandlet på samme måte som beskrevet i eksempel XXVII og ga 880 mg å^- J- ftalimido-desacetoksycefalosporansyre med en renhet på 84%. Utbyttet var 72%. XXVII was repeated with 1.1 g (3 mmol) of phthalimidopenicillin sulfoxide with the difference that 0.25 ml of α-picoline hydrobromide solution and 0.3 ml of α-picoline were replaced by 0.5 ml (3 mmol) of a. 6-molar solution of α-picoline hydrobromide in methylene chloride. The trimethylsilyl derivative of phthalimidopenicillin sulfoxide was formed in situ. The reaction mixture was treated in the same manner as described in Example XXVII and gave 880 mg of ω-J-phthalimido-desacetoxycephalosporanic acid with a purity of 84%. The yield was 72%.
Eksemp<e>l_XXIX Example<e>l_XXIX
Forsøket som er beskrevet under eksempel The experiment described under example
XXVII ble gjentatt med 1,3 g (3 mmol) benzensulfonamido-metylpenicillinsulfoksyd. Trimetylsilylderivatet av ben- XXVII was repeated with 1.3 g (3 mmol) of benzenesulfonamido-methylpenicillin sulfoxide. The trimethylsilyl derivative of ben-
zensulfonaraidometylpenicillinsulfoksyd ble dannet in situ. zensulfonaraidomethylpenicillin sulfoxide was formed in situ.
1,3 g A^-7-benzensulfonamidometyl-desacetoksycefalosporansyre ble oppnådd, med en renhet på 63%. Utbyttet var 66%. Eksempel_XXX_ (a) Til 1,1 g (3 mmol) fenoksymetylpenicillinsulfoksyd ble det tilsatt 20 ml dioksan, 2,5 ml (10 mmol) N,0-bis(trimetylsilyl)-acetamid, 0,6 ml (6 mmol) a-pikolin og en 6-molar oppløsning av a-pikolinhydrobromid i 0,5 ml metylenklorid (3 mmol). Trimetylsilylderivatet av fenoksymetylpenicillinsulfoksyd ble dannet in situ. Blandingen ble kokt under tilbakeløp i 4,5 timer og deretter behandlet slik som i eksempel II. Utbyttet av A^-7-fenoksyacetamido-desacetoksycefalosporansyre var 71%, bedømt ved en direkte mikrobiologisk prøve ved bruk av Escherichia coli som forsøksmikroorganisme. (b) Forsøket som er beskrevet under (a) ble gjentatt, bortsett fra at reaksjonsblandingen ble opparbeidet slik som beskrevet i eksempel XXVII, noe som resulterte i 860 mg A -7-fenoksyacetamido-desacetoksycefalosporansyre av en renhet på 85%, bedømt ved PMR-spektret ved bruk av 2,6-dikloracetofenon som intern referanse. Utbyttet var 70%. 1.3 g of N-7-benzenesulfonamidomethyl-desacetoxycephalosporanic acid was obtained, with a purity of 63%. The yield was 66%. Example_XXX_ (a) To 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide was added 20 ml of dioxane, 2.5 ml (10 mmol) of N,0-bis(trimethylsilyl)-acetamide, 0.6 ml (6 mmol) of a- picoline and a 6-molar solution of α-picoline hydrobromide in 0.5 ml of methylene chloride (3 mmol). The trimethylsilyl derivative of phenoxymethylpenicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and then treated as in Example II. The yield of ?-7-phenoxyacetamido-desacetoxycephalosporanic acid was 71%, judged by a direct microbiological test using Escherichia coli as the test microorganism. (b) The experiment described under (a) was repeated, except that the reaction mixture was worked up as described in Example XXVII, resulting in 860 mg of A -7-phenoxyacetamido-desacetoxycephalosporanic acid of 85% purity as judged by PMR -spectrum using 2,6-dichloroacetophenone as an internal reference. The yield was 70%.
Eksemp<e>l_XXXI Example<e>l_XXXI
Til en suspensjon av 1,35 g (3 mmol) av cyklo-heksylammoniumsaltet av benzylpenicillinsulfoksyd i 15 ml dioksan ble det tilsatt 2,8 ml (11 mmol) N,0-bis(trimetylsilyl )acetamid og 6 ml av en 0,5-molar oppløsning av hydrogenbromid i dioksan. Trimetylsilylderivatet av benzylpenicillinsulfoksyd ble dannet in situ. Blandingen ble kokt under tilbakeløp i 4,5 timer og utbyttet av A^-7-fenylacetamido-desacetoksycefalosporansyre ble be- To a suspension of 1.35 g (3 mmol) of the cyclohexylammonium salt of benzylpenicillin sulfoxide in 15 ml of dioxane was added 2.8 ml (11 mmol) of N,0-bis(trimethylsilyl)acetamide and 6 ml of a 0.5 -molar solution of hydrogen bromide in dioxane. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and the yield of ?-7-phenylacetamido-desacetoxycephalosporanic acid was
dømt til å være 55% ved en mikrobiologisk prøve. judged to be 55% by a microbiological test.
Eksemp<e>l_XXXII Example<e>l_XXXII
Fremstilling av det blandede anhydrid av fenoksymetylpenicillinsulfoksyd og eddiksyre. Preparation of the mixed anhydride of phenoxymethylpenicillin sulfoxide and acetic acid.
(a) En oppløsning av 0,28 ml (3 mmol) acetyl- (a) A solution of 0.28 ml (3 mmol) of acetyl-
bromid i 5 ml 1,2-diloretan ble tilsatt til en oppløsning av 1,1 g (3 mmol) fenoksymetylpenicillinsulfoksyd og 0,72 ml (9mmol) pyridin i 20 ml 1,2-dikloretan. Etter omrøring i 1 time ved 0°C, ble blandingen filtrert og fordampet til tørr tilstand. Restskummet (1,08 g, 2,6 mmol) var det blandede anhydrid av fenoksymetylpenicillin og eddiksyre. bromide in 5 ml of 1,2-dichloroethane was added to a solution of 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide and 0.72 ml (9 mmol) of pyridine in 20 ml of 1,2-dichloroethane. After stirring for 1 hour at 0°C, the mixture was filtered and evaporated to dryness. The residual foam (1.08 g, 2.6 mmol) was the mixed anhydride of phenoxymethylpenicillin and acetic acid.
Analyse av IR-spektret: (i CHCl^): 1820; l800 Analysis of the IR spectrum: (in CHCl^): 1820; l800
og 1758 cm-1.and 1758 cm-1.
Analyse av PMR-spektret (i CDCl^),: 1,35 (s,3);" 1,74 (s,3); 2,32 (s,3); 4,55 (s,2); 4,67 (s,l); 5,17 (d,l, J=4,5 Hz); 6,12 (q,l,J=ll Hz og J=4,5 Hz); 6,98 (s,5). (b) 2,2 g (5 mmol) av anhydridet av fenoksymetyl-penicillinsulf oksyd og eddiksyre ble oppløst i 30 ml dioksan. Etter tilsetting av 3 ml (11,7 mmol) N,0-bis(trimetylsilyl)acetamid, 1,1 ml (15 mmol) pyridin og 0,6 ml diklormetan som inneholdt 3,6 mmol ot-pikolinhydrobrpmid, ble blandingen oppvarmet til tilbakeløpstemperatur i 4,5.timer. Reaksjonsblandingen ble avkjølt til romtemperatur og helt opp i en omrørt blanding av 400 ml av en 0,75-molar vandig kaliumfosfatoppløsning, som var bufret til pH 7, og 100 ml etylacetat. Etter justering av pH-verdien til 7 med 4N-kaliumhydroksyd, ble blandingen overført til en skilletrakt, rystet og satt hen. Det vandige sjikt ble separert, vasket med 100 ml etylacetat og, etter justering av pH-verdien til 2 med 4N-svovel-syreoppløsning, ekstrahert to ganger med 200 ml etylacetat. Etter tørking av reaksjonsblandingen over vannfritt magnesiumsulfat, ble etylacetat fordampet under redusert trykk. Den tørkede rest (1,28 g) inneholdt 86% A<5->7-fenoksyacetamido-desacetoksyc efalosporansyre, bedømt ved PMR-spektroskopi ved bruk av 2,6-dikloracetofenon som intern referanse. Utbyttet var 63%. Analysis of the PMR spectrum (in CDCl^),: 1.35 (p,3);" 1.74 (p,3); 2.32 (p,3); 4.55 (p,2); 4 .67 (s,l); 5.17 (d,l, J=4.5 Hz); 6.12 (q,l,J=ll Hz and J=4.5 Hz); 6.98 (s .5). (b) 2.2 g (5 mmol) of the anhydride of phenoxymethylpenicillin sulfoxide and acetic acid were dissolved in 30 ml of dioxane. After the addition of 3 ml (11.7 mmol) of N,0-bis(trimethylsilyl) acetamide, 1.1 ml (15 mmol) of pyridine and 0.6 ml of dichloromethane containing 3.6 mmol of o-picoline hydrochloride, the mixture was heated to reflux for 4.5 hours.The reaction mixture was cooled to room temperature and poured into a stirred mixture of 400 mL of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and 100 mL of ethyl acetate After adjusting the pH to 7 with 4N potassium hydroxide, the mixture was transferred to a separatory funnel, shaken, and set aside The aqueous layer was separated, washed with 100 ml of ethyl acetate and, after adjusting the pH to 2 with 4N sulfuric acid solution, extracted twice with 200 ml of ethyl acetate. g of the reaction mixture over anhydrous magnesium sulfate, ethyl acetate was evaporated under reduced pressure. The dried residue (1.28 g) contained 86% Δ<5->7-phenoxyacetamido-desacetoxyc ephalosporanic acid as judged by PMR spectroscopy using 2,6-dichloroacetophenone as an internal reference. The yield was 63%.
Dette eksempel viser at anhydridet som dannes som mellomprodukt kan separeres fra reaksjonsblandingen, This example shows that the anhydride formed as an intermediate can be separated from the reaction mixture,
og, som når anhydridet dannes in situ, kan benyttes til ringforstørrelse. and, as when the anhydride is formed in situ, can be used for ring enlargement.
EksemDel_XXXIII EczemaDel_XXXIII
En blanding av 1,05 g (3 mmol) benzylpenicillinsulfoksyd, 0,9 ml (9 mmol) ot-pikolin og en oppløsning av 3,0 mmol hydrogenbromid i dioksan ble kokt under tilbakeløp i 4,5 timer med forskjellige mengder N,0-bis(trimetylsilyl)-acetamid, slik som angitt nedenfor. (Det totale volum var alltid 2,4 ml). Utbytte av A^-7_fenylacetamido-desacetoksy-cef alosporansyre ble bedømt ved mikrobiologisk prøving, og resultatene er angitt i den følgende tabell. A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 0.9 ml (9 mmol) of ot-picoline and a solution of 3.0 mmol of hydrogen bromide in dioxane was refluxed for 4.5 hours with various amounts of N.0 -bis(trimethylsilyl)-acetamide, as indicated below. (The total volume was always 2.4 ml). The yield of ?-7-phenylacetamido-desacetoxy-cephalosporanic acid was assessed by microbiological testing, and the results are given in the following table.
Tabellen viser at det høyeste utbytte under de ovenfor angitte betingelser var 85% og at dette ble oppnådd med en mengde på omkring 9-10 mmol N,0-bis(trimetylsilyl)-acetamid. The table shows that the highest yield under the conditions stated above was 85% and that this was achieved with an amount of around 9-10 mmol of N,0-bis(trimethylsilyl)-acetamide.
Eksemp_el_XXXlv Example_el_XXXlv
Til en til 0°C avkjølt oppløsning av 1060 mg eller 3 mmol benzylpenicillinsulfoksyd i 0,72 ml eller 9 mmol pyridin og 20 ml butylacetat settes 0,24 ml eller 3 mmol acetylbromid. Etter omrøring i 30 minutter ved romtemperatur tilsettes 2,1 g eller 9 mmol N,N'-bis(trimetylsilyl)-urinstoff og blandingen To a solution cooled to 0°C of 1060 mg or 3 mmol of benzylpenicillin sulfoxide in 0.72 ml or 9 mmol of pyridine and 20 ml of butyl acetate is added 0.24 ml or 3 mmol of acetyl bromide. After stirring for 30 minutes at room temperature, 2.1 g or 9 mmol of N,N'-bis(trimethylsilyl)urea are added and the mixture
oppvarmes under tilbakeløp i 2\ time. heated under reflux for 2\ hours.
Utbytte av A^-7-fenylacetamido-desacetoksycefalosporansyre utgjør 77% av det teoretiske. The yield of A^-7-phenylacetamido-desacetoxycephalosporanic acid amounts to 77% of the theoretical.
Eksemgel_XXXV Exemgel_XXXV
En blanding av 525 mg eller 1,5 mmol benzylpenicillinsulfoksyd, 0,12 ml eller 1,5 mmol pyridin, 0,074 ml eller 1 mmol acetylbromid og 10 ml toluen oppvarmes i 5 timer til 100°C med forskjellige mengder N,N'-bis(trimetylsilyl)-urinstoff. Utbytte av A 3-7-fenylacetamido-desacetoksycefalosporansyre ble bestemt ved mikrobiologisk prøving. Resultatene er sammenfattet i den følgende tabell: A mixture of 525 mg or 1.5 mmol of benzyl penicillin sulfoxide, 0.12 ml or 1.5 mmol of pyridine, 0.074 ml or 1 mmol of acetyl bromide and 10 ml of toluene is heated for 5 hours at 100°C with various amounts of N,N'-bis (trimethylsilyl)urea. Yield of A 3-7-phenylacetamido-desacetoxycephalosporanic acid was determined by microbiological testing. The results are summarized in the following table:
Eksemp_el_XXXVI Example_el_XXXVI
En blanding av 525 mg eller 1,5 mmol benzylpenicillinsulfoksyd, 0,24 ml eller 3 mmol pyridin, 0,04 ml eller 0,4 mmol fosfortribromid og 10 ml toluen oppvarmes i 5 timer til 100°C med forskjellige mengder N,N'-bis(trimetylsilyl)-urinstoff. Utbytte av A 3-7-fenylacetamido-desacetoksycefalosporansyre blir bestemt ved mikrobiologisk prøving. Resultatene er sammenfattet i den følgende tabell. A mixture of 525 mg or 1.5 mmol of benzylpenicillin sulfoxide, 0.24 ml or 3 mmol of pyridine, 0.04 ml or 0.4 mmol of phosphorus tribromide and 10 ml of toluene is heated for 5 hours at 100°C with various amounts of N,N' -bis(trimethylsilyl)-urea. The yield of A 3-7-phenylacetamido-desacetoxycephalosporanic acid is determined by microbiological testing. The results are summarized in the following table.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3863771 | 1971-08-17 | ||
| GB5951671A GB1409415A (en) | 1971-08-17 | 1971-12-21 | Penicillin sulphoxides and their use in preparing delta3-7- substituted amino-descetoxy-cephalosporins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO144153B true NO144153B (en) | 1981-03-23 |
| NO144153C NO144153C (en) | 1981-07-01 |
Family
ID=26263869
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2942/72A NO144153C (en) | 1971-08-17 | 1972-08-16 | PROCEDURE FOR PREPARATION OF DELTA3-7-ACYLAMIDO-3-METHYL-CEFEM-4-CARBOXYLIC ACIDS |
| NO2262/73A NO144152C (en) | 1971-08-17 | 1973-05-30 | 6-ACYL-AMINOPENICILLANIC ANHYRIDES USED AS PRESENT IN THE PREPARATION OF THE SIMILAR 7-ACYL-AMINODEACETOXYXYPHALOSPORAN ACIDS |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2262/73A NO144152C (en) | 1971-08-17 | 1973-05-30 | 6-ACYL-AMINOPENICILLANIC ANHYRIDES USED AS PRESENT IN THE PREPARATION OF THE SIMILAR 7-ACYL-AMINODEACETOXYXYPHALOSPORAN ACIDS |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5438117B2 (en) |
| AR (1) | AR193426A1 (en) |
| AT (1) | AT336181B (en) |
| BE (1) | BE787618A (en) |
| CA (1) | CA1014146A (en) |
| CH (1) | CH576982A5 (en) |
| CS (1) | CS197212B2 (en) |
| DD (1) | DD100263A5 (en) |
| DE (2) | DE2240224C3 (en) |
| DK (1) | DK142174B (en) |
| ES (1) | ES405883A1 (en) |
| FI (1) | FI58643C (en) |
| FR (1) | FR2150785B1 (en) |
| GB (1) | GB1409415A (en) |
| HU (1) | HU169534B (en) |
| IE (1) | IE36638B1 (en) |
| IL (1) | IL40143A (en) |
| LU (1) | LU65904A1 (en) |
| NL (1) | NL177597C (en) |
| NO (2) | NO144153C (en) |
| PH (2) | PH13845A (en) |
| RO (1) | RO63401A (en) |
| SE (1) | SE404927B (en) |
| SU (1) | SU500754A3 (en) |
| YU (1) | YU39899B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2222094A1 (en) * | 1972-05-05 | 1973-11-15 | Hoechst Ag | PROCESS FOR THE PRODUCTION OF AMINOACETIDINONES |
| GB1472866A (en) * | 1974-06-12 | 1977-05-11 | Farmaceutici Italia | Cephalosporins and intermediates therefor |
| GB1467355A (en) * | 1974-08-07 | 1977-03-16 | Lepetit Spa | Preparation of 6-aminopenicillanic acid 7-aminocephalospo ranic acid and derivatives thereof |
| ES431585A1 (en) * | 1974-11-02 | 1976-11-16 | Gema Sa | Process for the conversion of 6-aminopenicillanic acid (6-APA) in 7-aminodesacetoxycephalosporanic acid (7-ADCA) |
| PL94023B1 (en) * | 1974-12-18 | 1977-07-30 | Politechnika Gdanska | |
| GB1472864A (en) * | 1975-04-05 | 1977-05-11 | Farmaceutici Italia | Method of preparing cephalosporins |
| US4008231A (en) * | 1975-09-15 | 1977-02-15 | Eli Lilly And Company | Preparation of 3-methoxymethylcephalosporins |
| IT1063088B (en) * | 1976-06-01 | 1985-02-11 | Dobfar Spa | AZETIDINONIC DERIVATIVES AND PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE |
| US4322347A (en) | 1978-04-03 | 1982-03-30 | Bristol-Myers Company | 2-Carbamoyloxymethyl-penicillin derivatives |
| US4310459A (en) * | 1978-04-03 | 1982-01-12 | Bristol-Myers Company | Process for producing carbamoyl substituted penams and carbamoyl substituted cephams from penicillin sulfoxide esters |
| US4426520A (en) | 1978-04-03 | 1984-01-17 | Bristol-Myers Company | 3-Carbamoyloxy-cepham-4-carboxylic acid derivatives |
| US4518773A (en) * | 1978-04-03 | 1985-05-21 | Bristol-Myers Company | "3-Carbamoyloxy cephalosporins" |
| IT1124802B (en) * | 1979-10-29 | 1986-05-14 | Dobfar Spa | BORONATED DERIVATIVES OF 6-PENICILLANIC ACID AND PROCEDURE FOR THEIR PREPARATION |
| US4374982A (en) | 1979-11-07 | 1983-02-22 | Bristol-Myers Company | Cepham compounds |
| JPS5716006A (en) * | 1980-07-03 | 1982-01-27 | Mitsui Toatsu Chem Inc | Suspension polymerization of vinyl chloride |
-
0
- BE BE787618D patent/BE787618A/en not_active IP Right Cessation
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1971
- 1971-12-21 GB GB5951671A patent/GB1409415A/en not_active Expired
-
1972
- 1972-08-03 SU SU1817032A patent/SU500754A3/en active
- 1972-08-15 IE IE1136/72A patent/IE36638B1/en unknown
- 1972-08-15 PH PH13802A patent/PH13845A/en unknown
- 1972-08-16 JP JP8204972A patent/JPS5438117B2/ja not_active Expired
- 1972-08-16 SE SE7210625A patent/SE404927B/en unknown
- 1972-08-16 DD DD165088A patent/DD100263A5/xx unknown
- 1972-08-16 FI FI2271/72A patent/FI58643C/en active
- 1972-08-16 IL IL40143A patent/IL40143A/en unknown
- 1972-08-16 CH CH1216172A patent/CH576982A5/xx not_active IP Right Cessation
- 1972-08-16 YU YU2100/72A patent/YU39899B/en unknown
- 1972-08-16 CA CA149,545A patent/CA1014146A/en not_active Expired
- 1972-08-16 FR FR7229365A patent/FR2150785B1/fr not_active Expired
- 1972-08-16 NO NO2942/72A patent/NO144153C/en unknown
- 1972-08-16 AR AR243595A patent/AR193426A1/en active
- 1972-08-16 CS CS725688A patent/CS197212B2/en unknown
- 1972-08-16 HU HUGI178A patent/HU169534B/hu unknown
- 1972-08-16 AT AT704072A patent/AT336181B/en not_active IP Right Cessation
- 1972-08-16 DE DE2240224A patent/DE2240224C3/en not_active Expired
- 1972-08-16 DK DK406072AA patent/DK142174B/en not_active IP Right Cessation
- 1972-08-16 LU LU65904A patent/LU65904A1/xx unknown
- 1972-08-16 ES ES405883A patent/ES405883A1/en not_active Expired
- 1972-08-16 DE DE2264648*A patent/DE2264648A1/en active Pending
- 1972-08-16 RO RO7200071975A patent/RO63401A/en unknown
- 1972-08-17 NL NLAANVRAGE7211213,A patent/NL177597C/en not_active IP Right Cessation
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1973
- 1973-05-30 NO NO2262/73A patent/NO144152C/en unknown
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1977
- 1977-12-06 PH PH20519A patent/PH15675A/en unknown
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