NO159659B - PROCEDURE FOR THE PREPARATION OF 1,1-DIOXOPENICILLANOYLOXYMETHYL-6- (2-AMINO-2-PHENYLACETAMIDO) PENICILLANATE ANTIBIOTICS. - Google Patents
PROCEDURE FOR THE PREPARATION OF 1,1-DIOXOPENICILLANOYLOXYMETHYL-6- (2-AMINO-2-PHENYLACETAMIDO) PENICILLANATE ANTIBIOTICS. Download PDFInfo
- Publication number
- NO159659B NO159659B NO83831024A NO831024A NO159659B NO 159659 B NO159659 B NO 159659B NO 83831024 A NO83831024 A NO 83831024A NO 831024 A NO831024 A NO 831024A NO 159659 B NO159659 B NO 159659B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- mixture
- formula
- penicillanate
- ethyl acetate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 33
- -1 2-AMINO-2-PHENYLACETAMIDO Chemical class 0.000 title description 18
- 238000002360 preparation method Methods 0.000 title description 9
- 239000003242 anti bacterial agent Substances 0.000 title description 7
- 229940088710 antibiotic agent Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 62
- 239000002253 acid Substances 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 229910000510 noble metal Inorganic materials 0.000 claims description 5
- 239000002516 radical scavenger Substances 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 100
- 239000000203 mixture Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 230000003647 oxidation Effects 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 238000007327 hydrogenolysis reaction Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 239000012286 potassium permanganate Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 230000001590 oxidative effect Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- OSORMYZMWHVFOZ-UHFFFAOYSA-N phenethyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCC1=CC=CC=C1 OSORMYZMWHVFOZ-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 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 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229960003975 potassium Drugs 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000005695 dehalogenation reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 3
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- XWDSFLSFDJZQTM-ALEPSDHESA-N (2s,5r,6r)-6-iodo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2[C@H](I)C(=O)N21 XWDSFLSFDJZQTM-ALEPSDHESA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- 230000007935 neutral effect Effects 0.000 description 2
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SIWNEELMSUHJGO-UHFFFAOYSA-N 2-(4-bromophenyl)-4,5,6,7-tetrahydro-[1,3]oxazolo[4,5-c]pyridine Chemical compound C1=CC(Br)=CC=C1C(O1)=NC2=C1CCNC2 SIWNEELMSUHJGO-UHFFFAOYSA-N 0.000 description 1
- DTHIEIUKBSDERX-UHFFFAOYSA-N 2-methylpropylsulfonyloxymethyl 2-methylpropane-1-sulfonate Chemical compound CC(C)CS(=O)(=O)OCOS(=O)(=O)CC(C)C DTHIEIUKBSDERX-UHFFFAOYSA-N 0.000 description 1
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
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- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- MGWIVXXTDAHZPB-UHFFFAOYSA-N benzenesulfonyloxymethyl benzenesulfonate Chemical compound C=1C=CC=CC=1S(=O)(=O)OCOS(=O)(=O)C1=CC=CC=C1 MGWIVXXTDAHZPB-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- TUDWMIUPYRKEFN-UHFFFAOYSA-N bromoiodomethane Chemical compound BrCI TUDWMIUPYRKEFN-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012971 dimethylpiperazine Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- MKACCASHGOXABG-UHFFFAOYSA-N hexylsulfonyloxymethyl hexane-1-sulfonate Chemical compound CCCCCCS(=O)(=O)OCOS(=O)(=O)CCCCCC MKACCASHGOXABG-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- IQLZWWDXNXZGPK-UHFFFAOYSA-N methylsulfonyloxymethyl methanesulfonate Chemical compound CS(=O)(=O)OCOS(C)(=O)=O IQLZWWDXNXZGPK-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Denne oppfinnelse vedrører en fremgangsmåte ved fremstilling av 1,l-dioksopenicillanoyloksymetyl-6-(2-amino-2-fenylacetamido)penicillanat-antibiotika med formel (II) This invention relates to a process for the production of 1,1-dioxopenicillanoyloxymethyl-6-(2-amino-2-phenylacetamido)penicillanate antibiotics with formula (II)
eller et farmasøytisk godtagbart syreaddisjonssalt derav. or a pharmaceutically acceptable acid addition salt thereof.
US-patent 4.234.579 beskriver penicillansyre-1,1-dioksyd US Patent 4,234,579 describes penicillanic acid 1,1-dioxide
og estere derav som er lett hydrolyserbare in vivo, deres anvendelse som antibakterielle midler og for å øke effektiviteten av Ø-laktam-antibiotika mot mange Ø-laktamase-dannende bakterier. and esters thereof which are readily hydrolyzable in vivo, their use as antibacterial agents and to increase the effectiveness of β-lactam antibiotics against many β-lactamase-producing bacteria.
US-patent 4.244.951 beskriver nye antibakterielle midler US patent 4,244,951 describes new antibacterial agents
med formel (VIII) hvor penicillansyre-1,1-dioksyd er bundet til kjente penicillin-antibiotika via en metylendiokso-gruppe, with formula (VIII) where penicillanic acid-1,1-dioxide is bound to known penicillin antibiotics via a methylenedioxo group,
dvs. i.e.
fø birth
hvor R er acylgruppen i et naturlig eller halvsyntetisk penicillin. Spesielt foretrukne betydninger for R omfatter 2-amino-2-fenylacetyl og 2-amino-2-(p-hydroksyfenyl)-acetyl. Forbindelsene med formel (VIII) fremstilles f.eks. ved omsetning av et karboksylatsalt av pénicillinet så som natrium-eller kaliumsaltet eller et tertiært aminsalt med en halogenmetylester (eller beslektet ester) av penicillansyre-1,1-dioksyd. Halogenmetylester-mellomproduktene fremstilles ved forestring where R is the acyl group in a natural or semi-synthetic penicillin. Particularly preferred meanings for R include 2-amino-2-phenylacetyl and 2-amino-2-(p-hydroxyphenyl)-acetyl. The compounds of formula (VIII) are prepared, e.g. by reacting a carboxylate salt of the penicillin such as the sodium or potassium salt or a tertiary amine salt with a halomethyl ester (or related ester) of penicillanic acid 1,1-dioxide. The halomethyl ester intermediates are produced by esterification
av penicillansyre-1,1-dioksyd. of penicillanic acid 1,1-dioxide.
Harrison et al, Journal of the Chemical Society (London), Perkin I, 1772 (1976) beskriver: (a) oksydasjon av 6,6-dibrompenicillansyre med m-klorperbenzoesyre, for å danne en blanding av de tilsvarende a- og /3-sulfoksyder; (b) oksydasjon av metyl-6,6-dibrompenicillanat med m-klorperbenzoesyre for å danne et metyl-6,6-dibrompenicillanat-l,1-dioksyd; (c) oksydasjon av metyl-6-a-klor-penicillanat med m-klor-perbenzoesyre-, for å danne en blanding av de tilsvarende a- og Ø-sulfoksyder; og (d) oksydasjon av metyl-6-brompenicillanat med m-klorperbenzoesyre, for å danne en blanding av de tilsvarende a- og 3-sulfoksyder. Harrison et al, Journal of the Chemical Society (London), Perkin I, 1772 (1976) describe: (a) oxidation of 6,6-dibromopenicillanic acid with m-chloroperbenzoic acid, to form a mixture of the corresponding a- and /3 -sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with m-chloroperbenzoic acid to form a methyl 6,6-dibromopenicillanate 1,1-dioxide; (c) oxidation of methyl 6-α-chloropenicillanate with m-chloro-perbenzoic acid to form a mixture of the corresponding α- and β-sulfoxides; and (d) oxidation of methyl 6-bromopenicillanate with m-chloroperbenzoic acid, to form a mixture of the corresponding α- and β-sulfoxides.
Clayton, Journal of the Chemical Society (London) (C), Clayton, Journal of the Chemical Society (London) (C),
2123 (1969) beskriver: (a) fremstilling av 6,6-dibrom- og 6,6-dijodpenicillansyre; (b) oksydasjon av 6,6-dibrompenicillansyre med natriumperjodat for å danne en blanding av de tilsvarende sulfoksyder; (c) hydrogenolyse av metyl-6,6-dibrom-penicillanat for å danne metyl-6-a-brompenicillanat; (d) hydrogenolyse av 6,6-dibrompenicillansyre og dens metyl-ester for å danne henholdsvis penicillansyre og dens metyl-ester; og (e) hydrogenolyse av en blanding av metyl-6,6-dijod-penicillanat og metyl-6ct-jodpenicillanat for å danne rent metyl-6-a-jodpenicillanat. 2123 (1969) describes: (a) preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate to form a mixture of the corresponding sulfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to form methyl 6-α-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid and its methyl ester to form penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6α-iodopenicillanate to form pure methyl 6-α-iodopenicillanate.
Belgisk patent 882.028 beskriver en fremgangsmåte for fremstilling av penicillansyre-1,1-dioksyd og dens in vivo lett hydrolyserbare estere ved oksydasjon av 6-halogen-penicillanat eller et 6,6-dihalogenpenicillanat til det tilsvarende 1,1-dioksyd, og derefter dehalogenering for å danne det ønskede penicillanat-1,1-dioksyd. Belgian patent 882,028 describes a process for the preparation of penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters by oxidation of 6-halopenicillanate or a 6,6-dihalopenicillanate to the corresponding 1,1-dioxide, and then dehalogenation to form the desired penicillanate 1,1-dioxide.
US-patent 3.293.242 beskriver 6-(2-azido-2-fenylacetamido)-penicillansyre og salter derav. US Patent 3,293,242 describes 6-(2-azido-2-phenylacetamido)-penicillanic acid and salts thereof.
Japansk Kokai 78-37,691; Chem. Abstr., 89, 109466v (1978) beskriver 6-[2-azido-2-(p-hydroksyfenyl)acetamido]penicillansyre og reduksjonen av denne med hydrogen og palladium-på-kull for å danne 6- [2-amino-2--(p-hydroksyf enyl) acetamido] penicillansyre. Japanese Kokai 78-37,691; Chem. Abstr., 89, 109466v (1978) describes 6-[2-azido-2-(p-hydroxyphenyl)acetamido]penicillanic acid and its reduction with hydrogen and palladium-on-charcoal to form 6-[2-amino-2 --(p-Hydroxy enyl) acetamido] penicillanic acid.
Det karakteristiske for foreliggende oppfinnelse er at en forbindelse med formel The characteristic of the present invention is that a compound of formula
hvor R<1> er som angitt ovenfor, Q er N3 eller NHC02CH2C6H4R<4>where R<1> is as defined above, Q is N3 or NHC02CH2C6H4R<4>
hvor R<4> er H, Cl, Br, N02, CH3 eller OCH3; Y og Z er hver Cl, where R<4> is H, Cl, Br, NO2, CH3 or OCH3; Y and Z are each Cl,
Br eller I, eller Y er H og Z er Cl, Br eller I, bringes i kontakt med hydrogen i nærvær av en edelmetall-katalysator, i det minste to molekvivalenter syrebindende middel, eller når Y Br or I, or Y is H and Z is Cl, Br or I, is contacted with hydrogen in the presence of a noble metal catalyst, at least two molar equivalents of acid scavenging agent, or when Y
er H, i det minste en molekvivalent syrebindende middel, og et reaksj onsinert oppløsningsmiddel. is H, at least one molar equivalent of acid scavenging agent, and a reactive solvent.
Fremgangsmåten ifølge foreliggende oppfinnelse står i motsetning til innholdet av Baltzer et al., J. Antibiotics, 33, 1183(1980) og britisk patent 2,044,255. Baltzer et al. beskriver ustabiliteten til 1,1-dioksymetylenester-bindingen mellom beta-laktamase-inhibitoren og penicillin-antibiotika-delene av kon-jugatester-forbindelsene, såsom de med formel (II) i foreliggende oppfinnelse under nøytrale eller alkaliske betingelser. I britisk patent 2,044,255 utføres hydrogeneringen som der er eksempli-fisert under betingelser som enten opprettholder en sur pH ved tilsetning av sure reagenser eller ved dannelse av syrer under reaksjonsforløpet. I motsetning til disse litteraturhenvisninger kan fremgangsmåten ifølge foreliggende oppfinnelse utføres i nærvær av et syrebindende middel som fører til nøytrale til alkaliske reaksjonsbetingeIser. The method of the present invention is in contrast to the contents of Baltzer et al., J. Antibiotics, 33, 1183(1980) and British Patent 2,044,255. Baltzer et al. describes the instability of the 1,1-dioxymethylene ester bond between the beta-lactamase inhibitor and the penicillin antibiotic portions of the conjugate ester compounds, such as those of formula (II) of the present invention under neutral or alkaline conditions. In British patent 2,044,255, the hydrogenation exemplified there is carried out under conditions which either maintain an acidic pH by adding acidic reagents or by forming acids during the course of the reaction. In contrast to these literature references, the method according to the present invention can be carried out in the presence of an acid-binding agent which leads to neutral to alkaline reaction conditions.
Forbindelsene med formlene (I) og (II) er her benevnt som derivater av penicillanoyloksymetyl-penicillanat. Forbindelsen med formel (I) hvor R er hydrogen og Y og Z er hver Br, og Q er N^, er benevnt som 1,l-diokso-6,6-dibrom-penicillanoyloksymetyl-6-(2-azido-2-fenylacetamido)-penicillanat. The compounds with the formulas (I) and (II) are here referred to as derivatives of penicillanoyloxymethyl penicillanate. The compound of formula (I) where R is hydrogen and Y and Z are each Br, and Q is N^, is designated as 1,1-dioxo-6,6-dibromo-penicillanoyloxymethyl-6-(2-azido-2- phenylacetamido)-penicillanate.
Mellomproduktet med formel (I) og fremstilling av dette The intermediate product of formula (I) and preparation thereof
er nærmere omtalt i norsk patentsøknad 82.0898. is described in more detail in Norwegian patent application 82.0898.
I forbindelser hvor Y er H og Z er Cl, Br eller I, kan Z-substituenten være i a-konfigurasjon, Ø-konfigurasjon, eller kan være en blanding av de to isomerer. Alle slike forbindelser omfattes av oppfinnelsen. In compounds where Y is H and Z is Cl, Br or I, the Z substituent may be in the α-configuration, Ø-configuration, or may be a mixture of the two isomers. All such compounds are covered by the invention.
Fremgangsmåter for fremstilling av penicillanoyloksymetyl-penicillanater med formel (II) ved forestring som illustrert nedenfor er beskrevet i US-patent 4.244.951 og nederlandsk patentansøkni-ng 8.000.775 publisert 15. august 1980, svarende Methods for the preparation of penicillanoyloxymethyl penicillanates of formula (II) by esterification as illustrated below are described in US patent 4,244,951 and Dutch patent application 8,000,775 published on August 15, 1980, corresponding
til britisk patentansøkning 2.044.255: to British Patent Application 2,044,255:
I de ovenstående formler er en av A og B -CH„X , og den annen 11 er M , hvor X er en god utgående gruppe, f.eks. Cl, Br, I, In the above formulas, one of A and B is -CH„X , and the other 11 is M , where X is a good leaving group, e.g. Cl, Br, I,
CH3S020 eller toluensulfonyloksy; og M^" er et karboksylatsalt-dannende kation, f.eks. natrium, kalium, trietylammonium eller tetrabutylammonium; og Q<1> er en vanlig aminobeskyttende gruppe, f.eks. benzyloksykarbonyl. Det første produkt som oppnås, er det aminobeskyttede derivat av (II) som gir den ønskede antibiotiske forbindelse ved fjernelse av beskyttelsesgruppen Q ved standard metoder. CH 3 SO 2 O or toluenesulfonyloxy; and M^" is a carboxylate salt-forming cation, e.g., sodium, potassium, triethylammonium, or tetrabutylammonium; and Q<1> is a common amino-protecting group, e.g., benzyloxycarbonyl. The first product obtained is the amino-protected deriv. of (II) which gives the desired antibiotic compound by removal of the protecting group Q by standard methods.
Ovennevnte nederlandske og den tilsvarende britiske ansøkning beskriver også en fremgangsmåte for fremstilling av forbindelser med formel (II) hvor R er hydrogen, ved kobling av klormety1-6-(2-azido-2-fenylacetamido)penicillanat og et salt av penicillansyre-1,1-dioksyd, og hydrogenering av mellomproduktet 1,1-dioksopenicillanoyloksymety1-6-(2-azido-2-fenyl-acetamido) penicillanat. The above-mentioned Dutch and the corresponding British application also describe a process for the preparation of compounds of formula (II) where R is hydrogen, by coupling chloromethyl-6-(2-azido-2-phenylacetamido)penicillanate and a salt of penicillanic acid-1, 1-dioxide, and hydrogenation of the intermediate 1,1-dioxopenicillanoyloxymethyl-6-(2-azido-2-phenyl-acetamido) penicillanate.
Ved de tidligere kjente metoder er 1,1-dioksopenicillansyre-utgangsmaterialet med formel (IX), A = H, oppnådd f.eks. ved dehalogenering av det tilsvarende 6-halogen- eller 6,6-dihalogen-penicillansyre-sulfon. Esteren (IX), hvor A er Cf^X<1>, er oppnådd fra syren ved visse forestringsmetoder. In the previously known methods, the 1,1-dioxopenicillanic acid starting material of formula (IX), A = H, is obtained, e.g. by dehalogenation of the corresponding 6-halo- or 6,6-dihalo-penicillanic acid sulfone. The ester (IX), where A is Cf^X<1>, is obtained from the acid by certain methods of esterification.
Reaksjonsskjema A viser fremstilling av forbindelsene med formel (I) og deres omdannelse til antibiotiske forbindelser med formel (II) ved samtidig hydrogenolyse av halogengruppene Y og Z og reduksjon av azido- eller NHC02CH2C6H4R<4->gruppen til NH2 ved omsetning av forbindelse (I) med hydrogen i nærvær av en katalysator . Reaction scheme A shows the preparation of the compounds of formula (I) and their conversion to antibiotic compounds of formula (II) by simultaneous hydrogenolysis of the halogen groups Y and Z and reduction of the azido or NHC02CH2C6H4R<4-> group to NH2 by reaction of compound (I ) with hydrogen in the presence of a catalyst.
Halogenpenicillansyre-utgangsmaterialene med formel (III) hvor M er hydrogen, fremstilles f.eks. fra 6-amino-penicillansyre eller det tilsvarende sulfoksyd eller sulfon ved omsetning med salpetersyrling og behandling av den resulterende 6-diazo-forbindelse med et halogen eller hydrogenhalogenid med formel Y-Z, hvor Y og Z er som angitt ovenfor, ved kjente metoder. Se f.eks. Clayton et al., Journal of Chemical Society (London) (C), 2123 (1969). av klormetyl-6-(2-azido-2-fenylacetamido)penicillanat og et salt av penicillansyre-1,1-dioksyd, og hydrogenering av mellomproduktet 1,l-dioksopenicillanoyloksymetyl-6-(2-azido-2-fenyl-acetamido) penicillanat. The halopenicillanic acid starting materials of formula (III) where M is hydrogen are prepared, e.g. from 6-amino-penicillanic acid or the corresponding sulfoxide or sulfone by reaction with nitric acid and treatment of the resulting 6-diazo compound with a halogen or hydrogen halide of the formula Y-Z, where Y and Z are as indicated above, by known methods. See e.g. Clayton et al., Journal of the Chemical Society (London) (C), 2123 (1969). of chloromethyl-6-(2-azido-2-phenylacetamido)penicillanate and a salt of penicillanic acid 1,1-dioxide, and hydrogenation of the intermediate 1,1-dioxopenicillanoyloxymethyl-6-(2-azido-2-phenylacetamido) penicillanate.
Ved de tidligere kjente metoder er 1,1-dioksopenicillansyre-utgangsmaterialet med formel (IX), A = H, oppnådd f.eks. ved dehalogenering av det tilsvarende 6-halogen- eller 6,6-dihalogen-penicillansyre-sulfon. Esteren (IX), hvor A er CR^ X , er oppnådd fra syren ved visse forestringsmetoder. In the previously known methods, the 1,1-dioxopenicillanic acid starting material of formula (IX), A = H, is obtained, e.g. by dehalogenation of the corresponding 6-halo- or 6,6-dihalo-penicillanic acid sulfone. The ester (IX), where A is CR^ X , is obtained from the acid by certain methods of esterification.
Reaksjonsskjerna A viser fremstilling av forbindelsene med formel (I) og deres omdannelse til antibiotiske forbindelser med formel (II) ved samtidig hydrogenolyse av halogengruppene Y og Z og reduksjon av azido- eller NHC02CH2CgH4R<4->gruppen til NH2 ved omsetning av forbindelse (I) med hydrogen i nærvær av en katalysator . Reaction core A shows the preparation of the compounds of formula (I) and their conversion to antibiotic compounds of formula (II) by simultaneous hydrogenolysis of the halogen groups Y and Z and reduction of the azido or NHC02CH2CgH4R<4-> group to NH2 by reaction of compound (I ) with hydrogen in the presence of a catalyst.
Halogenpenicillansyre-utgangsmaterialene med formel (III) hvor M er hydrogen, fremstilles f.eks. fra 6-amino-penicillansyre eller det tilsvarende sulfoksyd eller sulfon ved omsetning med salpetersyrling og behandling av den resulterende 6-diazo-forbindelse med et halogen eller hydrogenhalogenid med formel Y-Z, hvor Y og Z er som angitt ovenfor, ved kjente metoder. Se f.eks. Clayton et al., Journal of Chemical Society (London) (C), 2123 (1969). The halopenicillanic acid starting materials of formula (III) where M is hydrogen are prepared, e.g. from 6-amino-penicillanic acid or the corresponding sulfoxide or sulfone by reaction with nitric acid and treatment of the resulting 6-diazo compound with a halogen or hydrogen halide of the formula Y-Z, where Y and Z are as indicated above, by known methods. See e.g. Clayton et al., Journal of the Chemical Society (London) (C), 2123 (1969).
Selv om forskjellige fremgangsmåter kan anvendes for omdannelse av mellomprodukter med formel (I) til de antibiotiske forbindelser med formel (II) , er en særlig hensiktsmessig og foretrukket fremgangsmåte samtidig hydrogenolyse av halogengruppene Y og Z som definert ovenfor, og reduksjon av azido-eller benzyloksykarbonylamino-gruppen Q, som definert ovenfor, til NH2 ved hjelp av hydrogen i nærvær av en edelmetall-katalysator. En særlig hensiktsmessig fremgangsmåte for ut-førelse av denne samtidige hydrogenolyse og reduksjon er å omrøre eller riste en oppløsning av en forbindelse med formel (I) under en atmosfære av hydrogen eller hydrogen blandet med et inert fortynningsmiddel så som nitrogen eller argon, i nærvær av en edelmetall-hydrogeneringskatalysator og et reaksjonsinert oppløsningsmiddel. Egnede oppløsningsmidler for denne hydrogeneringsreaksjon er de som i alt vesentlig oppløser utgangsforbindelsen med formel (I), men som ikke selv utsettes for hydrogenering eller hydrogenolyse. Eksempler på slike oppløsningsmidler omfatter lavere alkanoler så som metanol, etanol og isopropanol; etere så som dietyleter, tetrahydrofuran, dioksan og 1,2-dimetoksyetan; lavmolekylære estere så som etylacetat og butylacetat; tertiære amider så Although different methods can be used for the conversion of intermediates of formula (I) to the antibiotic compounds of formula (II), a particularly suitable and preferred method is simultaneous hydrogenolysis of the halogen groups Y and Z as defined above, and reduction of azido or benzyloxycarbonylamino -group Q, as defined above, to NH2 by means of hydrogen in the presence of a noble metal catalyst. A particularly suitable method for carrying out this simultaneous hydrogenolysis and reduction is to stir or shake a solution of a compound of formula (I) under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a noble metal hydrogenation catalyst and a reaction inert solvent. Suitable solvents for this hydrogenation reaction are those which essentially dissolve the starting compound of formula (I), but which are not themselves subjected to hydrogenation or hydrogenolysis. Examples of such solvents include lower alkanols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate; tertiary amides so
som N,N-dimetylformamid, N,N-dimetylacetamid og N-metyl-pyrrolidon; metylenklorid og blandinger derav. such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-pyrrolidone; methylene chloride and mixtures thereof.
Dessuten er det ofte ønskelig å utføre denne omsetning Moreover, it is often desirable to carry out this turnover
i nærvær av en tilstrekkelig mengde av et syrebindende middel til å binde én av eller begge molekvivalentene av dannet hydrogenhalogenid. Eksempler på egnede syrebindende midler omfatter natriumbikarbonat, kalsiumkarbonat, trinatriumfosfat, kaliumcitrat og tertiære aminer så som trietylamin, N,N-dimetylan-ilin, N-metylmorf olin, N-metylpiperidin , N,N<1->dimetylpiperazin og lignende. Innføring av hydrogen-gassen i reaksjonsmediet oppnås vanligvis ved å utføre omsetningen i et lukket kar som inneholder forbindelsen med formel (I), oppløsningsmidlet, katalysatoren og hydrogenet. Trykket inne i reaksjonskaret kan variere fra ca. 1 til ca. in the presence of a sufficient amount of an acid binding agent to bind one or both of the molar equivalents of hydrogen halide formed. Examples of suitable acid-binding agents include sodium bicarbonate, calcium carbonate, trisodium phosphate, potassium citrate and tertiary amines such as triethylamine, N,N-dimethylaniline, N-methylmorpholine, N-methylpiperidine, N,N<1->dimethylpiperazine and the like. Introduction of the hydrogen gas into the reaction medium is usually achieved by carrying out the reaction in a closed vessel containing the compound of formula (I), the solvent, the catalyst and the hydrogen. The pressure inside the reaction vessel can vary from approx. 1 to approx.
100 kg/cm 2. Det foretrukne trykkområde, når atmosfæren inne i reaksjonskaret er tilnærmet rent hydrogen, er fra ca. 2 til ca. 100 kg/cm 2. The preferred pressure range, when the atmosphere inside the reaction vessel is almost pure hydrogen, is from approx. 2 to approx.
2 2
5 kg/cm . Omsetningen med hydrogen foretas vanligvis ved en temperatur fra ca. 0 til ca. 60°C, og fortrinnsvis fra ca. 25 til ca. 50°C. Ved anvendelse av dé foretrukne temperatur- og trykk-verdier, finner hydrogenolyse av halogenene og reduksjon av gruppen Q vanligvis sted i løpet av noen få timer, f.eks. 5 kg/cm. The reaction with hydrogen is usually carried out at a temperature of approx. 0 to approx. 60°C, and preferably from approx. 25 to approx. 50°C. Using the preferred temperature and pressure values, hydrogenolysis of the halogens and reduction of the group Q usually takes place within a few hours, e.g.
fra ca. 2 til ca. 20 timer. De foretrukne edelmetallkatalysatorer som anvendes ved denne hydrogeneringsreaksjon, er den type midler som er kjent innen teknikken for denne form for omdannelse, f.eks. nikkel, palladium, platina og rhodium. from approx. 2 to approx. 20 hours. The preferred noble metal catalysts used in this hydrogenation reaction are the type of agents known in the art for this type of conversion, e.g. nickel, palladium, platinum and rhodium.
Palladium er særlig foretrukket. Katalysatoren er vanligvis Palladium is particularly preferred. The catalyst is usually
til stede i en mengde fra ca. 0,1 til ca. 25 vekt%, og fortrinnsvis fra ca. 1 til ca. 10 vekt%, basert på forbindelsen med formel (I). Det er ofte hensiktsmessig å fordele katalysatoren på en inert bærer, og en særlig hensiktsmessig katalysator er palladium fordelt på en inert bærer så som kull. En annen hensiktsmessig katalysator er palladium-på-kalsiumkarbonat hvor kalsiumkarbonatet tjener som en bærer for edelmetallet og som syrebindende middel. present in an amount from approx. 0.1 to approx. 25% by weight, and preferably from approx. 1 to approx. 10% by weight, based on the compound of formula (I). It is often appropriate to distribute the catalyst on an inert carrier, and a particularly suitable catalyst is palladium distributed on an inert carrier such as coal. Another suitable catalyst is palladium-on-calcium carbonate where the calcium carbonate serves as a carrier for the precious metal and as an acid binding agent.
Når hydrogenolysen og reduksjonen er tilnærmet fullstendig, isoleres det ønskede antibiotikum med formel (II) ved standard metoder, f.eks. fjernes katalysatoren ved filtrering, opp-løsningsmidlet avdampes og eventuelt renses produktet ved velkjente metoder så som krystallisering eller ved kromatografi. When the hydrogenolysis and reduction are almost complete, the desired antibiotic of formula (II) is isolated by standard methods, e.g. the catalyst is removed by filtration, the solvent is evaporated and, if necessary, the product is purified by well-known methods such as crystallization or by chromatography.
Alternativt kan produktet med formel (II) isoleres i form Alternatively, the product of formula (II) can be isolated in form
av et farmasøytisk godtagbart syreaddisjonssalt, f.eks. ved behandling av filtratet oppnådd ved fjernelse av katalysatoren eller en oppløsning av den isolerte, frie base, med en ekvivalent mengde av en farmasøytisk godtagbar syre og fjernelse av opp-løsningsmidlet, f.eks. ved filtrering eller avdampning. Eksempler på farmasøytisk godtagbare syrer som kan anvendes, omfatter saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, eddiksyre, maleinsyre, fumarsyre, ravsyre, melkesyre, vinsyre, sitronsyre, glukonsyre, sakkarinsyre og p-toluensulfonsyre. of a pharmaceutically acceptable acid addition salt, e.g. by treating the filtrate obtained by removing the catalyst or a solution of the isolated free base with an equivalent amount of a pharmaceutically acceptable acid and removing the solvent, e.g. by filtration or evaporation. Examples of pharmaceutically acceptable acids which may be used include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, gluconic acid, saccharin acid and p-toluenesulfonic acid.
Det skal understrekes at hydroklorid-, hydrobromid- og hydrojodid-saltet eller blandinger derav av forbindelser med formel (II) oppnås direkte fra hydrogeneringsblandingen hvis It should be emphasized that the hydrochloride, hydrobromide and hydroiodide salt or mixtures thereof of compounds of formula (II) are obtained directly from the hydrogenation mixture if
man anvender bare én molekvivalent syrebindende middel for utgangsmaterialene med formel (I) hvor hver av Y og Z er Cl, only one molar equivalent of acid-binding agent is used for the starting materials of formula (I) where each of Y and Z is Cl,
Br eller I, eller ikke noe syrebindende middel anvendes for utgangsmaterialene med formel (I) hvor Y er H og Z er Cl, Br eller I. Br or I, or no acid binding agent is used for the starting materials of formula (I) where Y is H and Z is Cl, Br or I.
Som nevnt ovenfor er forbindelsene med formel (I) nyttige mellomprodukter, for fremstilling av antibakterielle midler med formlene (II) og (VIII) beskrevet i US-patent 4.244.951 og britisk patentansøkning 2.044.255. As mentioned above, the compounds of formula (I) are useful intermediates for the preparation of antibacterial agents of formulas (II) and (VIII) described in US Patent 4,244,951 and British Patent Application 2,044,255.
Forbindelsene med formel (II) og (VIII) har in vivo antibakteriell aktivitet i pattedyr, og denne aktivitet kan påvises ved standardmetoder for penicillinforbindelser. F.eks. administreres forbindelsen med formel (II) til mus hvor akutte infeksjoner er fremkalt ved intraperitoneal innpodning med en standardisert kultur av en patogen bakterie. Alvorligheten av infeksjonen standardiseres slik at musene får én til ti ganger LD100 ^LD100: minimum innpodning som er nødvendig for konsekvent å drepe 100% av kontrollmusene). Ved forsøkets slutt bedømmes forbindelsens aktivitet ved å telle antall overlevende som har vært utsatt for bakterien og også har fått forbindelsen med formel (II). Forbindelsene med formel (II) kan administreres ved både oral (p.o.) bg subkutan (s.c.) administrering. The compounds of formula (II) and (VIII) have in vivo antibacterial activity in mammals, and this activity can be demonstrated by standard methods for penicillin compounds. E.g. the compound of formula (II) is administered to mice in which acute infections have been induced by intraperitoneal inoculation with a standardized culture of a pathogenic bacterium. The severity of the infection is standardized so that the mice receive one to ten times the LD100 ^LD100: minimum inoculation required to consistently kill 100% of control mice). At the end of the experiment, the activity of the compound is assessed by counting the number of survivors who have been exposed to the bacteria and have also received the compound of formula (II). The compounds of formula (II) can be administered by both oral (p.o.) and subcutaneous (s.c.) administration.
In vivo aktiviteten av de antibakterielle forbindelser In vivo activity of the antibacterial compounds
(II) og (VIII) gjør dem egnet for bekjempelse av bakterie-infeksjoner i pattedyr, innbefattet mennesker, ved både oral og parenteral administrering. Forbindelsene er nyttige for bekjempelse av infeksjoner som forårsakes av påvirkelige b bakterier hos mennesker. Generelt er det substituenten R som bestemmer hvorvidt en gitt bakterie vil påvirkes av en gitt forbindelse med formel (VIII). En forbindelse med formel (VIII) nedbrytes til den tilsvarende forbindelse med formel (VII) (II) and (VIII) make them suitable for combating bacterial infections in mammals, including humans, by both oral and parenteral administration. The compounds are useful for combating infections caused by susceptible b bacteria in humans. In general, it is the substituent R that determines whether a given bacterium will be affected by a given compound of formula (VIII). A compound of formula (VIII) breaks down to the corresponding compound of formula (VII)
(eller et salt derav) og penicillansyre-1,1-dioksyd (XIII) efter administrering til et pattedyr enten oralt eller parenteralt. (or a salt thereof) and penicillanic acid 1,1-dioxide (XIII) after administration to a mammal either orally or parenterally.
Penicillansyre-1,1-dioksyd virker da som en Ø-laktamase-inhibitor og øker den antibakterielle effektivitet av forbindelsen med formel (VII) (eller et salt derav) . Når R<*3> er D-2-amino-2-fenylacetyl eller D-2-amino-2-[4-hydroksyfenyl]-acetyl, er forbindelsene nyttige til bekjempelse av infeksjoner forårsaket av påvirkelige stammer av Escherichia coli og Staphylococcus aureus. Penicillanic acid 1,1-dioxide then acts as an β-lactamase inhibitor and increases the antibacterial effectiveness of the compound of formula (VII) (or a salt thereof). When R<*3> is D-2-amino-2-phenylacetyl or D-2-amino-2-[4-hydroxyphenyl]-acetyl, the compounds are useful in combating infections caused by susceptible strains of Escherichia coli and Staphylococcus aureus .
Ved bestemmelse av hvorvidt en spesiell stamme av Staphylococcus aureus eller Escherichia coli er følsom overfor When determining whether a particular strain of Staphylococcus aureus or Escherichia coli is sensitive to
en spesiell forbindelse med formel (II) eller (VIII), kan man anvende den tidligere beskrevne in vivo undersøkelse. Alterna-tivt kan man måle den minimum hemmende konsentrasjon (MIC) a particular compound of formula (II) or (VIII), one can use the previously described in vivo examination. Alternatively, one can measure the minimum inhibitory concentration (MIC)
av en 1:1 blanding av forbindelsen med formel (VII) (eller dens salt) og forbindelsen med formel (XIII) (eller dens salt). MIC-verdiene kan måles ved fremgangsmåten anbefalt av International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson og Sherris, Acta. Pathologica et Microbiologia Scandinav. Supp. 217, section B: 64-68 [1971]), som benytter hjerne-hjerte-infusjons- (BHI) agar og podestoff-dupliserende anordning. Vekst-tuber for bruk natten over fortynnes 100 ganger for anvendelse som standard podestoff (20.000-10.000 celler i ca. 0,002 ml anbringes på agaroverflaten; 20 ml BHI agar/skål). Tolv dobbelte fortynninger av prøveforbindelsen anvendes, med begynnelseskonsentrasjon av prøveforbindelsen på 200 Mg/ml. of a 1:1 mixture of the compound of formula (VII) (or its salt) and the compound of formula (XIII) (or its salt). The MIC values can be measured by the method recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav. Supp. 217, section B: 64-68 [1971]), which uses brain-heart infusion - (BHI) agar and inoculum duplicating device. Growth tubes for overnight use are diluted 100-fold for use as standard inoculum (20,000-10,000 cells in approx. 0.002 ml are placed on the agar surface; 20 ml BHI agar/dish). Twelve-fold dilutions of the test compound are used, with an initial concentration of the test compound of 200 Mg/ml.
Man ser bort fra enkeltkolonier når man undersøker platene Individual colonies are disregarded when examining the plates
efter 18 timer ved 37°C. Prøveorganismens mottagelighet after 18 hours at 37°C. Susceptibility of the test organism
(MIC) ansees som den laveste konsentrasjon for en forbindelse (MIC) is considered the lowest concentration for a compound
som er i stand til å frembringe fullstendig hemning av veksten som bedømt med det blotte øye. which is capable of producing complete inhibition of growth as judged by the naked eye.
De følgende eksempler og fremstillinger skal tjene til The following examples and presentations will serve
å illustrere oppfinnelsen ytterligere. Infrarøde spektra (IR) to further illustrate the invention. Infrared spectra (IR)
ble målt ufortynnet, som nujol oppslemming eller som kaliumbromid-skiver (KBr-skiver) og diagnostiske absorpsjonsbånd er angitt i bølgetall (cm . Kjernemagnetiske resonans-spektra (NMR) ble målt ved 60 MHz for oppløsninger i deuterert kloroform (CDC13), D20, CD3SOCD3, eller deuterert aceton (CD3COCD3), og topp-stillinger er angitt i deler pr. million nedover i feltet fra tetrametylsilan. De følgende forkortelser for topp-former were measured undiluted, as Nujol slurry or as potassium bromide discs (KBr discs) and diagnostic absorption bands are given in wavenumber (cm . Nuclear magnetic resonance (NMR) spectra were measured at 60 MHz for solutions in deuterated chloroform (CDC13), D20, CD3SOCD3, or deuterated acetone (CD3COCD3), and peak positions are given in parts per million downfield from tetramethylsilane.The following abbreviations for peak shapes
er anvendt: s, singlett; d, dublett; t, triplett; q, kvartett; m, multiplett; dd, dobbel dublett. are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double duplicate.
Eksempel 1 (mellomprodukt) Example 1 (intermediate)
Klormetyl- 6, 6- dibrompenicillanat Chloromethyl- 6, 6- dibromopenicillanate
6,6-dibrompenicillansyre (8,0 g, 22 mmol) ble omrørt med 75 ml metylenklorid, og 35 ml vann ble tilsatt. Til denne oppløsning ble satt tetrabutylammoniumhydroksyd for å regulere pH-verdien til 8. Det organiske lag ble fraskilt, og den vandige fase ble ekstrahert med 30 ml metylenklorid. De samlede organiske lag ble inndampet til tørrhet i vakuum for å danne tetrabutylammoniumsaltet av 6,6-dibrompenicillansyre, 14,2 g, som en lysebrun olje. Til denne ble satt 40 ml klorjodmetan, og den resulterende blanding ble omrørt under nitrogen i 3 timer ved romtemperatur. Reaksjonsblandingen ble konsentrert i vakuum, residuet ble lagret hatten over ved romtemperatur og renset ved kromatografi på 300 g silikagel, idet eluering ble foretatt med 95:5 (efter volum) toluen/etylacetat. Fraksjoner inneholdende det minst polare materiale ble samlet og inndampet for å gi 5,4 g (59%) av det ønskede produkt, sm.p. 105-106°C. <1>H-NMR (CDC13) ppm (6): 1,6 (s, 3H), 1,75 (s, 3H), 4,62 6,6-Dibromopenicillanic acid (8.0 g, 22 mmol) was stirred with 75 mL of methylene chloride, and 35 mL of water was added. To this solution was added tetrabutylammonium hydroxide to adjust the pH to 8. The organic layer was separated and the aqueous phase was extracted with 30 ml of methylene chloride. The combined organic layers were evaporated to dryness in vacuo to give the tetrabutylammonium salt of 6,6-dibromopenicillanic acid, 14.2 g, as a light brown oil. To this was added 40 ml of chloroiodomethane, and the resulting mixture was stirred under nitrogen for 3 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue was stored at room temperature and purified by chromatography on 300 g of silica gel, elution being carried out with 95:5 (by volume) toluene/ethyl acetate. Fractions containing the least polar material were collected and evaporated to give 5.4 g (59%) of the desired product, m.p. 105-106°C. <1>H-NMR (CDCl 3 ) ppm (6): 1.6 (s, 3H), 1.75 (s, 3H), 4.62
(s, 1H), 5,8 (dd, 2H), 5,82 (s, 1H). (s, 1H), 5.8 (dd, 2H), 5.82 (s, 1H).
Når den ovenstående fremgangsmåte gjentas, bortsett fra at det der anvendte klorjodmetan erstattes med en ekvimolar mengde bromjodmetan, dijodmetan, di(metylsulfonyloksy)metan, di(isobutylsulfonyloksy)metan, di(n-heksylsulfonyloksy)metan, di(benzensulfonyloksy)metan eller en forbindelse med formelen (R2C6H4S020)2CH2 hvor R<2> er 4-C1, 2-Br, 4-1, 3-N02, 4-CH3, 3-(CH3)2CH, 4-CH30, 3-C2H50 eller 4-n-C3H70, får man henholdsvis : brommetyl-6,6-dibrompenicillanat, When the above procedure is repeated, except that the chloroiodomethane used there is replaced with an equimolar amount of bromoiodomethane, diiodomethane, di(methylsulfonyloxy)methane, di(isobutylsulfonyloxy)methane, di(n-hexylsulfonyloxy)methane, di(benzenesulfonyloxy)methane or a compound of the formula (R2C6H4S020)2CH2 where R<2> is 4-C1, 2-Br, 4-1, 3-N02, 4-CH3, 3-(CH3)2CH, 4-CH30, 3-C2H50 or 4-n -C3H70, you get respectively: bromomethyl-6,6-dibromopenicillanate,
jodmety1-6,6-dibrompenicillanat, iodomethyl 1-6,6-dibromopenicillanate,
metylsulfonyloksymetyl-6,6-dibrompenicillanat, methylsulfonyloxymethyl-6,6-dibromopenicillanate,
isobutylsulfonyloksymetyl-6,6-dibrompenicillanat, n-heksylsulfonyloksymetyl-6,6-dibrompenicillanat, benzensulfonyloksymetyl-6,6-dibrompenicillanat, og isobutylsulfonyloxymethyl-6,6-dibromopenicillanate, n-hexylsulfonyloxymethyl-6,6-dibromopenicillanate, benzenesulfonyloxymethyl-6,6-dibromopenicillanate, and
R ? -CgH^-sulfonyloksymetyl-6,6-dibrompenicillanater, hvor R 2er R? -CgH^-sulfonyloxymethyl-6,6-dibromopenicillanates, where R 2 is
som angitt ovenfor for di(substituert fenylsulfonyloksy)metan-reagenset. as indicated above for the di(substituted phenylsulfonyloxy)methane reagent.
Eksempel IA (mellomprodukt) Example IA (intermediate product)
Jodmetyl- 6, 6- dibrompenicillanat Iodomethyl- 6, 6- dibromopenicillanate
Til 25 ml aceton ble satt 4,15 g (10,2 mmol) klormetyl-6,6-dibrompenicillansyre og 7,5 g (50 mmol) natriumjodid. Blandingen ble omrørt natten over ved romtemperatur, og 4.15 g (10.2 mmol) of chloromethyl-6,6-dibromopenicillanic acid and 7.5 g (50 mmol) of sodium iodide were added to 25 ml of acetone. The mixture was stirred overnight at room temperature, and
acetonet ble avdampet for å gi et mørkt residuum. Dette ble oppløst i 150 ml etylacetat, vasket med vann (3 x 25 ml) , the acetone was evaporated to give a dark residue. This was dissolved in 150 ml of ethyl acetate, washed with water (3 x 25 ml),
mettet saltoppløsning (25 ml), tørret (MgSO^), og oppløsnings-midlet ble inndampet i vakuum for å gi en gjenværende olje som ble renset ved kromatografi på 100 g silikagel, idet eluering ble foretatt med 1:1 (efter volum) etylacetat/heksan. saturated brine (25 ml), dried (MgSO 4 ), and the solvent was evaporated in vacuo to give a residual oil which was purified by chromatography on 100 g of silica gel, eluting with 1:1 (by volume) ethyl acetate /hexane.
30 ml fraksjoner ble oppsamlet. Produktet ble eluert i fraksjonene 4-6., som ble blandet og inndampet for å gi 5,95 g farveløs olje som krystalliserte ved henstand, sm.p. 67-68°C. <1>H-NMR (CDC13) ppm (6): 1,55 (s, 3H), 1,65 (s, 3H), 4,54 30 ml fractions were collected. The product was eluted in fractions 4-6, which were combined and evaporated to give 5.95 g of colorless oil which crystallized on standing, m.p. 67-68°C. <1>H-NMR (CDCl 3 ) ppm (6): 1.55 (s, 3H), 1.65 (s, 3H), 4.54
(s, 1H), 5,8 (s, 1H), 5,98 (s, 2H). (s, 1H), 5.8 (s, 1H), 5.98 (s, 2H).
Ved anvendelse av brommétyl-6,6-dibrompenicillanat, brommetyl-6,6-diklorpenicillanat, klormetyl-6,6-diklorpenicillanat, klormetyl-6-brom-6-klorpenicillanat, klormetyl-6-klor-6-jod-penicillanat , klormetyl-6-brom-6-jodpenicillanat eller brom-metyl-6-brom-6-jodpenicillanat istedenfor klormetyl-6,6-dibrompenicillanat ved den ovenfor angitte fremgangsmåte, oppnås When using bromomethyl-6,6-dibromopenicillanate, bromomethyl-6,6-dichloropenicillanate, chloromethyl-6,6-dichloropenicillanate, chloromethyl-6-bromo-6-chloropenicillanate, chloromethyl-6-chloro-6-iodo-penicillanate, chloromethyl -6-bromo-6-iodopenicillanate or bromo-methyl-6-bromo-6-iodopenicillanate instead of chloromethyl-6,6-dibromopenicillanate in the above-mentioned method is obtained
i hvert tilfelle den tilsvarende jodmetylester. in each case the corresponding iodomethyl ester.
Eksempel 2 (mellomprodukt) Example 2 (intermediate)
Klormetyl- 6, 6- dibrompenicillanat- l, 1- dioksyd Chloromethyl-6,6-dibromopenicillanate-1,1-dioxide
En oppløsning av 7,1 g (17,4 mmol) klormetyl-6,6-dibrompenicillanat i 75 ml etylacetat ble avkjølt til 0°C, og 7,3 g (36 mmol) m-klor-perbenzoesyre ble tilsatt. Blandingen ble omrørt under nitrogen ved 0°C natten over, fortynnet til 150 ml med etylacetat, og 50 ml vann ble tilsatt ved 0°C. Tilstrekkelig natriumbisulfitt ble tilsatt til å ødelegge overskudd av persyre, blandingen ble regulert fra pH 2 til pH 7,5 med natriumbikarbonat, og det organiske lag ble fraskilt og vasket med 50 ml mettet natriumbikarbonat, 50 ml vann og 25 ml saltoppløsning. De vaskede ekstrakter ble tørret (MgSO^), konsentrert til tørrhet i vakuum, og residuet ble renset ved kromatografi på 300 g silikagel, idet eluering ble foretatt med 9:1 (efter volum) toluen/heksan for å gi 5,0 g (65%) av det ønskede dioksyd som et krystallinsk, fast stoff, A solution of 7.1 g (17.4 mmol) of chloromethyl-6,6-dibromopenicillanate in 75 ml of ethyl acetate was cooled to 0°C, and 7.3 g (36 mmol) of m-chloro-perbenzoic acid was added. The mixture was stirred under nitrogen at 0°C overnight, diluted to 150 mL with ethyl acetate, and 50 mL of water was added at 0°C. Sufficient sodium bisulfite was added to destroy excess peracid, the mixture was adjusted from pH 2 to pH 7.5 with sodium bicarbonate, and the organic layer was separated and washed with 50 mL saturated sodium bicarbonate, 50 mL water, and 25 mL brine. The washed extracts were dried (MgSO 4 ), concentrated to dryness in vacuo, and the residue was purified by chromatography on 300 g of silica gel, eluting with 9:1 (by volume) toluene/hexane to give 5.0 g ( 65%) of the desired dioxide as a crystalline solid,
sm.p. 95-96°c. sm.p. 95-96°c.
<1>H-NMR (CDC13) ppm (6): 1,5 (s, 3H), 1,7 (s, 3H), 4,58 (s, 1H), 5,04 (s, 1H), 5,8 (dd, 2H). <1>H-NMR (CDCl 3 ) ppm (6): 1.5 (s, 3H), 1.7 (s, 3H), 4.58 (s, 1H), 5.04 (s, 1H), 5.8 (dd, 2H).
Analyse: Analysis:
Beregnet for CgH10N05SBr2Cl: C 24,59, H 2,29, N 3,18 Funnet: C 24,63, H 2,49, N 3,31. Calculated for CgH10N05SBr2Cl: C 24.59, H 2.29, N 3.18 Found: C 24.63, H 2.49, N 3.31.
En annen, mer polar komponent ble isolert fra kromatografikolonnen, 0,8 g. Denne ble identifisert som en 9:1 blanding av a- og ø-sulfoksydene av klormetyl-6,6-dibrompenicillanat ved ^"H-NMR. Another, more polar component was isolated from the chromatography column, 0.8 g. This was identified as a 9:1 mixture of the α- and β-sulfoxides of chloromethyl-6,6-dibromopenicillanate by 1 H-NMR.
Eksempel 2A (mellomprodukt) Example 2A (intermediate)
Jodmetyl- 6, 6- dibrompenicillanat- l, 1- dioksyd Iodomethyl-6,6-dibromopenicillanate-1,1-dioxide
Til 40 ml aceton ble satt 0,25 g (0,5 mmol) jodmety1-6,6-dibrompenicillanat, og blandingen ble omrørt inntil man fikk en oppløsning, 10 ml vann ble tilsatt, fulgt av tilstrekkelig konsentrert fosforsyre til å regulere blandingen til pH 4,0. Derefter ble 158 mg (1 mmol) pulverisert kaliumpermanganat tilsatt, og blandingen ble omrørt ved romtemperatur i 1,25 timer. Etylacetat, 100 ml, og vann, 50 ml, ble tilsatt. Den resulterende blanding ble regulert til pH 2,0 med 6N saltsyre, og natriumbisulfitt ble tilsatt for å forbruke overskudd av oksydasjonsmiddel (pH 2,9). Det organiske lag ble fraskilt, den vandige fase ble ekstrahert med 50 ml etylacetat, og de samlede organiske lag ble vasket med mettet saltoppløsning (3 x 25 ml). Efter tørring over vannfritt natriumsulfat og avdampning av oppløsningsmidlet fikk man 0,29 g farveløs olje. Oljen ble renset ved kromatografi på 25 g silikagel, idet eluering ble foretatt med 1:1 etylacetat/heksan, og man tok 15 ml fraksjoner. Fraksjonene 4 og 5 ble blandet og inndampet i vakuum for å gi 0,27 g (100%) farveløs olje som krystalliserte ved henstand, sm.p. 71-73°C. To 40 ml of acetone was added 0.25 g (0.5 mmol) of iodomethyl-6,6-dibromopenicillanate, and the mixture was stirred until a solution was obtained, 10 ml of water was added, followed by sufficient concentrated phosphoric acid to adjust the mixture to pH 4.0. Then 158 mg (1 mmol) of powdered potassium permanganate was added and the mixture was stirred at room temperature for 1.25 hours. Ethyl acetate, 100 ml, and water, 50 ml, were added. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid, and sodium bisulfite was added to consume excess oxidant (pH 2.9). The organic layer was separated, the aqueous phase was extracted with 50 mL of ethyl acetate, and the combined organic layers were washed with saturated saline (3 x 25 mL). After drying over anhydrous sodium sulfate and evaporation of the solvent, 0.29 g of colorless oil was obtained. The oil was purified by chromatography on 25 g of silica gel, eluting with 1:1 ethyl acetate/hexane, and 15 ml fractions were taken. Fractions 4 and 5 were combined and evaporated in vacuo to give 0.27 g (100%) of a colorless oil which crystallized on standing, m.p. 71-73°C.
"""H-NMR (CDC13) ppm (6): 1,5 (s, 3H) , 1,62 (s, 3H) , 4,49 (s, 1H) , 5,02 (s, 1H), 5,98 (dd, 2H). """H-NMR (CDCl 3 ) ppm (6): 1.5 (s, 3H) , 1.62 (s, 3H) , 4.49 (s, 1H) , 5.02 (s, 1H), 5.98 (dd, 2H).
Anvendelse av en ekvivalent mengde natriumpermanganat eller kalsiumpermanganat istedenfor kaliumpermanganat ved den ovenfor beskrevne fremgangsmåte ga det samme produkt på lignende måte. Using an equivalent amount of sodium permanganate or calcium permanganate instead of potassium permanganate in the above described process gave the same product in a similar manner.
Forsøk på å fremstille jodmetyl-6,6-dibrompenicillanat-1,1-dioksyd fra klormetylesteren fremstilt i eksempel 2, ved behandling med natriumjodid i aceton ved fremgangsmåten ifølge eksempel IA, ga jodmetyl-6-a-brompenicillanat-l,1-dioksyd. <1>H-NMR (CDC13) ppm/6: 1,55 (s, 3H), 1,70 (s, 3H), 4,43 (s, 1H), 5.2 (d, 1H), 5,75 (d, 1H), 6,0 (dd, 2H). Attempts to prepare iodomethyl-6,6-dibromopenicillanate-1,1-dioxide from the chloromethyl ester prepared in Example 2, by treatment with sodium iodide in acetone by the method of Example IA, gave iodomethyl-6-a-bromopenicillanate-1,1-dioxide . <1>H-NMR (CDC13) ppm/6: 1.55 (s, 3H), 1.70 (s, 3H), 4.43 (s, 1H), 5.2 (d, 1H), 5.75 (d, 1H), 6.0 (dd, 2H).
Eksempel 3 (mellomprodukt) Example 3 (intermediate)
Jodmetyl- 6- brom- 6- klorpenicillanat- l, 1- dioksyd Iodomethyl- 6- bromo- 6- chlorpenicillanate- 1, 1- dioxide
En oppløsning av 7,6 g (17,4 mmol) jodmetyl-6-brom-6-klorpenicillanat i 75 ml etylacetat ble avkjølt til 0°C, og 7.3 g (36 mmol) m-klorperbenzoesyre ble tilsatt. Blandingen ble omrørt under nitrogen ved 0°C natten over, fortynnet til 150 ml med etylacetat, og 50 ml vann ble tilsatt ved 0°C. Tilstrekkelig natriumbisulfitt ble tilsatt til å ødelegge overskudd av persyre, blandingen ble regulert fra pH 2 til pH 7,5 med natriumbikarbonat, og det organiske lag ble fraskilt og vasket med 50 ml mettet natriumbikarbonat, 50 ml vann og 25 ml saltoppløsning. De vaskede ekstrakter ble tørret (MgSO^), konsentrert til tørrhet i vakuum, og residuet ble renset ved kromatografi på silikagel. A solution of 7.6 g (17.4 mmol) of iodomethyl-6-bromo-6-chloropenicillanate in 75 ml of ethyl acetate was cooled to 0°C, and 7.3 g (36 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred under nitrogen at 0°C overnight, diluted to 150 mL with ethyl acetate, and 50 mL of water was added at 0°C. Sufficient sodium bisulfite was added to destroy excess peracid, the mixture was adjusted from pH 2 to pH 7.5 with sodium bicarbonate, and the organic layer was separated and washed with 50 mL saturated sodium bicarbonate, 50 mL water, and 25 mL brine. The washed extracts were dried (MgSO 4 ), concentrated to dryness in vacuo, and the residue was purified by chromatography on silica gel.
Eksempel 4 (mellomprodukt) Example 4 (intermediate)
Jodmetyl- 6, 6- diklorpenicillanat- l, 1- dioksyd Iodomethyl-6,6-dichloropenicillanate-1,1-dioxide
Til en oppløsning av 4,09 g (0,01 mol) jodmetyl-6,6-diklorpenicillanat i 50 ml aceton settes 2,5 ml (0,24 mol) To a solution of 4.09 g (0.01 mol) iodomethyl-6,6-dichloropenicillanate in 50 ml acetone add 2.5 ml (0.24 mol)
30% hydrogenperoksyd og 1 ml 0,5M vandig natrium-wolframat. Blandingen oppvarmes ved tilbakeløpstemperatur i 1 time og omrøres natten over ved romtemperatur. Avdampning av opp-løsningsmidlet gir råproduktet som renses ved kromatografi på silikagel. 30% hydrogen peroxide and 1 ml of 0.5M aqueous sodium tungstate. The mixture is heated at reflux temperature for 1 hour and stirred overnight at room temperature. Evaporation of the solvent gives the crude product which is purified by chromatography on silica gel.
Når vandig kaliummolybdat eller zirkoniumtetraklorid anvendes istedenfor natrium-wolframat ved den ovenfor beskrevne fremgangsmåte, er resultatet i alt vesentlig det samme. When aqueous potassium molybdate or zirconium tetrachloride is used instead of sodium tungstate in the method described above, the result is essentially the same.
Når metanol, etanol, isopropanol, metyletylketon eller deres blandinger med vann anvendes som oppløsningsmiddel istedenfor aceton og omsetningen utføres ved fra 25 til 60°C, oppnås tittelforbindelsen på lignende måte. When methanol, ethanol, isopropanol, methyl ethyl ketone or their mixtures with water are used as solvent instead of acetone and the reaction is carried out at from 25 to 60°C, the title compound is obtained in a similar manner.
Eksempel 5 (mellomprodukt) Example 5 (intermediate)
Klormetyl- 6- g- brompenicillanat- l, 1- dioksyd Chloromethyl-6-g-bromopenicillanate-1,1-dioxide
Til en oppløsning av 3,52 g (8 mmol) klormetyl-6,6-dibrompenicillanat-l , 1-dioksyd i tørr benzen (100 ml) under nitrogen, settes ved 0°C 2,32 g (8 mmol) tri-n-butyltinnhydrid. Den resulterende blanding omrøres natten over ved romtemperatur, oppløsningsmidlet avdampes i vakuum, og residuet renses ved kolonnekromatografi på silikagel for å gi tittelforbindelsen. 2.32 g (8 mmol) of tri- n-butyltin hydride. The resulting mixture is stirred overnight at room temperature, the solvent is evaporated in vacuo, and the residue is purified by column chromatography on silica gel to give the title compound.
Alternativt oppnås det samme produkt ved å anvende klormetyl-6,6-dibrompenicillansyre ved den ovenfor beskrevne fremgangsmåte og ved.å oksydere det resulterende sulfid, klormety1-6-0-brompenicillanat, til sulfonet ved fremgangsmåten ifølge eksempel 2, 2A, 3 eller 4. Alternatively, the same product is obtained by using chloromethyl-6,6-dibromopenicillanic acid by the method described above and by oxidizing the resulting sulfide, chloromethyl-6-0-bromopenicillanate, to the sulfone by the method according to examples 2, 2A, 3 or 4 .
Eksempel 6 (mellomprodukt) Example 6 (intermediate)
Jodmetyl- 6- g- brompenicillanat- l, 1- dioksyd Iodomethyl-6-g-bromopenicillanate-1,1-dioxide
En oppløsning av 0,12 g (0,33 mmol) klormetyl-6-/3-brompenicillanat-1,1-dioksyd og 0,25 g (1,66 mmol) natriumjodid A solution of 0.12 g (0.33 mmol) of chloromethyl-6-(3-bromopenicillanate-1,1-dioxide) and 0.25 g (1.66 mmol) of sodium iodide
i 5 ml aceton ble omrørt i 30 timer ved romtemperatur. Den resulterende blekgule suspensjon ble inndampet til tørrhet, og residuet ble tatt opp i 50 ml etylacetat, vasket suksessivt med 2 x 10 ml vann, 10 ml mettet saltoppløsning og tørret over vannfritt natriumsulfat. Den resulterende oppløsning ble inndampet ved redusert trykk for å gi tittelforbindelsen, som et fast stoff, 0,14 g. in 5 ml of acetone was stirred for 30 hours at room temperature. The resulting pale yellow suspension was evaporated to dryness, and the residue was taken up in 50 mL of ethyl acetate, washed successively with 2 x 10 mL of water, 10 mL of saturated saline, and dried over anhydrous sodium sulfate. The resulting solution was evaporated under reduced pressure to give the title compound as a solid, 0.14 g.
<1>H-NMR (CDC13) ppm (6): 1,45 (s, 3H), 1,65 (s, 3H), 4,5 (s, 1H), 4,83 (d, 1H), 5,42 (d, 1H), 6,0 (dd, 2H). <1>H-NMR (CDCl 3 ) ppm (6): 1.45 (s, 3H), 1.65 (s, 3H), 4.5 (s, 1H), 4.83 (d, 1H), 5.42 (d, 1H), 6.0 (dd, 2H).
Eksempel 7 (mellomprodukt) Example 7 (intermediate)
6- g- brompenicillansyre- l, 1- dioksyd 6- g- bromopenicillanic acid- 1, 1- dioxide
Til en omrørt blanding av 560 ml vann, 300 ml diklormetan og 56,0 g 6-a-brompenicillansyre ble satt 4N natriumhydroksyd-oppløsning inntil man fikk en stabil pH på 7,2. Dette krevde 5 5 ml natriumhydroksyd. Blandingen ble omrørt ved pH 7,2 i To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-a-bromopenicillanic acid was added 4N sodium hydroxide solution until a stable pH of 7.2 was obtained. This required 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 in
10 minutter og ble derefter filtrert. Lagene ble separert, 10 minutes and was then filtered. The teams were separated,
og den organiske fase ble kastet. Den vandige fase ble derefter hellet raskt under omrøring i en oksyderende blanding som var fremstilt som følger. and the organic phase was discarded. The aqueous phase was then poured rapidly with stirring into an oxidizing mixture prepared as follows.
I en 3 liters kolbe ble blandet 63,2 g kaliumpermanganat, 1000 ml vann og 48,0 g eddiksyre. Denne blanding ble omrørt i 15 minutter ved 20°C og ble derefter avkjølt til 0°C. In a 3 liter flask, 63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid were mixed. This mixture was stirred for 15 minutes at 20°C and then cooled to 0°C.
Efter at 6-a-brompenicillansyre-oppløsningen var satt til den oksyderende blanding, ble et kjølebad på -15°C holdt rundt reaksjonsblandingen. Den indre temperatur steg til 15°C og sank derefter til 5°C over en periode på 20 minutter. På dette punkt ble 30,0 g natriummetabisulfitt tilsatt under omrøring over en 10 minutters periode ved ca. 10°C. Efter ytterligere 15 minutter ble blandingen filtrert, og filtratets pH-verdi ble senket til 1,2 ved tilsetning av 170 ml 6N saltsyre. Den vandige fase ble ekstrahert med kloroform og derefter med etylacetat. Både kloroformekstraktene og etylacetatekstraktene ble tørret under anvendelse av vannfritt magnesiumsulfat, og de ble derefter inndampet i vakuum. Kloroformoppløsningen ga 10,0 g (16% utbytte) av tittelforbindelsen. Etylacetat-oppløsningen ga 57 g av en olje som ble utgnidd under heksan. Man fikk et hvitt, fast stoff. Det ble frafiltrert for å After the 6-a-bromopenicillanic acid solution was added to the oxidizing mixture, a cooling bath of -15°C was maintained around the reaction mixture. The internal temperature rose to 15°C and then fell to 5°C over a period of 20 minutes. At this point, 30.0 g of sodium metabisulphite was added with stirring over a 10 minute period at approx. 10°C. After a further 15 minutes, the mixture was filtered, and the filtrate's pH value was lowered to 1.2 by adding 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform and then with ethyl acetate. Both the chloroform and ethyl acetate extracts were dried using anhydrous magnesium sulfate and then evaporated in vacuo. The chloroform solution gave 10.0 g (16% yield) of the title compound. The ethyl acetate solution gave 57 g of an oil which was triturated under hexane. A white, solid substance was obtained. It was filtered out to
gi 41,5 g (66% utbytte) av tittelforbindelsen, sm.p. 134°C (dekomp.). give 41.5 g (66% yield) of the title compound, m.p. 134°C (decomp.).
Analyse: Beregnet for CgH^0BrN0^S: Analysis: Calculated for CgH^0BrN0^S:
C 30,78, H 3-,23, Br 25,60, N 4,49, S 10,27%, C 30.78, H 3-.23, Br 25.60, N 4.49, S 10.27%,
Funnet: Found:
C 31,05, H 3,24, Br 25,54, N 4,66, S 10,21%. C 31.05, H 3.24, Br 25.54, N 4.66, S 10.21%.
Oksydasjon av 6-a-klorpenicillansyre og 6-a-jod-penicillansyre med kaliumpermanganat i henhold til den ovenfor beskrevne fremgangsmåte gir henholdsvis 6-ct-klorpenicillansyre-1,1-dioksyd og 6-a-jodpenicillansyre-1,1-dioksyd. Oxidation of 6-α-chloropenicillanic acid and 6-α-iodopenicillanic acid with potassium permanganate according to the method described above yields 6-α-chloropenicillanic acid 1,1-dioxide and 6-α-iodopenicillanic acid 1,1-dioxide, respectively.
Eksempel 8(mellomprodukt) Example 8 (intermediate)
6- <3- klorpenicillansyre- l, 1- dioksyd 6- <3- chlorpenicillanic acid- 1, 1- dioxide
En oksyderende oppløsning ble fremstilt fra 185 mg kaliumpermanganat, 0,063 ml 85% fosforsyre og 5 ml vann. Denne oksyderende oppløsning ble satt dråpevis til en oppløsning av 150 mg natrium-6-ø-klorpenicillanat i 5 ml vann ved 0-5°C inntil den fiolette farve av kaliumpermanganatet holdt seg. An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of sodium 6-o-chloropenicillanate in 5 ml of water at 0-5°C until the violet color of the potassium permanganate remained.
Ca. halvparten av den oksyderende oppløsning var nødvendig. About. half of the oxidizing solution was required.
På dette punkt ble kaliumpermanganat-farven fjernet ved tilsetning av fast natriumbisulfitt, og derefter ble reaksjonsblandingen filtrert. Etylacetat ble satt til filtratet, og pH-verdien ble regulert til 1,8. Lagene ble separert, og det vandige lag ble ekstrahert videre med etylacetat. De samlede etylacetatlag ble vasket med vann, tørret og inndampet i vakuum for å gi 118 mg av tittelforbindelsen. At this point, the potassium permanganate color was removed by addition of solid sodium bisulfite, and then the reaction mixture was filtered. Ethyl acetate was added to the filtrate and the pH was adjusted to 1.8. The layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound.
NMR-spekteret (i CD3COCD3) viste absorpsjon ved 5,82 (d, 1H), 5,24 (d, 1H), 4,53 (s, 1H), 1,62 (s, 3H) og 1,50 (s, 3H) ppm. The NMR spectrum (in CD3COCD3) showed absorption at 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H) and 1.50 ( s, 3H) ppm.
Det ovenstående produkt ble oppløst i tetrahydrofuran, The above product was dissolved in tetrahydrofuran,
og et likt volum vann ble tilsatt. pH-verdien ble regulert til 6,8 under anvendelse av fortynnet natriumhydroksyd, tetrahydrofuranet ble fjernet ved inndampning i vakuum, og den gjenværende vandige oppløsning ble frysetørret. Dette ga natriumsaltet av tittelforbindelsen. and an equal volume of water was added. The pH was adjusted to 6.8 using dilute sodium hydroxide, the tetrahydrofuran was removed by evaporation in vacuo, and the remaining aqueous solution was freeze-dried. This gave the sodium salt of the title compound.
Eksempel 9 (mellomprodukt) Example 9 (intermediate)
6- <3- brompenicillansyre- l, 1- dioksyd 6- <3- bromopenicillanic acid- 1, 1- dioxide
Til en oppløsning av 255 mg natrium-6-Ø-brompenicillanat To a solution of 255 mg of sodium 6-Ø-bromopenicillanate
i 5 ml vann, ved 0 til 5°C, ble satt en oppløsning fremstilt fra 140 mg kaliumpermanganat, 0,11 ml 85% fosforsyre og 5 ml vann, ved 0 til 5°C. pH-verdien ble holdt mellom 6,0 og 6,4 under tilsetningen. Reaksjonsblandingen ble omrørt ved pH 6,3 in 5 ml of water, at 0 to 5°C, was placed a solution prepared from 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water, at 0 to 5°C. The pH value was maintained between 6.0 and 6.4 during the addition. The reaction mixture was stirred at pH 6.3
i 15 minutter, og derefter ble den fiolette oppløsning dekket med etylacetat. pH-verdien ble regulert til 1,7, og 330 mg natriumbisulfitt ble tilsatt. Efter 5 minutter ble lagene fraskilt, og det vandige lag ble ekstrahert videre med etylacetat. De samlede etylacetatoppløsninger ble vasket med salt-oppløsning, tørret (MgSO^) og inndampet i vakuum. Dette ga 216 mg av tittelforbindelsen som hvite krystaller. NMR-spekteret (i D20) viste absorpsjoner ved 5,78 (d, 1H, for 15 minutes, and then the violet solution was covered with ethyl acetate. The pH was adjusted to 1.7 and 330 mg of sodium bisulfite was added. After 5 minutes, the layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. This gave 216 mg of the title compound as white crystals. The NMR spectrum (in D 2 O) showed absorptions at 5.78 (d, 1H,
J = 4Hz), 5,25 (d, 1H, J = 4Hz), 4,20 (s, 1H), 1,65 (s, 3H) og 1,4 6 (s, 3H) ppm. J = 4Hz), 5.25 (d, 1H, J = 4Hz), 4.20 (s, 1H), 1.65 (s, 3H) and 1.4 6 (s, 3H) ppm.
Eksempel 10 (mellomprodukt) Example 10 (intermediate)
Klormetyl- 6- a- klorpenicillanat Chlormethyl- 6-a- chlorpenicillanate
En blanding av 2,35 g (0,01 mol) 6-a-klorpenicillansyre A mixture of 2.35 g (0.01 mol) of 6-α-chloropenicillanic acid
og 5,0 ml vann behandles med 5,0 ml 2N kaliumhydroksyd. Kaliumbikarbonat (6,0 g), tetrabutylammoniumhydrogensulfat (0,34 g, 0,001 mol), diklormetan (20 ml) og klormetyl-klorsulfat (1,64 g, 0,011 mol) tilsettes, og den resulterende blanding omrøres ved 25 til 30°C i 2 timer. Reaksjonsblandingen filtreres og lagene separeres. Den organiske fase tørres (Na2S04) og inndampes til tørrhet for å gi tittelforbindelsen. and 5.0 ml of water is treated with 5.0 ml of 2N potassium hydroxide. Potassium bicarbonate (6.0 g), tetrabutylammonium hydrogen sulfate (0.34 g, 0.001 mol), dichloromethane (20 mL) and chloromethyl chlorosulfate (1.64 g, 0.011 mol) are added and the resulting mixture is stirred at 25 to 30°C for 2 hours. The reaction mixture is filtered and the layers are separated. The organic phase is dried (Na 2 SO 4 ) and evaporated to dryness to give the title compound.
Eksempel 11 (mellomprodukt) Example 11 (intermediate)
Klormetyl- 6- a- klorpenicillanat- l- oksyd Chloromethyl-6-a-chlorpenicillanate-1-oxide
Til en omrørt oppløsning av 8,49 g (0,03 mol) klormetyl-6-a-klorpenicillanat i 200 ml kloroform settes ved 0°C en oppløsning av 6,12 g (0,03 mol) 3-klorperbenzoesyre i 100 ml kloroform. Omrøring fortsettes i 1,5 timer ved 0-5°C. A solution of 6.12 g (0.03 mol) 3-chloroperbenzoic acid in 100 ml is added to a stirred solution of 8.49 g (0.03 mol) chloromethyl-6-a-chloropenicillanate in 200 ml chloroform at 0°C chloroform. Stirring is continued for 1.5 hours at 0-5°C.
Derefter filtreres reaksjonsblandingen, vaskes med natrium-bikarbonatoppløsning, vann og tørres (Na2S04). Avdampning av oppløsningsmidlet i vakuum gir den rå tittelforbindelse som en blanding av a- og Ø-sulfoksyder som eventuelt kan renses ved kromatografi på silikagel. The reaction mixture is then filtered, washed with sodium bicarbonate solution, water and dried (Na 2 SO 4 ). Evaporation of the solvent in vacuum gives the crude title compound as a mixture of α- and Ø-sulfoxides which can optionally be purified by chromatography on silica gel.
Alternativt fremstilles tittelforbindelsen ved oksydasjon av 6-a-klorpenicillansyre ved oksydasjon med en ekvivalent 3-klorperbenzoesyre i tetrahydrofuran ved 0-25°C i ca. 1 time, i henhold til fremgangsmåten ifølge Harrison et al., Jour. Chem. Soc. (London), Perkin I, 1772 (1976). Det resulterende 6-a-klorpenicillansyre-l-oksyd forestres derefter ved fremgangsmåten ifølge eksempel 1 for å danne den ønskede klormetyl-ester. Alternatively, the title compound is prepared by oxidation of 6-α-chloropenicillanic acid by oxidation with an equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25°C for approx. 1 hour, according to the method of Harrison et al., Jour. Chem. Soc. (London), Perkin I, 1772 (1976). The resulting 6-α-chloropenicillanic acid 1-oxide is then esterified by the method of Example 1 to form the desired chloromethyl ester.
De gjenværende 6-substituerte penicillanat-estere og 6,6-dihalogenpenicillanat-estere fremstilt i eksemplene 1 og IB omdannes til de tilsvarende 1-oksyder ved den ovenfor beskrevne fremgangsmåte. The remaining 6-substituted penicillanate esters and 6,6-dihalopenicillanate esters prepared in examples 1 and 1B are converted to the corresponding 1-oxides by the method described above.
Den samme forbindelse oppnås ved omsetning av 0,1 mol klormetyl-6-a-klorpenicillanat i 150 ml isopropanol inneholdende 0,8 ml 0,5M natrium-wolframat (Na2W04) eller en ekvivalent mengde kaliummolybdat (K-jMoO^) med 0,1 mol hydrogenperoksyd (30%). Peroksydet settes langsomt til de andre reagenser ved 60°C, hvorefter blandingen får avkjøles mens den omrøres natten over. Produktet isoleres som beskrevet ovenfor. The same compound is obtained by reacting 0.1 mol of chloromethyl-6-a-chloropenicillanate in 150 ml of isopropanol containing 0.8 ml of 0.5M sodium tungstate (Na2W04) or an equivalent amount of potassium molybdate (K-jMoO^) with 0, 1 mol of hydrogen peroxide (30%). The peroxide is slowly added to the other reagents at 60°C, after which the mixture is allowed to cool while it is stirred overnight. The product is isolated as described above.
Eksempel 12 (mellomprodukt) Example 12 (intermediate)
Klormetyl- 6- a- klorpenicillanat- l, 1- dioksyd Chloromethyl-6-α-chlorpenicillanate-1,1-dioxide
Til en oppløsning av 2,83 g, 0,01 mol klormetyl-6-a-klorpenicillanat i 50 ml kloroform settes 4,32 g (0,025 mol) m-klorperbenzoesyre, og blandingen omrøres under en nitrogen-atmosfære i 36 timer ved romtemperatur. Oppløsningsmidlet avdampes i vakuum, residuet fordeles mellom etylacetat og vann ved pH 6,0, og natriumbisulfitt tilsettes inntil en prøve på tilstedeværelse av peroksyder er negativ. pH-verdien reguleres til 8,0, lagene separeres, og den organiske fase vaskes med saltoppløsning, tørres (Na2S04) og inndampes til tørrhet i vakuum for å gi tittelforbindelsen. To a solution of 2.83 g, 0.01 mol of chloromethyl-6-α-chloropenicillanate in 50 ml of chloroform is added 4.32 g (0.025 mol) of m-chloroperbenzoic acid, and the mixture is stirred under a nitrogen atmosphere for 36 hours at room temperature . The solvent is evaporated in vacuo, the residue is partitioned between ethyl acetate and water at pH 6.0, and sodium bisulphite is added until a test for the presence of peroxides is negative. The pH is adjusted to 8.0, the layers are separated, and the organic phase is washed with brine, dried (Na 2 SO 4 ) and evaporated to dryness in vacuo to give the title compound.
Alternativt oppnås tittelforbindelsen ved oksydasjon av det samme utgangsmateriale i metanol eller etanol inneholdende en katalytisk mengde natriumwolframat og tilsetning av 2 molekvivalenter hydrogenperoksyd ved temperaturer fra 20 til 60°C. Alternatively, the title compound is obtained by oxidation of the same starting material in methanol or ethanol containing a catalytic amount of sodium tungstate and addition of 2 molar equivalents of hydrogen peroxide at temperatures from 20 to 60°C.
Eksempel 13 (mellomprodukt) Example 13 (intermediate)
1, l- diokso- 6, 6- dibrompenicillanoyloksymetyl- 6-( D- 2- azido- 2-fenylacetamido) penicillanat 1, l- dioxo- 6, 6- dibromopenicillanoyloxymethyl- 6-( D- 2- azido- 2-phenylacetamido) penicillanate
Til en blanding av 0,232 g. (0,37 mmol) tetrabutylammonium-6-(D-2-azido-2-fenylacetamido)penicillanat<*> og 10 ml aceton ble satt 0,20 g (0,37 mmol) jodmetyl-6,6-dibrompenicillanat-l , 1-dioksyd , og blandingen omrøres ved romtemperatur i 30 minutter. Ytterligere 50 mg tetrabutylammonium-D-(2-azido-2-fenylacetamido)penicillanat ble tilsatt, og omrøring ble fortsatt i 30 minutter. Reaksjonsblandingen ble konsentrert til tørrhet, og residuet ble påført på en kolonne av silikagel (50 g). Eluering med 1:1 (volum/volum) etylacetat/heksan ble utført, idet man tok fraksjoner på 7 ml. Fraksjonene 17-24 ble samlet og inndampet i vakuum for i gi 0,14 g (49%) av det ønskede produkt som en lysegul olje. 0.20 g (0.37 mmol) of iodomethyl- 6,6-dibromopenicillanate-1,1-dioxide, and the mixture is stirred at room temperature for 30 minutes. An additional 50 mg of tetrabutylammonium D-(2-azido-2-phenylacetamido)penicillanate was added and stirring was continued for 30 minutes. The reaction mixture was concentrated to dryness and the residue was applied to a column of silica gel (50 g). Elution with 1:1 (v/v) ethyl acetate/hexane was performed, taking 7 mL fractions. Fractions 17-24 were combined and evaporated in vacuo to give 0.14 g (49%) of the desired product as a pale yellow oil.
<1>H NMR (CDC13) ppm (6): 1,4 (s, 3H), 1,5 (s, 3H), 1,59 (s, 3H), 1,62 (s, 3H), 4,4 (s, 1H), 4,5 (s, 1H), 4,97 (s, 1H) , 5,04 <1>H NMR (CDCl3 ) ppm (6): 1.4 (s, 3H), 1.5 (s, 3H), 1.59 (s, 3H), 1.62 (s, 3H), 4 .4 (s, 1H), 4.5 (s, 1H), 4.97 (s, 1H) , 5.04
(s, 1H), 5,4-5,70 (m, 2H), 5,85 (s, 2H), 7,05 (d, 1H), 7,35 (s, 1H), 5.4-5.70 (m, 2H), 5.85 (s, 2H), 7.05 (d, 1H), 7.35
(s, 5H); Infrarødet (ufortynnet) cm<-1>: 1810, 1775. (p, 5H); Infrared (undiluted) cm<-1>: 1810, 1775.
<*> Tetrabutylammoniumsaltet ble fremstilt som følger: <*> The tetrabutylammonium salt was prepared as follows:
1 g natrium-D-2-azido-2-fenylacetamido-penicillanat, 1 g sodium D-2-azido-2-phenylacetamido-penicillanate,
50 ml etylacetat og 25 ml vann ble blandet og regulert til pH 2,0 (2N HC1). Det organiske lag ble fraskilt, vasket med saltoppløsning (10 ml), og oppløsningsmidlet ble avdampet i vakuum. Det gjenværende skum ble oppløst i 30 ml metylenklorid, 15 ml vann ble tilsatt, og 40% tetrabutylammoniumhydroksyd-oppløsning ble tilsatt inntil den vandige fase nådde pH 8,0. Det organiske lag ble fraskilt, det vandige lag ble ekstrahert igjen med metylenklorid (2 x 20 ml), og de samlede ekstrakter ble tørret (Na2S0^) og konsentrert til tørrhet for å gi en hard gummi. Denne ble utgnidd med etylacetat (2 x 10 ml) og etyleter (2 x 10 ml). Det resulterende hvitaktige, faste stoff ble lufttørret for å gi 1,25 g av det ønskede tetrabutyl-ammoniumsalt. 50 ml of ethyl acetate and 25 ml of water were mixed and adjusted to pH 2.0 (2N HCl). The organic layer was separated, washed with brine (10 mL), and the solvent was evaporated in vacuo. The remaining foam was dissolved in 30 mL of methylene chloride, 15 mL of water was added, and 40% tetrabutylammonium hydroxide solution was added until the aqueous phase reached pH 8.0. The organic layer was separated, the aqueous layer was re-extracted with methylene chloride (2 x 20 mL), and the combined extracts were dried (Na 2 SO 4 ) and concentrated to dryness to give a hard gum. This was triturated with ethyl acetate (2 x 10 ml) and ethyl ether (2 x 10 ml). The resulting whitish solid was air dried to give 1.25 g of the desired tetrabutyl ammonium salt.
oppløsningsmidlet i vakuum gir den rå tittelforbindelse som en blanding av a- og Ø-sulfoksyder som eventuelt kan renses ved kromatografi på silikagel. the solvent in vacuum gives the crude title compound as a mixture of α- and Ø-sulfoxides which can optionally be purified by chromatography on silica gel.
Alternativt fremstilles tittelforbindelsen ved oksydasjon av 6-a-klorpenicillansyre ved oksydasjon med en ekvivalent 3-klorperbenzoesyre i tetrahydrofuran ved 0-25°C i ca. 1 time, i henhold til fremgangsmåten ifølge Harrison et al., Jour. Chem. Soc. (London), Perkin I, 1772 (1976). Det resulterende 6-a-klorpenicillansyre-l-oksyd forestres derefter ved fremgangsmåten ifølge eksempel 1 for å danne den ønskede klormetyl-ester. Alternatively, the title compound is prepared by oxidation of 6-α-chloropenicillanic acid by oxidation with an equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25°C for approx. 1 hour, according to the method of Harrison et al., Jour. Chem. Soc. (London), Perkin I, 1772 (1976). The resulting 6-α-chloropenicillanic acid 1-oxide is then esterified by the method of Example 1 to form the desired chloromethyl ester.
De gjenværende 6-substituerte penicillanat-estere og 6,6-dihalogenpenicillanat-estere fremstilt i eksemplene 1 og IB omdannes til de tilsvarende 1-oksyder ved den ovenfor beskrevne fremgangsmåte. The remaining 6-substituted penicillanate esters and 6,6-dihalopenicillanate esters prepared in examples 1 and 1B are converted to the corresponding 1-oxides by the method described above.
Den samme forbindelse oppnås ved omsetning av 0,1 mol klormetyl-6-a-klorpenicillanat i 150 ml isopropanol inneholdende 0,8 ml 0,5M natrium-wolframat (Na2W04) eller en ekvivalent mengde kaliummolybdat (K2Mo04) med 0,1 mol hydrogenperoksyd (30%). Peroksydet settes langsomt til de andre reagenser ved 60°C, hvorefter blandingen får avkjøles mens den omrøres natten over. Produktet isoleres som beskrevet ovenfor. The same compound is obtained by reacting 0.1 mol of chloromethyl-6-α-chloropenicillanate in 150 ml of isopropanol containing 0.8 ml of 0.5 M sodium tungstate (Na2W04) or an equivalent amount of potassium molybdate (K2Mo04) with 0.1 mol of hydrogen peroxide (30%). The peroxide is slowly added to the other reagents at 60°C, after which the mixture is allowed to cool while it is stirred overnight. The product is isolated as described above.
Eksempel 12 (mellomprodukt) Example 12 (intermediate)
Klormetyl- 6- a- klorpenicillanat- l, 1- dioksyd Chloromethyl-6-α-chlorpenicillanate-1,1-dioxide
Til en oppløsning av 2,83 g, 0,01 mol klormetyl-6-a-klorpenicillanat i 50 ml kloroform settes 4,32 g (0,025 mol) m-klorperbenzoesyre, og blandingen omrøres under en nitrogen-atmosfære i 36 timer ved romtemperatur. Oppløsningsmidlet avdampes i vakuum, residuet fordeles mellom etylacetat og vann ved pH 6,0, og natriumbisulfitt tilsettes inntil en prøve på tilstedeværelse av peroksyder er negativ. pH-verdien reguleres til 8,0, lagene separeres, og den organiske fase vaskes med saltoppløsning, tørres (Na2S04) og inndampes til tørrhet i vakuum for å gi tittelforbindelsen. To a solution of 2.83 g, 0.01 mol of chloromethyl-6-α-chloropenicillanate in 50 ml of chloroform is added 4.32 g (0.025 mol) of m-chloroperbenzoic acid, and the mixture is stirred under a nitrogen atmosphere for 36 hours at room temperature . The solvent is evaporated in vacuo, the residue is partitioned between ethyl acetate and water at pH 6.0, and sodium bisulphite is added until a test for the presence of peroxides is negative. The pH is adjusted to 8.0, the layers are separated, and the organic phase is washed with brine, dried (Na 2 SO 4 ) and evaporated to dryness in vacuo to give the title compound.
Alternativt oppnås tittelforbindelsen ved oksydasjon av det samme utgangsmateriale i metanol eller etanol inneholdende en katalytisk mengde natriumwolframat og tilsetning av 2 molekvivalenter hydrogenperoksyd ved temperaturer fra 20 til 60°C. Alternatively, the title compound is obtained by oxidation of the same starting material in methanol or ethanol containing a catalytic amount of sodium tungstate and addition of 2 molar equivalents of hydrogen peroxide at temperatures from 20 to 60°C.
Eksempel 13 (mellomprodukt) Example 13 (intermediate)
1, l- diokso- 6, 6- dibrompenicillanoyloksymetyl- 6-( D- 2- azido- 2-fenylacetamido) penicillanat 1, l- dioxo- 6, 6- dibromopenicillanoyloxymethyl- 6-( D- 2- azido- 2-phenylacetamido) penicillanate
Til en blanding av 0,232 g. (0,37 mmol) tetrabutylammonium-6-(D-2-azido-2-fenylacetamido)penicillanat<*> og 10 ml aceton ble satt 0,20 g (0,37 mmol) jodmetyl-6,6-dibrompenicillanat-l , 1-dioksyd , og blandingen omrøres ved romtemperatur i 30 minutter. Ytterligere 50 mg tetrabutylammonium-D-(2-azido-2-fenylacetamido)penicillanat ble tilsatt, og omrøring ble fortsatt i 30 minutter. Reaksjonsblandingen ble konsentrert til tørrhet, og residuet ble påført på en kolonne av silikagel (50 g). Eluering med 1:1 (volum/volum) etylacetat/heksan ble utført, idet man tok fraksjoner på 7 ml. Fraksjonene 17-24 ble samlet og inndampet i vakuum for i gi 0,14 g (49%) av det ønskede produkt som en lysegul olje. 0.20 g (0.37 mmol) of iodomethyl- 6,6-dibromopenicillanate-1,1-dioxide, and the mixture is stirred at room temperature for 30 minutes. An additional 50 mg of tetrabutylammonium D-(2-azido-2-phenylacetamido)penicillanate was added and stirring was continued for 30 minutes. The reaction mixture was concentrated to dryness and the residue was applied to a column of silica gel (50 g). Elution with 1:1 (v/v) ethyl acetate/hexane was performed, taking 7 mL fractions. Fractions 17-24 were combined and evaporated in vacuo to give 0.14 g (49%) of the desired product as a pale yellow oil.
<1>H NMR (CDC13) ppm (6): 1,4 (s, 3H), 1,5 (s, 3H), 1,59 (s, 3H), 1,62 (s, 3H) , 4,4 (s, 1H) , 4,5 (s, 1H) , 4,97 (s, 1H) , 5,04 <1>H NMR (CDCl3 ) ppm (6): 1.4 (s, 3H), 1.5 (s, 3H), 1.59 (s, 3H), 1.62 (s, 3H), 4 .4 (s, 1H) , 4.5 (s, 1H) , 4.97 (s, 1H) , 5.04
(s, 1H), 5,4-5,70 (m, 2H), 5,85 (s, 2H), 7,05 (d, 1H), 7,35 (s, 5H); Infrarødet (ufortynnet) cm<-1>: 1810, 1775. (s, 1H), 5.4-5.70 (m, 2H), 5.85 (s, 2H), 7.05 (d, 1H), 7.35 (s, 5H); Infrared (undiluted) cm<-1>: 1810, 1775.
<*> Tetrabutylammoniumsaltet ble fremstilt som følger: <*> The tetrabutylammonium salt was prepared as follows:
1 g natrium-D-2-azido-2-fenylacetamido-penicillanat, 1 g sodium D-2-azido-2-phenylacetamido-penicillanate,
50 ml etylacetat og 25 ml vann ble blandet og regulert til pH 2,0 (2N HC1). Det organiske lag ble fraskilt, vasket med saltoppløsning (10 ml), og oppløsningsmidlet ble avdampet i vakuum. Det gjenværende skum ble oppløst i 30 ml metylenklorid, 15 ml vann ble tilsatt, og 40% tetrabutylammoniumhydroksyd-oppløsning ble tilsatt inntil den vandige fase nådde pH 8,0. Det organiske lag ble fraskilt, det vandige lag ble ekstrahert igjen med metylenklorid (2 x 20 ml), og de samlede ekstrakter ble tørret (Na2S0^) og konsentrert til tørrhet for å gi en hard gummi. Denne ble utgnidd med etylacetat (2 x 10 ml) og etyleter (2 x 10 ml). Det resulterende hvitaktige, faste stoff ble lufttørret for å gi 1,25 g av det ønskede tetrabutyl-ammoniumsalt. 50 ml of ethyl acetate and 25 ml of water were mixed and adjusted to pH 2.0 (2N HCl). The organic layer was separated, washed with brine (10 mL), and the solvent was evaporated in vacuo. The remaining foam was dissolved in 30 mL of methylene chloride, 15 mL of water was added, and 40% tetrabutylammonium hydroxide solution was added until the aqueous phase reached pH 8.0. The organic layer was separated, the aqueous layer was re-extracted with methylene chloride (2 x 20 mL), and the combined extracts were dried (Na 2 SO 4 ) and concentrated to dryness to give a hard gum. This was triturated with ethyl acetate (2 x 10 ml) and ethyl ether (2 x 10 ml). The resulting whitish solid was air dried to give 1.25 g of the desired tetrabutyl ammonium salt.
Eksempel 14 (mellomprodukt) Example 14 (intermediate)
lyl- diokso- 6, 6- dibrompenicillanoyloksymetyl- 6-[ D- 2- benzyloksykarbonylamino- 2-( p- hydroksyfenyl) acetamido] penicillanat lyl- dioxo- 6, 6- dibromopenicillanoyloxymethyl- 6-[ D- 2- benzyloxycarbonylamino- 2-( p- hydroxyphenyl) acetamido] penicillanate
Til en blanding av 101,3 g (0,25 mol) 6-[D-2-benzyloksykarbonylamino-2-(p-hydroksyfenyl)acetamido]penicillansyre, To a mixture of 101.3 g (0.25 mol) 6-[D-2-benzyloxycarbonylamino-2-(p-hydroxyphenyl)acetamido]penicillanic acid,
250 ml vann, 500 ml metylenklorid og 84,8 g (0,25 mol) tetrabutylammoniumbisulfat ved 5°C settes 125 ml 2N natriumhydroksyd mens blandingen holdes ved 5-10°C. Det organiske To 250 ml of water, 500 ml of methylene chloride and 84.8 g (0.25 mol) of tetrabutylammonium bisulphate at 5°C, 125 ml of 2N sodium hydroxide are added while the mixture is kept at 5-10°C. The organic
lag fraskilles, og den vandige fase ekstraheres med metylenklorid. De samlede organiske lag tørres (Na2S04), og opp-løsningsmidlet avdampes i vakuum. Residuet oppløses i 1000 ml etylacetat, inndampes i vakuum til ca. 300 ml og avkjøles natten over. Det utfelte tetrabutylammonium-6-[D-2-benzyloksykarbonylamino-2-(p-hydroksyfenyl)acetamido]penicillanat opp-samles ved filtrering og tørres i vakuum. layers are separated, and the aqueous phase is extracted with methylene chloride. The combined organic layers are dried (Na 2 SO 4 ), and the solvent is evaporated in vacuo. The residue is dissolved in 1000 ml of ethyl acetate, evaporated in vacuo to approx. 300 ml and cool overnight. The precipitated tetrabutylammonium 6-[D-2-benzyloxycarbonylamino-2-(p-hydroxyphenyl)acetamido]penicillanate is collected by filtration and dried in a vacuum.
Til 74,1 g (0,10 mol) tetrabutylammonium-6-[D-2-benzyloksykarbonylamino-2-(p-hydroksyfenyl)acetamido]penicillanat i 1000 ml metyletylketon settes 4 9,8 g (0,10 mol) metylsulfonyl-oksymetyl-6 , 6-dibrompenicillanat-l , 1-dioksyd , og den resulterende blanding omrøres ved 50°C i 1 time. Oppløsningsmidlet avdampes i vakuum, og residuet fordeles mellom etylacetat og vann. Det vandige lag fraskilles, vaskes med etylacetat, 49.8 g (0.10 mol) methylsulfonyl- oxymethyl-6,6-dibromopenicillanate-1,1-dioxide, and the resulting mixture is stirred at 50°C for 1 hour. The solvent is evaporated in vacuo, and the residue is distributed between ethyl acetate and water. The aqueous layer is separated, washed with ethyl acetate,
og de samlede organiske lag vaskes med saltoppløsning og tørres (Na2S04). Avdampning av etylacetatet i vakuum gir tittelforbindelsen. and the combined organic layers are washed with saline and dried (Na 2 SO 4 ). Evaporation of the ethyl acetate in vacuo gives the title compound.
Eksempel 15 (mellomprodukt) Example 15 (intermediate)
1, l- diokso- 6- j3- brompenicillanoyloksymetyl- 6- ( D- 2- azido- 2- f enyl-acetamido) penicillanat 1, l- dioxo- 6- j3- bromopenicillanoyloxymethyl- 6-( D- 2- azido- 2- phenyl-acetamido) penicillanate
Til en blanding av 0,152 g (0,25 mmol) tetrabutylammonium-(D-2-azido-2-fenylacetamido)penicillanat og 5,0 ml aceton ble satt 0,14 g (0,25 mmol) jodmety1-6-0-brompenicillanat-1,1-dioksyd. Den resulterende farveløse blanding ble omrørt ved romtemperatur i 30 minutter, oppløsningsmidlet ble avdampet i vakuum, og residuet ble kromatografert på en kolonne av silikagel (25 g), idet eluering ble foretatt med 1:1 (volum/volum) etylacetat/heksan. Fraksjoner på 6 ml ble tatt med ca. 30 sekunders mellomrom. Fraksjonene 13-17 ble samlet og konsentrert i vakuum for å gi 0,125 g av det ønskede produkt som et skum. 0.14 g (0.25 mmol) of iodomethyl-6-0- bromopenicillanate-1,1-dioxide. The resulting colorless mixture was stirred at room temperature for 30 minutes, the solvent was evaporated in vacuo, and the residue was chromatographed on a column of silica gel (25 g), eluting with 1:1 (v/v) ethyl acetate/hexane. Fractions of 6 ml were taken with approx. 30 second intervals. Fractions 13-17 were combined and concentrated in vacuo to give 0.125 g of the desired product as a foam.
<1>H-NMR (CDC13) ppm (6): 1,4 (s, 3H), 1,5 (s, 3H), 1,6 (s, 3H), (1,65 (s, 3H), 4,42 (s, 1H), 4,5 (s, 1H), 4,75 (d, 1H), 5,07 <1>H-NMR (CDCl 3 ) ppm (6): 1.4 (s, 3H), 1.5 (s, 3H), 1.6 (s, 3H), (1.65 (s, 3H) , 4.42 (s, 1H), 4.5 (s, 1H), 4.75 (d, 1H), 5.07
(s, 1H) , 5,3 (d, 1H), 5,4-5,75 (m, 2H), 5,85 (s, bred, 2H), (s, 1H) , 5.3 (d, 1H), 5.4-5.75 (m, 2H), 5.85 (s, wide, 2H),
7,1 (d, 1H), 7,35 (s, 5H); 7.1 (d, 1H), 7.35 (s, 5H);
Infrarødt (ufortynnet) cm"<1>: 1800, 1775. Infrared (undiluted) cm"<1>: 1800, 1775.
Eksempel 16 (mellomprodukt) Example 16 (intermediate)
1, l- diokso- 6- a- brompenicillanoyloksymety1- 6-( D- 2- azido- 2- fenyl-acetamido) penicillanat 1, l- dioxo- 6- a- bromopenicillanoyloxymethyl- 6-( D- 2- azido- 2- phenyl-acetamido) penicillanate
En blanding av 0,308 g (0,5 mmol) tetrabutylammonium-(D-2-azido-2-fenylacetamido)penicillanat, 0,219 g (0,485 mmol) jodmetyl-6-a-brompenicillanat-l,1-dioksyd og 10 ml aceton ble omrørt 30 minutter ved romtemperatur. Oppløsningsmidlet ble avdampet i vakuum, og residuet ble kromatografert på en kolonne av 50 g silikagel, idet eluering ble foretatt med 1:1 (volum/ volum) etylacetat/heksan. De produktholdige fraksjoner ble samlet, og oppløsningsmidlet ble avdampet i vakuum for å gi 0,125 g A mixture of 0.308 g (0.5 mmol) tetrabutylammonium-(D-2-azido-2-phenylacetamido)penicillanate, 0.219 g (0.485 mmol) iodomethyl-6-a-bromopenicillanate-1,1-dioxide and 10 ml of acetone was stirred 30 minutes at room temperature. The solvent was evaporated in vacuo, and the residue was chromatographed on a column of 50 g silica gel, eluting with 1:1 (volume/volume) ethyl acetate/hexane. The product-containing fractions were pooled and the solvent was evaporated in vacuo to give 0.125 g
(38%) av tittelforbindelsen som en olje. (38%) of the title compound as an oil.
<1>H-NMR (CDC13) ppm (6): 1,43 (s, 3H), 1,5 (s, 3H), 1,6 (s, 3H), 1,66 (s, 3H) , 4,4 (s, 2H) , 4,64 (d, 1H), 5,05 (s, 1H) , 5,1 <1>H-NMR (CDCl 3 ) ppm (6): 1.43 (s, 3H), 1.5 (s, 3H), 1.6 (s, 3H), 1.66 (s, 3H), 4.4 (s, 2H) , 4.64 (d, 1H), 5.05 (s, 1H) , 5.1
(d, 1H), 5,4-5,7 (m, 2H), 5,85 (s, 2H), 7,08 (d, 1H), 7,35 (d, 1H), 5.4-5.7 (m, 2H), 5.85 (s, 2H), 7.08 (d, 1H), 7.35
(s, 5H); Infrarødt (ufortynnet) cm"<1>: 1795, 1775. (p, 5H); Infrared (undiluted) cm"<1>: 1795, 1775.
Eksempel 17 Example 17
1, l- dioksopenicillanoyloksymetyl- 6-( D- 2- amino- 2- fenylacetamido)-penicillanat 1,1-Dioxopenicillanoyloxymethyl-6-(D-2-amino-2-phenylacetamido)-penicillanate
En blanding av 1,2 g 5% palladium-på-kalsiumkarbonat A mixture of 1.2 g of 5% palladium-on-calcium carbonate
og 30 ml 1:1 (efter volum) isopropanol/metylenklorid ble hydrogenert ved 3,52 kg/cm 2i 30 minutter. Til denne blanding ble satt 0,25 g (0,32 mmol) 1,l-diokso-6,6-dibrompenicillanoyloksymetyl-6-(D-2-azidp-2-fenylacetamido)penicillanat oppløst i 3 ml metylenklorid. Den resulterende blanding ble hydrogenert ved 3,52 kg/cm 2i 1 time. Katalysatoren ble fjernet ved filtrering, og vasking ble foretatt med 30 ml 1:1 isopropanol/ metylenklorid. Filtratet ble konsentrert i vakuum for å gi et lysebrunt, fast stoff. Dette ble utgnidd med 15 ml etyleter, and 30 mL of 1:1 (by volume) isopropanol/methylene chloride was hydrogenated at 3.52 kg/cm 2 for 30 minutes. To this mixture was added 0.25 g (0.32 mmol) of 1,1-dioxo-6,6-dibromopenicillanoyloxymethyl-6-(D-2-azidp-2-phenylacetamido)penicillanate dissolved in 3 ml of methylene chloride. The resulting mixture was hydrogenated at 3.52 kg/cm 2 for 1 hour. The catalyst was removed by filtration, and washing was carried out with 30 ml of 1:1 isopropanol/methylene chloride. The filtrate was concentrated in vacuo to give a light brown solid. This was rubbed with 15 ml of ethyl ether,
filtrert, vasket med 10 ml eter og lufttørret for å gi 0,195 g produkt. filtered, washed with 10 ml of ether and air dried to give 0.195 g of product.
<1>H-NMR (CDC13) ppm (6): 1,5 (d, 6H), 1,6 (d, 6H), 3,55 (d, 2H), 4,45 (s, 1H) , 4,55 (s, 1H), 4,6-4,75 (m, 2H), 5,5-5,7 (m, 2H) , 5,9 (q, 2H), 7,4 (s, 4H), 8,1 (d, 1H). <1>H-NMR (CDCl 3 ) ppm (6): 1.5 (d, 6H), 1.6 (d, 6H), 3.55 (d, 2H), 4.45 (s, 1H), 4.55 (s, 1H), 4.6-4.75 (m, 2H), 5.5-5.7 (m, 2H), 5.9 (q, 2H), 7.4 (s, 4H), 8.1 (d, 1H).
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO831024A NO159659C (en) | 1981-03-23 | 1983-03-23 | PROCEDURE TE FOR PREPARATION OF 1,1-DIOXOPENICILYXYMETHYL-6- (2-AMINO-2-PHENYLACETAMIDO) PENICILLANATE ANTIBIOTICS. |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US24645681A | 1981-03-23 | 1981-03-23 | |
NO820898A NO159658C (en) | 1981-03-23 | 1982-03-18 | INTERMEDIATE FOR PREPARATION OF 1,1-DIOXO-PENICILLANOYLOXYMETHYL-6- (2-AMINO-2-PHENYL-ACETAMIDO) PENICILLANATE ANTIBIOTICS. |
NO831024A NO159659C (en) | 1981-03-23 | 1983-03-23 | PROCEDURE TE FOR PREPARATION OF 1,1-DIOXOPENICILYXYMETHYL-6- (2-AMINO-2-PHENYLACETAMIDO) PENICILLANATE ANTIBIOTICS. |
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NO831024L NO831024L (en) | 1982-09-24 |
NO159659B true NO159659B (en) | 1988-10-17 |
NO159659C NO159659C (en) | 1989-01-25 |
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NO831024A NO159659C (en) | 1981-03-23 | 1983-03-23 | PROCEDURE TE FOR PREPARATION OF 1,1-DIOXOPENICILYXYMETHYL-6- (2-AMINO-2-PHENYLACETAMIDO) PENICILLANATE ANTIBIOTICS. |
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