NO743667L - - Google Patents
Info
- Publication number
- NO743667L NO743667L NO743667A NO743667A NO743667L NO 743667 L NO743667 L NO 743667L NO 743667 A NO743667 A NO 743667A NO 743667 A NO743667 A NO 743667A NO 743667 L NO743667 L NO 743667L
- Authority
- NO
- Norway
- Prior art keywords
- group
- methyl
- cephem
- hydrogen
- compound
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 109
- -1 2,2,2-trichloroethoxycarbonyl Chemical group 0.000 claims description 107
- 229910052739 hydrogen Inorganic materials 0.000 claims description 82
- 239000001257 hydrogen Substances 0.000 claims description 82
- 125000004432 carbon atom Chemical group C* 0.000 claims description 78
- 150000001782 cephems Chemical class 0.000 claims description 58
- FZEVMBJWXHDLDB-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1CC=CN2C(=O)C[C@H]21 FZEVMBJWXHDLDB-ZCFIWIBFSA-N 0.000 claims description 56
- 150000002431 hydrogen Chemical class 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 49
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 42
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 31
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- SXBDXXFTJVHSAF-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-3-en-8-one Chemical compound S1C=CCN2C(=O)C[C@H]21 SXBDXXFTJVHSAF-ZCFIWIBFSA-N 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 16
- 125000005633 phthalidyl group Chemical group 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 230000010933 acylation Effects 0.000 claims description 10
- 238000005917 acylation reaction Methods 0.000 claims description 10
- 230000029936 alkylation Effects 0.000 claims description 10
- 238000005804 alkylation reaction Methods 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229910052717 sulfur Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 238000012546 transfer Methods 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 150000008064 anhydrides Chemical group 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 3
- 125000003368 amide group Chemical group 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 124
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 80
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 49
- 239000007787 solid Substances 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- 239000000725 suspension Substances 0.000 description 20
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 239000003242 anti bacterial agent Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 12
- 150000003536 tetrazoles Chemical class 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 238000001665 trituration Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 150000001540 azides Chemical class 0.000 description 5
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical compound ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- ZMMRLWFGWQVVJD-UHFFFAOYSA-O (n,n-dimethylcarbamimidoyl)-dimethylazanium;azide Chemical compound [N-]=[N+]=[N-].CN(C)C(N)=[N+](C)C ZMMRLWFGWQVVJD-UHFFFAOYSA-O 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 3
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001447 alkali salts Chemical class 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- DGJSPZSLNNDPQC-ZMMDDIOLSA-N (6r)-5-oxo-5$l^{4}-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound C1=CCS(=O)[C@H]2N1C(=O)C2 DGJSPZSLNNDPQC-ZMMDDIOLSA-N 0.000 description 2
- MAFIPFSQYBWLAM-BAFYGKSASA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid Chemical compound OC(=O)C1C=CS[C@@H]2CC(=O)N12 MAFIPFSQYBWLAM-BAFYGKSASA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
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- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000002959 penams Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- HWEXKRHYVOGVDA-UHFFFAOYSA-M sodium;3-trimethylsilylpropane-1-sulfonate Chemical compound [Na+].C[Si](C)(C)CCCS([O-])(=O)=O HWEXKRHYVOGVDA-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
"Antibakterielle cefemderivater og frem-"Antibacterial cephem derivatives and pro-
gangsmåte for fremstilling derav" method of manufacture thereof"
Foreliggende oppfinnelse vedrører cefemderivater. The present invention relates to cephem derivatives.
Forbindelsene er antibakterielle midler som er verdifulle som dyreffirtilsetninger, som terapeutiske midler for kontroll av infeksjonssykdommer som skyldes gram-positive og gram-negative bakterier, og for sterilisering av hospitaloverflatér o.l.j og nye mellomprodukter for fremstilling av disse. Mer spesielt er de antibakterielle forbindelser ifølge foreliggende oppfinnelse acylerte derivater av 7-amino-3-substituerte-A 3-cefemforbindelser som inneholder en 5-tetrazolylgruppe i 4-stllling. The compounds are antibacterial agents which are valuable as animal fur additives, as therapeutic agents for the control of infectious diseases caused by gram-positive and gram-negative bacteria, and for sterilizing hospital surfaces, etc. and new intermediates for their production. More particularly, the antibacterial compounds according to the present invention are acylated derivatives of 7-amino-3-substituted-A 3-cephem compounds containing a 5-tetrazolyl group in the 4-position.
Til tross for det store antall cefemderivater som er blitt foreslått som antibakterielle midler, eksisterer det enda et behov for nye midler. Despite the large number of cephem derivatives that have been proposed as antibacterial agents, there still exists a need for new agents.
De antibakterielle forbindelser Ifølge oppfinnelsen, og mellomproduktene som de fremstilles fra ved acylering, er nye forbindelser, og de kunne ikke forutsees ut fra det som var kjent på området. I U.S.-patentene 3.427.302 og 3.468.874 beskrives penamderivater som omfatter en tetrazolylgruppe som del av 6-acylaminosubstituenten og i japansk patent nr. 71-38503 beskrives cefemderivater som omfatter en tetrazolylgruppe som del av 7-acylaminosubstituenten. Cefemderivater med en tetrazolyl-tiometylgruppe i 3-stilling er også kjente forbindelser (U.S.-patent nr. 3.641.021). Forbindelsene ifølge foreliggende oppfinnelse er kasakterisert ved at de har en tetrazolylgruppe bundet direkte til cefemkjernen. The antibacterial compounds according to the invention, and the intermediates from which they are produced by acylation, are new compounds, and they could not be predicted from what was known in the field. In U.S. patents 3,427,302 and 3,468,874 penam derivatives are described which comprise a tetrazolyl group as part of the 6-acylamino substituent and in Japanese patent no. 71-38503 cephem derivatives are described which comprise a tetrazolyl group as part of the 7-acylamino substituent. Cephem derivatives with a tetrazolyl-thiomethyl group in the 3-position are also known compounds (U.S. Patent No. 3,641,021). The compounds according to the present invention are characterized in that they have a tetrazolyl group attached directly to the cephem nucleus.
En oversikt over de biologiske og ikke-biologiske anvendelser av tetrazoler er angitt av Benson, "Heterocyclic Compounds", Elderfield, Ed., Vol. 8, John Wiley&Sons, Inc., New York, An overview of the biological and non-biological applications of tetrazoles is given by Benson, "Heterocyclic Compounds", Elderfield, Ed., Vol. 8, John Wiley&Sons, Inc., New York,
N.Y., 1967, kap. 1 mens en samling av cefemreferanser er angitt i U.S.-patent nr. 3.766.176. N.Y., 1967, ch. 1 while a collection of cephem references is set forth in U.S. Patent No. 3,766,176.
Det har nå vist seg at visse 7-acylamino-3-substituerte-4-(tetrazol-5-yl)-A 3-cefemderivater og salter av disse er anvendbare som antibakterielle midler/mens visse 7-substituerte amino-3-substituerte-4-karbamoyl- og 4- (tetrazol-5-yl)-A3*- og -A<2->cefemderivater er nyttige som mellomprodukter for fremstillingen av disse antibiotika. It has now been shown that certain 7-acylamino-3-substituted-4-(tetrazol-5-yl)-A 3-cephem derivatives and salts thereof are useful as antibacterial agents/while certain 7-substituted amino-3-substituted- 4-carbamoyl and 4-(tetrazol-5-yl)-A3* and -A<2->cephem derivatives are useful as intermediates for the preparation of these antibiotics.
En foretrukket gruppe av forbindelser som er anvendbare som mellomprodukter er de som har formelen A preferred group of compounds useful as intermediates are those having the formula
hvor R er hydrogen eller en aminobeskyttende gruppe valgt fra gruppen som består av 2,2,2-trikloretoksykarbonyl, 2,2,2-tribrometoksykarbonyl, benzyloksykarbonyl og hvor R3, og Rg hver er hydrogen, klor, brom, fluor, metyl, metoksy eller fenyl» A er hydrogen, acetoksy, 1-metyltetrazolyltio eller 2-metyl-l,3,4-tiadiazolyl-5-tio, og R2 er en potensiell tetrazolbeskyttende gruppe valgt fra gruppen som består av wherein R is hydrogen or an amino protecting group selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromomethoxycarbonyl, benzyloxycarbonyl and wherein R3, and Rg are each hydrogen, chlorine, bromine, fluorine, methyl, methoxy or phenyl" A is hydrogen, acetoxy, 1-methyltetrazolylthio or 2-methyl-1,3,4-thiadiazolyl-5-thio, and R2 is a potential tetrazole protecting group selected from the group consisting of
hvor Rg er hydrogen, alkyl som inneholder fra 1 til 3 karbonatomer eller fenyl, R^er hydroksy, metoksy, alkanoyloksy som inneholder where Rg is hydrogen, alkyl containing from 1 to 3 carbon atoms or phenyl, R^ is hydroxy, methoxy, alkanoyloxy containing
fra 2 til 4 karbonatomer eller benzyloksy og Rq er hydrogen, hydroksy, fluor, klor, brom, jod, metyl, metoksy, alkanoyloksy som inneholder fra 2 til 4 karbonatomer, fenyl eller benzyloksy og from 2 to 4 carbon atoms or benzyloxy and Rq is hydrogen, hydroxy, fluorine, chlorine, bromine, iodo, methyl, methoxy, alkanoyloxy containing from 2 to 4 carbon atoms, phenyl or benzyloxy and
hvor Rg og R1Qhver er hydrogen eller metyl og X er oksygen eller svovel. En annen foretrukket klasse av forbindelser er mellomprodukter med formlene og salter av disse hvor R er hydrogen eller en aminobeskyttende gruppe valgt fra gruppen som består av 2,2,2-trikloretoksykarbonyl, 2,2,2-tribrometoksykarbonyl, benzyloksykarbonyl og where Rg and R1Q are each hydrogen or methyl and X is oxygen or sulfur. Another preferred class of compounds are intermediates of the formulas and salts thereof where R is hydrogen or an amino protecting group selected from the group consisting of 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromomethoxycarbonyl, benzyloxycarbonyl and
hvor R3, R4 og Rg hver er hydrogen, klor, brom, fluor, metyl, metoksy eller fenyl, A er hydrogen, acetoksy, l-metyl-5-tetrazolyl-tio eller 2-metyl-l,3,4-tiadiazolyl-5-tio, ^ er hydrogen, alkanoyloksymetyl som inneholder fra 3 til 6 karbonatomer, where R3, R4 and Rg are each hydrogen, chlorine, bromine, fluorine, methyl, methoxy or phenyl, A is hydrogen, acetoxy, 1-methyl-5-tetrazolyl-thio or 2-methyl-1,3,4-thiadiazolyl- 5-thio, ^ is hydrogen, alkanoyloxymethyl containing from 3 to 6 carbon atoms,
1-(alkanoyloksy)etyl som inneholder fra 4 til 7 karbonatomer, metoksymetyl eller ftalidyl, og R^ er hydrogen, alkanbyloksy-metyl som inneholder fra 3 til 6 karbonatomer, 1-(alkanoyloksy)-etyl som inneholder fra 4 til 7 karbonatomer, metoksymetyl, ftalidyl eller en potensiell tetrazolbeskyttende gruppe valgt fra gruppen som består av 1-(alkanoyloxy)ethyl containing from 4 to 7 carbon atoms, methoxymethyl or phthalidyl, and R^ is hydrogen, alkanebyloxymethyl containing from 3 to 6 carbon atoms, 1-(alkanoyloxy)ethyl containing from 4 to 7 carbon atoms, methoxymethyl, phthalidyl or a potential tetrazole protecting group selected from the group consisting of
hvor Rg er hydrogen, alkyl som inneholder fra 1 til 3 karbonatomer eller fenyl, R? er hydroksy, metoksy, alkanoyloksy som inneholder fra 2 til 4 karbonatomer eller benzyloksy og Rg er hydrogen, hydroksy, fluor, klor, brom, jod, metyl, metoksy, alkanoyloksy som inneholder fra 2 til 4 karbonatomer, fenyl eller benzyloksy og hvor R9og R1Qhver er hydrogen eller metyl og X er svovel eller oksygen• En tredje klasse av foretrukne cefemderivater og salter derav er de som har formlene where Rg is hydrogen, alkyl containing from 1 to 3 carbon atoms or phenyl, R? is hydroxy, methoxy, alkanoyloxy containing from 2 to 4 carbon atoms or benzyloxy and Rg is hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, methoxy, alkanoyloxy containing from 2 to 4 carbon atoms, phenyl or benzyloxy and where R9 and R1Q each is hydrogen or methyl and X is sulfur or oxygen• A third class of preferred cephem derivatives and salts thereof are those having the formulas
hvor Ar er cyano, brom, fenyl mono- eller disubstituert fenyl hvor hver substituent er hydroksy, fluor, klor, brom, amino, metoksy eller metyl, fenoksy, fentyltio, pyridyltio, tienyl, 2-metyl-l,3,4-tiadiazol-5-yltio eller 1-tetrazolyl, Q er hydrogen, hydroksy, azid, amino eller karboksy, n er et helt tall fra 0 til 1, where Ar is cyano, bromo, phenyl mono- or disubstituted phenyl where each substituent is hydroxy, fluoro, chloro, bromo, amino, methoxy or methyl, phenoxy, phentylthio, pyridylthio, thienyl, 2-methyl-1,3,4-thiadiazole -5-ylthio or 1-tetrazolyl, Q is hydrogen, hydroxy, azide, amino or carboxy, n is an integer from 0 to 1,
A er hydrogen, acetoksy, l-metyltetrazol-5-yltio eller 2-metyl-1,3,4-tiadiazol-5-yltio, og R. er hydrogen, alkanoyloksymetyl som Inneholder fra 3 til 6 karbonatomer, 1-(alkanoyloksy)etyl som inneholder fra 4 til 7 karbonatomer, metoksymetyl eller ftalidyl, under forutsetning av at når Ar er pyridyltio, fenoksy, fehyltio, 2-raetyl-l,3,4-tiadiazol-5-yltiometyl, cyano eller brom og n er lik 1, er Q hydrogen eller karboksy. A is hydrogen, acetoxy, 1-methyltetrazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio, and R. is hydrogen, alkanoyloxymethyl Containing from 3 to 6 carbon atoms, 1-(alkanoyloxy) ethyl containing from 4 to 7 carbon atoms, methoxymethyl or phthalidyl, provided that when Ar is pyridylthio, phenoxy, phenylthio, 2-raethyl-1,3,4-thiadiazol-5-ylthiomethyl, cyano or bromo and n is equal to 1 , Q is hydrogen or carboxy.
Foreliggende oppfinnelse omfatter også forbindelser av den teedje klassen hvor A, Q,n og R^ er som angitt og Ar er valgt fra gruppen som består av hydrogen, alkyl som inneholder fra 1 til 12 karbonatomer, alkenyl som inneholder fra 2 til 12 karbonatomer, cykloalkyl som inneholder fra 3 til 7 karbonatomer, cykloalkenyl som inneholder fra 5 til 8 karbonatomer, cykloheptatrienyl, 1,4-cykloheksadienyl, 1-aminocykloalkyl som inneholder fra 4 til 7 karbonatomer, 5-metyl-3-fenyl-4-isoksazolyl, 5-metyl-3-(o-klorfenyl)-4-isoksazolyl, 5-métyl-3-(2,6-diklorfenyl)-4-isoksazolyl, 5-mety1-3-(2-klor-6-fluorfenyl)-4-isoksazolyl, 2-alkoksy-l-naftyl hvor alkoksygruppen inneholder fra 1 til 4 karbonatomer, oydhonyl, furyl, pyridyl, tiazolyl, isotiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituert fenoksy, substituert fenyltio, substituert pyridyltio, substituert tienyl, substituert furyl, substituert pyridyl, substituert tetrazolyl, substituert tiazolyl, substituert isotiazolyl, substituert pyrimidinyl, substituert triazolyl, substituert imidazolyl og substituert pyrazolyl, idet hver substituert gruppe kan være substituert med inntil to grupper som er valgt fra gruppen som består av fluor, klor, brom, hydroksy, hydroksyrnetyl, The present invention also includes compounds of the third class where A, Q,n and R^ are as indicated and Ar is selected from the group consisting of hydrogen, alkyl containing from 1 to 12 carbon atoms, alkenyl containing from 2 to 12 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, cycloalkenyl containing from 5 to 8 carbon atoms, cycloheptatrienyl, 1,4-cyclohexadienyl, 1-aminocycloalkyl containing from 4 to 7 carbon atoms, 5-methyl-3-phenyl-4-isoxazolyl, 5 -methyl-3-(o-chlorophenyl)-4-isoxazolyl, 5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl, 5-methyl-3-(2-chloro-6-fluorophenyl)-4 -isoxazolyl, 2-alkoxy-l-naphthyl where the alkoxy group contains from 1 to 4 carbon atoms, oydhonyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted rt pyrimidinyl, substituted triazolyl, substituted imidazolyl and substituted pyrazolyl, each substituted group may be substituted with up to two groups selected from the group consisting of fluorine, chlorine, bromine, hydroxy, hydroxymethyl,
amino, N,H-dialkylamin hvor hver alkylgruppe inneholder fra 1 til 4 karbonatomer, alkyl som inneholder fra 1 til 4 karbonatomer, amino, N,H-dialkylamine where each alkyl group contains from 1 to 4 carbon atoms, alkyl containing from 1 to 4 carbon atoms,
aminometyl, aminoetyl, alkoksy som Inneholder fra 1 til 4 karbonatomer, alkyltio som inneholder fra 1 til 4 karbonatomer, 2-aminoetoksy og N-alkylamino som inneholder fra i til 4 karbonatomer. aminomethyl, aminoethyl, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, 2-aminoethoxy and N-alkylamino containing from 1 to 4 carbon atoms.
Som fagmannen lett vil forstå er ct-karbonatomet av den antibakterielle oefemsidekjeden til hvilken amino eller hydroksy, (Q) gruppen er bundet, er et asymmetrisk karbonatoin som tillater eksistensen av to optisk aktive isomerer, D- og L-diastereo-isomerene såvel som racematet, DL-formen. I henhold til det som tidligere er funnet når det gjelder aktiviteten av slike cefemforbindelser som har asymmetriske a-karbonatomer, er.forbindelser ifølge foreliggende oppfinnelse som har D-konfigurasjonen, mer virksomme enn de som har L-konfigurasjonen og er de foretrukne forbindelser, skjønt L- og DL-formene av forbindelsene omfattes også av foreliggende oppfinnelse. As those skilled in the art will readily appreciate, the ct carbon atom of the antibacterial oephem side chain to which the amino or hydroxy, (Q) group is attached is an asymmetric carbonatoin which allows the existence of two optically active isomers, the D and L diastereoisomers as well as the racemate , the DL form. According to what has been previously found regarding the activity of such cephem compounds having asymmetric α-carbon atoms, compounds of the present invention having the D configuration are more active than those having the L configuration and are the preferred compounds, although The L and DL forms of the compounds are also covered by the present invention.
Det er videre verdt å legge merke til at når det gjelder asymmetriske sentere, er det flere i A -céfem-kjernen, grunn-elementet som forbindelsene ifølge foreliggende oppfinnelse er avledet fra. Disse potensielle ytterligere isomerér er ikke vesentlig i denne forbindelse siden den anvendte 7-amino-A 3-oefera-4-karboksylsyrén som fører til produktene ifølge oppfinnelsen er den som fremstilles ved fermentering og er av en konfigurasjon. It is further worth noting that in the case of asymmetric centers, there are several in the A -céfem core, the basic element from which the compounds of the present invention are derived. These potential additional isomers are not significant in this connection since the 7-amino-A 3-oephera-4-carboxylic acid used leading to the products of the invention is that produced by fermentation and is of one configuration.
På lignende måte er betegnelsen "tetrazolrbeskyttende gruppe" eller "tetrazolyl-cefera-nitrogeh-beskyttende gruppe" ment å bety. alle kjente grupper, eller som er åpenbart for fagmannen, kan anvendes (a) for å tillate syntesen av forbindelser hvor R er en aminobeskyttende gruppe' og R er den tetrazolylcefem-nitrogen-beskyttende gruppen,.efter fremgangsmåten som går ut fra 7-(beskyttet amino)cefem-4-karboksylsyre som angitt i det følgende» og (b) kan fjernes fra forbindelsen hvor R 2 er den tetrazolyl-cefeiti-nitrogen-beskyttende gruppen, hvor R er valgt fra gruppen Similarly, the term "tetrazole protecting group" or "tetrazolyl-cefera-nitrogeh-protecting group" is intended to mean. all known groups, or which are obvious to the person skilled in the art, can be used (a) to allow the synthesis of compounds where R is an amino-protecting group' and R is the tetrazolylcephem-nitrogen-protecting group, following the procedure starting from 7-( protected amino)cephem-4-carboxylic acid as set forth below" and (b) can be removed from the compound wherein R 2 is the tetrazolyl-cepheity nitrogen-protecting group, wherein R is selected from the group
som består av hydrogen og en aminobeskyttende gruppe, og R 2 e.r den tetrazolylcefem-nitrogen-beskyttende gruppen, ved å anvende en fremgangsmåte hvor cefem-ringsystemet forblir i alt vesentlig, intakt. Det er likeledes evnen til den tetrazolylcefem-nitrogen-beskyttende gruppen å utføre en gitt funksjon, som skal omtales mer detaljert i det følgende, heller enn déns nøyaktige kjemiske struktur, som er viktig, og nyheten av de antibakterielle midler ifølge foreliggende oppfinnelse er ikke avhengig av strukturen av den beskyttende gruppen. Valg og bestemmelse av de egnede beskyttende gruppene kan lett og enkelt gjøres av fagmannen, og eksempler på en rekke anvendbare grupper er gitt i det følgende. which consists of hydrogen and an amino-protecting group, and R 2 is the tetrazolylcepheme-nitrogen-protecting group, by using a method in which the cepheme ring system remains substantially intact. It is likewise the ability of the tetrazolylcephem nitrogen protecting group to perform a given function, which will be discussed in more detail below, rather than its exact chemical structure, which is important, and the novelty of the antibacterial agents of the present invention does not depend of the structure of the protecting group. Selection and determination of the suitable protecting groups can easily and simply be done by the person skilled in the art, and examples of a number of applicable groups are given below.
Én utførelsesform ifølge oppfinnelsen omfatter en fremgangsmåte for fremstilling av forbindelser hvor arainogruppen i 7-stilling aoyleres. One embodiment according to the invention comprises a method for producing compounds where the araino group in the 7-position is aoylated.
En annen utførelsesform ifølge oppfinnelsen omfatter fremstillingen av forbindelser hvor aminogruppen i 7-stillingen béskyttes med én aminobeskyttende gruppe ved overføringen av amidet i 4-stilling til en tetrazolylgruppe, idet man beskytter amid- og den resulterende tetrazolylgruppe med en tetrazolylcefem-nitrogen-beskyttende gruppe. Another embodiment according to the invention comprises the preparation of compounds where the amino group in the 7-position is protected with one amino-protecting group by the transfer of the amide in the 4-position to a tetrazolyl group, protecting the amide and the resulting tetrazolyl group with a tetrazolyl cephem nitrogen-protecting group.
Foreliggende oppfinnelse vedrører visse nye forbindelser og nye preparater som er anvendbare som antibakterielle midler, og som mellomprodukter for fremstillingen av disse. For enkelthets skyld betegnes forbindelsene som derivater av A 3-cefem. Betegnelsen "A 3-cefem" er angitt av Morin et al. i Journal of The present invention relates to certain new compounds and new preparations which are usable as antibacterial agents, and as intermediate products for the production of these. For the sake of simplicity, the compounds are designated as derivatives of A 3 -cephem. The term "A 3-cephem" is given by Morin et al. in Journal of
the American Chemical Society, 84, 3400 (1962) og betyr strukturen the American Chemical Society, 84, 3400 (1962) and means the structure
Ved å anvende denne terminologi betegnes det velkjente antibiotikum cefalosporin C som 7-(5-amino-5-karboksyvaleramido)-3-acetoksy-3 Using this terminology, the well-known antibiotic cephalosporin C is designated as 7-(5-amino-5-carboxyvaleramido)-3-acetoxy-3
metyl-A -cefem-4-karboksylsyre.methyl-A-cephem-4-carboxylic acid.
Mange av forbindelsene ifølge foreliggende oppfinnelse er også 5-substituerte tetrazoler som kan eksistere 1 to isomere former, nemligi Many of the compounds according to the present invention are also 5-substituted tetrazoles which can exist in two isomeric forms, namely
Fagmannen vil forstå at når substituenten L betyr hydrogen så eksisterer de to fonner samtidig i en dynamisk, tautomer, likevektsblanding. I det tilfelle hvor L imidlertid er forskjellig fra hydrogen representérer de to former forskjellige kjemiske strukturer som ikke spontant går over i hverandre. Those skilled in the art will understand that when the substituent L means hydrogen, the two forms exist simultaneously in a dynamic, tautomeric, equilibrium mixture. However, in the case where L is different from hydrogen, the two forms represent different chemical structures that do not spontaneously intermingle.
Ifølge fremgangsmåten som anvendes for å syntetisere cefem-mellomproduktene og de antibakterielle midler ifølge foreliggende oppfinnelse er det to preparative veier, ben første illustreres som følgers hvor R, A, X^, Ar, n og Q er som angitt tidligere og R^og R^ hver er hydrogen. According to the method used to synthesize the cephem intermediates and the antibacterial agents of the present invention, there are two preparative routes, the first being illustrated as follows where R, A, X^, Ar, n and Q are as indicated previously and R^ and R ^ each is hydrogen.
7-karboksamido-3-substituerte-'A 3-cefem-4-karboksylsyrer (1), fremstillas eksperimentelt ved acylering av den tilsvarende 7-amino-cefemforbindelse, overføres til 4-karbamoylforbindelser (2) ved å omsette 4-karboksygruppen, aktivert som 2,4-dinitrofenol-ester, med et egnet amin, R^H,,. 7-carboxamido-3-substituted-'A 3-cephem-4-carboxylic acids (1), prepared experimentally by acylation of the corresponding 7-amino-cephem compound, are transferred to 4-carbamoyl compounds (2) by reacting the 4-carboxy group, activated as 2,4-dinitrophenol ester, with a suitable amine, R^H,,.
Fremstillingen av forbindelsene 2 hvor R er avledet fra trifenyImetyl, oppnås enten ved alkylering av 7-amino-forbindelsen, efterfulgt av dannelsen av 4-karbamoylgruppen som nevnt ovenfor, eller ved selektivt å fjerne R-acylgruppen i forbindelser med strukturen 2, slik som å fjerne 2,2,2-trihalogenetoksykarbonyl-gruppen ved å anvende eddiksyre og sinkstøv, og derefter alkylere 7-amino-4-karbamoylcefemforbindelsen med det6gnede trifenylmetyl-klorid. The preparation of the compounds 2 where R is derived from triphenylmethyl is achieved either by alkylation of the 7-amino compound, followed by the formation of the 4-carbamoyl group as mentioned above, or by selectively removing the R-acyl group in compounds with the structure 2, such as removing the 2,2,2-trihaloethoxycarbonyl group using acetic acid and zinc dust, and then alkylating the 7-amino-4-carbamoylcepheme compound with the denatured triphenylmethyl chloride.
Overføringen av 2 til 3 krever overføring av 4-karbamoylgruppen i 2 til det egnede iminoklorid, efterfulgt av omsetning av denne forbindelse mad azid. Dannelsen av iminokloridet utføres passende ved å anvende fosgen eller fosforpentaklorid i et reaksjonsinert løsningsmiddel slik som kloroform, mens omsetningen av iminokloridet med saltet av hydrazonsyre og tetrametylguanidin fører til dannelsen av tetrazolringen. Som fagmannen vil forstå kan det anvendes mange kilder for azid ved denne omsetningen og disse kilder omfatter salter av hydrazonsyre med uorganiske baser slik som natriumazid, litiumazld, kaliumazid og ammoniumazid. Siden mange metallazider er eksplosive, er det fordelaktig, og The conversion of 2 to 3 requires transfer of the 4-carbamoyl group in 2 to the appropriate imino chloride, followed by conversion of this compound to azide. The formation of the iminochloride is conveniently carried out by using phosgene or phosphorus pentachloride in a reaction-inert solvent such as chloroform, while the reaction of the iminochloride with the salt of hydrazoic acid and tetramethylguanidine leads to the formation of the tetrazole ring. As the person skilled in the art will understand, many sources of azide can be used in this reaction and these sources include salts of hydrazonic acid with inorganic bases such as sodium azide, lithium azide, potassium azide and ammonium azide. Since many metal azides are explosive, it is advantageous, and
i dette tilfelle foretrukket, at det anvendes azider dannet £ra organiske baser} tetrametylguanidinhydrogenazid er særlig egnet for dette formål. in this case it is preferred that azides formed from organic bases are used} tetramethylguanidine hydrogen azide is particularly suitable for this purpose.
Sekvenstrinnet for overføringen av 3> til A krever fjernelse av "den aminobeskyttende gruppen", R. Reaksjonsbetingelsene som anvendes for fjernelsen er gitt av hva slags gruppe som skal fjernes. Som nevnt tidligere kan 2,2,2-trihalogenetoksykarbonyl-gruppen passende fjernes ved å anvende sinkstøv og eddiksyre, trifenylmetylgruppen fjernes ved å anvende maursyre og benzdksy-karbonylgruppen fjernes ved å behandle 3^ med en blanding av trifluoreddiksyre/anisol (4il v/v) og trifluormetylsulfonsyre. The sequence step for the transfer of 3> to A requires the removal of "the amino protecting group", R. The reaction conditions used for the removal are given by the type of group to be removed. As mentioned earlier, the 2,2,2-trihaloethoxycarbonyl group can be conveniently removed by using zinc dust and acetic acid, the triphenylmethyl group is removed by using formic acid and the benzdoxycarbonyl group is removed by treating 3^ with a mixture of trifluoroacetic acid/anisole (4 µl v/v ) and trifluoromethylsulfonic acid.
I den sistnevnte metoden er det foretrukket at reaksjonen utføres ved isbadtemperatur (0°C) og i løpet av en begrenset tid, vanligvis 4-6 minutter. Dersom det anvendes høye temperaturer, slik som 25-40°C, eller langs reaksjonstider, slik som 1-3 timer, er det mulig å fjerne den "tetrazol-blokkerende" gruppen samtidig. In the latter method, it is preferred that the reaction is carried out at ice bath temperature (0°C) and during a limited time, usually 4-6 minutes. If high temperatures are used, such as 25-40°C, or along reaction times, such as 1-3 hours, it is possible to remove the "tetrazole-blocking" group at the same time.
Efter fjernelsen av den "amino-beskyttende" gruppen fjernes den variable R2ved behandling av 4_ eller p-toluensulfonayresaltet derav med den tidligere nevnte blanding av trifluoreddiksyre/- anisol. After the removal of the "amino-protecting" group, the variable R 2 is removed by treating the 4- or p-toluenesulfonyl salt thereof with the previously mentioned mixture of trifluoroacetic acid/anisole.
Aoylering av IS med den egnede karboksyl syre som erAoylation of IS with the appropriate carboxylic acid which is
aktivert enten som et syrehalogenid, aktivert ester, blandet anhydrid eller syren med et karbodiimid gir de antibakterielle forbindelser ifølge foreliggende oppfinnelse. activated either as an acid halide, activated ester, mixed anhydride or the acid with a carbodiimide give the antibacterial compounds according to the present invention.
Fagmannen vil lett forstå at tilstedeværelsen av andre funksjonelle grupper i den acylerende syren kan kreve at gruppene er maskert for å hindre dem i å delta i konkurerende reaksjoner. Those skilled in the art will readily appreciate that the presence of other functional groups in the acylating acid may require that the groups be masked to prevent them from participating in competing reactions.
Når acyleringen er avsluttet kan gruppene fjernes.When the acylation is finished, the groups can be removed.
Ved fremstillingen av forbindelser med strukturen 6,In the preparation of compounds with the structure 6,
hvor Q er amino, er det f.eks. nødvendig at aminogruppen er blokkert, fortrinnsvis med en t-butoksykarbonylgruppe, idet den blokkerende gruppen fjernes ved syrebehandling efter at acyleringen er avsluttet. En lignende praksis er nødvendig når Q er hydroksy, og i dette tilfelle anvendes en formylgruppe for å maskere hydroksygruppen. where Q is amino, it is e.g. necessary that the amino group is blocked, preferably with a t-butoxycarbonyl group, the blocking group being removed by acid treatment after the acylation has ended. A similar practice is required when Q is hydroxy, in which case a formyl group is used to mask the hydroxy group.
Forbindelsene med strukturen 6 hvor Ar er brom, n er lik 1 og Q er hydrogen kan i tillegg til sin antibakterielle virkning omsettes med merkaptaner og man får ytterligere antibakterielle forbindelser. The compounds with the structure 6 where Ar is bromine, n is equal to 1 and Q is hydrogen can, in addition to their antibacterial effect, be reacted with mercaptans and additional antibacterial compounds are obtained.
Utgangsmaterialene for sekvensen av reaksjoner er enten lett tilgjengelige som kommersielle reagenser eller kan fremstilles efter metoder angitt i litteraturen. 7-amino-3-substituerte-A<3->cefem-4-karboksylsyrene er f.eks. angitt i U.S.-patentena 3.641.021 og aminene R2NIi2 ^rems:t^lles passende ved en eller flere metoder som er angitt av Wagner og Zook, "Synthetic Organic Chemistry", John Wiley and Sons, Inc., New York, NY, 1956, kapittel 24, s. 653-727» mens trifenylmetylkloridene som anvendes kan fremstilles , efter metoder angitt av Bachmann, Org. Synthesis, 23, 100 (1943). The starting materials for the sequence of reactions are either readily available as commercial reagents or can be prepared according to methods indicated in the literature. The 7-amino-3-substituted-A<3->cephem-4-carboxylic acids are e.g. disclosed in U.S. Patent 3,641,021 and the amines R 2 NIi 2 ^rems:t^lles suitably by one or more of the methods set forth by Wagner and Zook, "Synthetic Organic Chemistry", John Wiley and Sons, Inc., New York, NY, 1956, chapter 24, pp. 653-727" while the triphenylmethyl chlorides used can be prepared according to methods indicated by Bachmann, Org. Synthesis, 23, 100 (1943).
Den annen fremgangsmåte som er anvendbar for syntesenThe other method applicable to the synthesis
av de antibakterielle forbindelser ifølge foreliggende oppfinnelse og for fremstillingen av mellomproduktene illustreres som følger: of the antibacterial compounds according to the present invention and for the production of the intermediate products is illustrated as follows:
hvor R, A, R2, Ar, a og Q sr som tidligere angitt og R^er metoksymetyl. where R, A, R 2 , Ar, a and Q are as previously indicated and R 2 is methoxymethyl.
7-acylamino-3-metyl-A -cefera-4-karboksylsyren 1 isomeriseres til den tilsvarende 7-acylamlno-3-metyl-A 2-cefem-4-karboksylsyra og tillater aktiveringen av 3-metyl i de følgende reaksjoner. The 7-acylamino-3-methyl-A-cefera-4-carboxylic acid 1 isomerizes to the corresponding 7-acylamlno-3-methyl-A 2-cephem-4-carboxylic acid and allows the activation of 3-methyl in the following reactions.
Fremstillingen av 4r-karbamoylgruppen i forbindelsene med strukturen 8 utføres efter tilsvarende metoder til de som er omtalt for den første syntesesekvensen. The production of the 4r-carbamoyl group in the compounds with the structure 8 is carried out according to similar methods to those described for the first synthesis sequence.
På ligne&de måte som for den første sekvensen overføres dessuten forbindelsene 8 til tetrazoler med strukturen 9 efter fremgangsmåter som omfatter dannelsen av iminokloridet og dets omsetning med azidet. In a similar way as for the first sequence, the compounds 8 are also transferred to tetrazoles with the structure 9 according to methods which include the formation of the imino chloride and its reaction with the azide.
Fjernelsen av den "tetrazol-beskyttende" gruppen i forbindelsene S> som fører til 10 utføres på samme måte som omtalt The removal of the "tetrazole-protecting" group in the compounds S > leading to 10 is carried out in the same manner as discussed
tidligere når det gjelder den første syntescveien og består i at man bringer 9 i berøring med trifluoreddiksyre/anisol ved 30-50°c i noen timer. earlier when it comes to the first synthesis path and consists in bringing 9 into contact with trifluoroacetic acid/anisole at 30-50°c for a few hours.
Før bromineringen av den aktiverte 3-metyl-substituenten blokkeres tetrazolet 10 ved alkylering med klormetyl-metyleter. Som fagmannen vil forstå kan alkylerlngen finne sted, og finner sted, ved begge N^og Nj-stillingene, idet alkylerlngen hovedsakelig ©r ved N2. Siden den blokkerende gruppen fjernes i et Before the bromination of the activated 3-methyl substituent, the tetrazole 10 is blocked by alkylation with chloromethyl methyl ether. As the person skilled in the art will understand, the alkylation can take place, and does take place, at both the N^ and Nj positions, the alkylation being mainly at N2. Since the blocking group is removed in a
senere trinn i sekvensen er det praktisk at de to isomerer ikke adskilles efter alkylerlngen. Begge isomerer tjener dessuten det samme formål og er lik©nyttige. later steps in the sequence, it is practical that the two isomers are not separated after the alkylation. Both isomers also serve the same purpose and are equally useful.
3-metyl-substituenten i 11 bromeres med N-bromsuccinimidThe 3-methyl substituent in 11 is brominated with N-bromosuccinimide
i nærvær av et peroksyd, en kjent bromeringsmetode. Efter av-slutningen av bromerlngen, isoleres ikke 3-bromraetylforbindelsen, men omsettes med et spesielt nukleofilt reagens slik som merkaptan eller et aoetatsalt som gir 12. in the presence of a peroxide, a known bromination method. After the completion of the bromination, the 3-bromoethyl compound is not isolated, but is reacted with a special nucleophilic reagent such as mercaptan or an acetate salt which gives 12.
Fjernelsen av den "amino-beskyttende" gruppen i 12 utføres efter metoder som er omtalt tidligere i den første syntesesekvensen0 The removal of the "amino-protecting" group in 12 is carried out according to methods discussed earlier in the first synthesis sequence0
På lignende måte utføres acyleringen av 13 ved å anvende de tidligere kjente metoder, idet man beskytter eller<M>raask©rer" eventuell® funksjonelle grupper i syren som skal acyleres og som kan konkurrere ved acyleringen med 7-aminogruppen i A<?*->c@fem (13). In a similar way, the acylation of 13 is carried out by using the previously known methods, protecting or masking any functional groups in the acid to be acylated and which may compete during the acylation with the 7-amino group in A<?* ->c@five (13).
2 3 Reisomeriseringen av A -bindingen av 14 til A -stillingen oppnås ved oksydasjon av svovelatomet i cefemmolekylet med en persyre slik som m-klorbenzoesyr©, og gir 15. Behandlingen av 15 med stannoklorid og acetylklorid resulterer i dannelsen av det ønskede A<3->cefem med strukturen 16. 2 3 The reisomerization of the A -bond of 14 to the A -position is achieved by oxidation of the sulfur atom in the cephem molecule with a peracid such as m-chlorobenzoic acid ©, and gives 15. The treatment of 15 with stannous chloride and acetyl chloride results in the formation of the desired A<3 ->cephem with the structure 16.
De N^- og N2-blokkerende gruppene fjernes fra 16 ved åThe N^ and N2 blocking groups are removed from 16 by
anvende trifluoreddiksyre/anisol som angitt tidligere og<w>maskerende"-grupper fjernes fra acylgruppen i 7-acylaminogruppen dersom disse finnes. use trifluoroacetic acid/anisole as indicated previously and<w>masking" groups are removed from the acyl group in the 7-acylamino group if these are present.
En modifikasjon av den annen reaksjonssekvens tillater fremstillingen av forbindelser hvor R^er avledet fra.ftalidyl eller en alkanoyloksymetyl- eller 1-(alkanoyloksy)etyl-gruppe. Fremgangsmåten som fører til fremstillingen av disse forbindelser anvender alkylering av tetrazolgruppen i 10 med et egnet alkanoyloksy-metylhalogenid eller 1-(alkanoyloksy)etylhalogenid (Ulich, et al, A modification of the second reaction sequence allows the preparation of compounds where R 1 is derived from phthalidyl or an alkanoyloxymethyl or 1-(alkanoyloxy)ethyl group. The procedure leading to the preparation of these compounds employs alkylation of the tetrazole group in 10 with a suitable alkanoyloxymethyl halide or 1-(alkanoyloxy)ethyl halide (Ulich, et al,
J. Am. Chem. Soc, 43, 660 (1921) og Éuranto, et al. Acta Chem. Scand., 20, 1273 (1966) eller ftalidylhalogenid i stedet for klormetyl-metyleter. Ftalidyl-, alkanoyloksymetyl- og 1-(alkanoyloksy)etyl-substituerte tetrazoler av sluttproduktene er forløpere til sluttproduktene og selv om disse ikke har noen virkning eller har en relativt lav virkning i og for seg mot mikroorganismer metaboliseres disse til det frie tetrazol (R-^H) når J. Am. Chem. Soc, 43, 660 (1921) and Éuranto, et al. Acta Chem. Scand., 20, 1273 (1966) or phthalidyl halide instead of chloromethyl methyl ether. Phthalidyl-, alkanoyloxymethyl- and 1-(alkanoyloxy)ethyl-substituted tetrazoles of the end products are precursors to the end products and even if these have no effect or have a relatively low effect in and of themselves against microorganisms, these are metabolized to the free tetrazole (R- ^H) when
de injiseres parenteralt i dyr og mennesker. Hastigheten av den metaboliske overføring av disse forbindelser til det frie tetrazol they are injected parenterally into animals and humans. The speed of the metabolic transfer of these compounds to the free tetrazole
er slik at man får en effektiv og forlenget konsentrasjon av det frie tetrazol i kroppen. Slike forbindelser er således depotkilder for det frie tetrazol-antibakterielle middel. is such that you get an effective and prolonged concentration of the free tetrazole in the body. Such compounds are thus depot sources for the free tetrazole antibacterial agent.
Når det gjelder den antibakterielle virkning av disse forløperformer er både N^- og N2-substituerte isomerer virksomme og nyttige. As far as the antibacterial action of these precursor forms is concerned, both N 1 - and N 2 -substituted isomers are effective and useful.
". Dersom ftalidyl-, alkanoyloksymetyl- eller 1-(alkanoyloksy)-etyl-, N^/N^substituerte tetrazoler syntetiseres efter den annen syntesevei, utelates reaksjons trinnet (16-+6) , og bare maskerings-gruppene fjernes fra acyIdelen av sidekjeden. ". If phthalidyl-, alkanoyloxymethyl- or 1-(alkanoyloxy)-ethyl-, N^/N^-substituted tetrazoles are synthesized according to the second synthesis route, the reaction step (16-+6) is omitted, and only the masking groups are removed from the acyl part of the side chain.
Det finnes alternative metoder for syntese av de antibakterielle produkter som inneholder en ftalidyl-, alkanoyloksymetyl- eller 1-(alkanoyloksy)etyl-gruppe i Nj/N2-stlllingen i tetrazolgruppen. En metode omfatter alkylerlngen av basesaltet av et egnet 7-amino-3-substituert-4-(tetrazol-S-yl)-A<3->cefem, efterfulgt av acyleringen av 7-aminogruppen som tidligere omtalt. There are alternative methods for the synthesis of the antibacterial products which contain a phthalidyl, alkanoyloxymethyl or 1-(alkanoyloxy)ethyl group in the Nj/N2 position in the tetrazole group. One method involves the alkylation of the base salt of a suitable 7-amino-3-substituted-4-(tetrazol-S-yl)-A<3->cephem, followed by the acylation of the 7-amino group as previously discussed.
Den annen metode anvender alkylering av basesaltet av et egnet 7-acylamino-3-substituert-4-(tetrazol-5-yl)-A3-cefem» begge metoder omfatter om nødvendig fjernelse av "maskerte" grupper fra sidekjeden. The second method uses alkylation of the base salt of a suitable 7-acylamino-3-substituted-4-(tetrazol-5-yl)-A3-cephem» both methods include, if necessary, removal of "masked" groups from the side chain.
Når det gjelder den annen serie av reaksjoner som fører til mellomprodukter og sluttprodukter ifølge foreliggende oppfinnelse As for the second series of reactions leading to intermediates and final products according to the present invention
er de foretrukne "amino-blokkerend©'' grupper 2,2,2-trihalogen-etoksykarbonyl-gruppen©. the preferred "amino-blocking" groups are the 2,2,2-trihalo-ethoxycarbonyl group.
Som tidligere angitt er©t karakteristisk trekk ved deAs previously stated, it is a characteristic feature of them
sure forbindelser ifølge foreliggende oppfinnelse, de hvor R^acidic compounds according to the present invention, those where R^
eller R^ er H eller Q er karboksy, at de har ovnen til å danne basiske salter. Syreklassene Ifølge foreliggende oppfinnelse overføres til basesaltene ved å omsette syren med en egnet base i et vandig eller ikke-vandig medium. Slike basiske reagenser som anvendes for fremstilling av saltene kan være av forskjellig slag, og er ment å omfatte slike baser som organiske aminer, ammoniakk, alkalimetallhydroksyder, karbonater, bikarbonater, hydrider og alkoksyder, såvel som jordalkalimetallhydroksyder, hydrider, alkoksyder og karbonater. Eksempler på slike baser er ammoniakk, primær©aminer slik som n-propylamin, n-butylamin, anilin, cyklp-heksylamin, benzylamin, p-toluidln, etylamin, oktylamin, sekundære aminer slik som dlcykloheksylamin og tertiære aminer slik som dietylanilin, N-metylpyrrolidin, N-metylmorfolin og 1,5-diaæa-bicyklo[4.3.0]-5-nonen, natriumhydroksyd, kaliumhydroksyd, ammoniumhy&roksyd, natriumetoksyd, kaliurametoksyd, magnesium-hydroksyd, kalsiumhydrid og bariumhydroksyd. or R^ is H or Q is carboxy, that they have the oven to form basic salts. The acid classes according to the present invention are transferred to the base salts by reacting the acid with a suitable base in an aqueous or non-aqueous medium. Such basic reagents used for the preparation of the salts can be of different types, and are intended to include such bases as organic amines, ammonia, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, hydrides, alkoxides and carbonates. Examples of such bases are ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidln, ethylamine, octylamine, secondary amines such as dlcyclohexylamine and tertiary amines such as diethylaniline, N- methylpyrrolidine, N-methylmorpholine and 1,5-diaea-bicyclo[4.3.0]-5-nonene, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.
Fagmannen vil lett forstå at noen av forbindelsene ifølge foreliggende oppfinnelse er tilstrekkelig basiske, nemlig de sluttprodukter hvor Q©r amino, til å danne syreaddisjonssalter» disse salter, særlig farmasøytisk aksepterbare syreaddisjonssalter, omfattes også av foreliggende oppfinnelse. The person skilled in the art will easily understand that some of the compounds according to the present invention are sufficiently basic, namely the end products where Q©r amino, to form acid addition salts" these salts, especially pharmaceutically acceptable acid addition salts, are also covered by the present invention.
De anvendbare mellomprodukter ifølge foreliggende oppfinnelse som inneholder en fri 7-aminogruppe eller en fri tetrazol-gruppe (R^* R^aH) ar dessuten også istand til å danne syreaddisjonssalter og basesalter. Disse salter anvendes enten for å karakterisere disse mellomprodukter, slik som syreaddisjonssalter, eller de anvendes i reaksjoner, slik som alkylering av basesaltet av tetrazoler. The usable intermediates according to the present invention which contain a free 7-amino group or a free tetrazole group (R^* R^aH) are also capable of forming acid addition salts and base salts. These salts are either used to characterize these intermediates, such as acid addition salts, or they are used in reactions, such as alkylation of the base salt of tetrazoles.
Ved utnyttelsen av den kjemoterapeutiske virkning av disse forbindelser ifølge foreliggende oppfinnelse som danner basiske salter, er det selvfølgelig foretrukket å anvende farmasøytisk aksepterbare salter. Selv om uløselighet i vann, høy giftighet eller mangel på krystallinsk egenskap kan gjøre noen salter uegnede eller mindre egnede for anvendelse som slike ved en gitt farmasøytisk anvendelse, kan de vannuløselige eller giftige saltene overføres til de tilsvarende syrer ved-spaltning av saltene, eller de kan alternativt overføres til ønskede farma-søytisk aksepterbare basiske salter. De foretrukne aksepterbare farmasøytiske salter omfatter natrium-, aluminium-, kalium-, kalsium-, magnesium-, ammonium- og substituerte ammoniumsalter, f.eks. prokain, dibenzylamin, N,N-bis(dehydroåbietyl)etylendiamin, 1-efenamin, N-etylpiperidin, N-benzyl-B-fenetylamin, N,N*-dibenzyletylendiamin, trietylamin, såvel som salter med andre aminer som er blitt anvendt for å fremstille salter med cefem-forbindelsene. When utilizing the chemotherapeutic effect of these compounds according to the present invention which form basic salts, it is of course preferred to use pharmaceutically acceptable salts. Although insolubility in water, high toxicity, or lack of crystalline property may render some salts unsuitable or less suitable for use as such in a given pharmaceutical application, the water-insoluble or toxic salts may be converted to the corresponding acids by cleavage of the salts, or the can alternatively be transferred to desired pharmaceutically acceptable basic salts. The preferred pharmaceutically acceptable salts include sodium, aluminum, potassium, calcium, magnesium, ammonium and substituted ammonium salts, e.g. procaine, dibenzylamine, N,N-bis(dehydroabiethyl)ethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-B-phenethylamine, N,N*-dibenzylethylenediamine, triethylamine, as well as salts with other amines which have been used for to prepare salts with the cefem compounds.
De nye cefemforbindelser utviser in vitro virkning mot en rekke mikroorganismer, som omfatter både gram-positiye og gram-negative bakterier. Den nyttige virkning kan lett demonstreres The new cephem compounds exhibit in vitro activity against a number of microorganisms, including both gram-positive and gram-negative bacteria. The beneficial effect can be easily demonstrated
ved in vitro tester mot forskjellige organismer 1 et brain-heart-infusjonsmedium ved den vanlige doble seriefortynningsteknikk. by in vitro tests against various organisms 1 a brain-heart infusion medium by the usual double serial dilution technique.
In vitro aktiviteten av de angitte forbindelser gjør dem anvendbare for topiske anvendelser 1 form av salver, kraner o.l., eller for steriliseringsformål, f.eks. sykehusutstyr. The in vitro activity of the indicated compounds makes them useful for topical applications in the form of ointments, taps, etc., or for sterilization purposes, e.g. hospital equipment.
De nye cefem-forbindelsene er effektive antibakterielle midler in vivo i dyr, og omfatter mennesker, ikke bare via parénteral administreringsvei, men også via oral administreringsvei. Legen vil selvfølgelig bestemme den optimale dose som vil være mest egnet for en gitt person, og den vil variere med alder, vekt og den spesielle pasients respons såvel som av arten og The new cefem compounds are effective antibacterial agents in vivo in animals, and include humans, not only by the parenteral route of administration, but also by the oral route of administration. The doctor will of course determine the optimal dose that will be most suitable for a given person, and this will vary with age, weight and the particular patient's response as well as the nature and
graden av symptomene, hva slags bakteriell infeksjon som skal behandles og de farmakodynamiske egenskaper av det spesielle the degree of the symptoms, the type of bacterial infection to be treated and the pharmacodynamic properties of the particular
middel som administreres. Man finner ofte at når preparatet administreres oralt er det nødvendig med større mengder av den agent administered. It is often found that when the preparation is administered orally, larger amounts of it are required
aktive bestanddel for å gi det samme nivå som man får med en mindre .: mengde administrert parenteralt. active ingredient to give the same level as obtained with a smaller amount administered parenterally.
På bakgrunn av det som er sagt ovenfor vil en effektiv daglig oral dose av forbindelsene Ifølge foreliggende oppfinnelse i mennesker være ca. 50-1000 mg/kg pr. dag, med et foretrukket område fra ca. 250-750 mg/kg pr. dag i enkle eller oppdelte doser, og en parénteral dose fra 25-500 mg/kg pr. dag, med et foretrukket område fra ca. 125-400 mg/kg pr. dag som vil effektivt lindre infeksjonssymptomene. Disse verdier er bare angitt for å illustrere og de kan selvfølgelig i de forskjellige tilfeller være høyere eller lavere. On the basis of what has been said above, an effective daily oral dose of the compounds according to the present invention in humans will be approx. 50-1000 mg/kg per day, with a preferred area from approx. 250-750 mg/kg per day in single or divided doses, and a parenteral dose from 25-500 mg/kg per day, with a preferred area from approx. 125-400 mg/kg per day which will effectively relieve the symptoms of infection. These values are only given to illustrate and they can of course be higher or lower in the various cases.
Foretrukne forbindelser ifølge foreliggende oppfinnelsePreferred compounds according to the present invention
som er anvendbare som mellomprodukter er 7-(2',2•,2•-trikloretoksykarboksamido) -3-metyl-4-[N- (p-metoksybenzyl)karbaaroyl]-A3-cefem, 7-(benzyloksykarboksamido)-3-metyl- -[N-(p-metoksybenzyl)-karbamoyl]-A<3->cefem, 7-(N-trifenylmetylamino)-3-metyl-4-[N-(p-metoksybensyl)karbamoyl]-A<3->cefem, 7-(2',2',2•-trikloretoksykarboks-amid)-3-acetoksymetyl-4-[N-(p-metoksybenzyl)karbamoyØ]-A -cefem, 7-(benzyloksykarboksamido)-3-acetoksyraetyl-4-[W-(p-metoksybenzyl)-karbamoyl]-^<3->cefem, 7-(N-trifenylmetylamino)-3-acetoksymetyl-4-[N-(p-metoksybenzyl)karbamoyl]-A3-cefem, 7-(2<1>,2•,2'-trikloretoksykarboksamido) -3-raetyl-4- [N- (p-raetoksybenzyl) karbamoyl ]-a2-cefem, 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-[l-(p-metoksybenzyl)tetrazol-5-yl]-a 3-cefem, 7-(N-trifenylamino)-3-metyl-4-ti-(p-metoksybenzyl)tetrazol-5-yl]-A -cefem, 7-amino-3-metyl-4-[1-(p-metoksybenzyl)tetrazol-5-yl]-A -cefem, 7-(benzyloksy-karboksamido) - 3-acetoksymetyl- 4- [1- (p-metoksybenzyl)tetrazol-5-yl]-A<3->cefem, 7-(2•,2•,2'-trikloretoksykarboksamido)-3-acetoksymetyl-4- [1-(p-metoksybenzyl)tetrazol-5-yl]-A -cefem, 7-amino-3-acetoksymetyl-4-[l-(p-metoksybenzyl)tetrazol-5-yl]-A<3->cefem, 7-(benzyloksykarboksamido)-3-(l-metyltetrazol-5-yltiometyl)-4-[1-(p-raetoksybenzyl)tetrazol-5-yl]-A3-cefem, 7-(2',2', 2'-trikloretoksykarboksamido) -3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-[1-(p-metoksybenzyl)tetrazol-5-yl]-A - i-cefem, 7-amino-3-(2-metyl-1,3,4-tiadiazol-5-yltiometyl)-4-[1-(p-metoksybenzyl)tetrazol-5-yl]-A3-cefem, 7- (2',2',2'-trikloretoksykarboksamido)-3-metyl-4-[1-(p-metoksybenzyl)tetrazol-5-yl]-A -cefem, 7-(benzyloksy-karboksamido )-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl) -4- [ 1- (p-metoksybenayl)tetrazol-5-yl]-A<3->cefem, 7-amino-3-metyl-4-(tetrazol-5- yl)-A 3 -cefem, 7-amino-3-acetoksymetyl-4-(tetrazol-5-yl)-a<3->cefem, 7-amino-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(tefcrazol-5-yl)-A<3->cefem, 7-amino-3-(lrmetyltetrazol-5-yltiometyl)-4-(tetrazol-5-yl)-a 3-cefem, 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-(tetrazol-5-yl)-A 2-cefem, 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-[1-(metoksymetyl)tetrazol-5-yl]-A 2-cefem, 7-(2',2',2'-trikloretokaykarbok8amido)-3-metyl-4-[2-(metoksymetyl)tetrazol-5-yl]-A 2 -cefem, 7-amino-3-metyl-4-[l-(metoksymetyl)tetrazol-5-yl3-A -cefem, 7-amino-3-metyl-4-[2-(metoksymetyl)tetrazol-5-yl]-A<2->cefem, 7-amino-3-acetoksymety1-4-t1-(metoksymetyl)tetrazol-5-yl]-A<2>-cefem, 7-amino-3-acetoksymetyl-4-[l-(metoksymetyl)tetrazol-5-yl]-A<2->cefem, which are useful as intermediates are 7-(2',2•,2•-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbaroyl]-A3-cephem, 7-(benzyloxycarboxamido)-3- methyl- -[N-(p-methoxybenzyl)-carbamoyl]-A<3->cephem, 7-(N-triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-A<3 ->cephem, 7-(2',2',2•-trichloroethoxycarboxamide)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-A -cephem, 7-(benzyloxycarboxamido)-3- acetoxyethyl-4-[N-(p-methoxybenzyl)-carbamoyl]-^<3->cephem, 7-(N-triphenylmethylamino)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-A3- cephem, 7-(2<1>,2•,2'-trichloroethoxycarboxamido)-3-raethyl-4- [N-(p-raethoxybenzyl)carbamoyl]-α2-cephem, 7-(2',2',2 '-trichloroethoxycarboxamido)-3-methyl-4-[l-(p-methoxybenzyl)tetrazol-5-yl]-α 3-cephem, 7-(N-triphenylamino)-3-methyl-4-thi-(p- methoxybenzyl)tetrazol-5-yl]-A -cephem, 7-amino-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A -cephem, 7-(benzyloxy-carboxamido) - 3-acetoxymethyl- 4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A<3->cephem, 7-(2• ,2•,2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A -cephem, 7-amino-3-acetoxymethyl-4-[l-(p -methoxybenzyl)tetrazol-5-yl]-α<3->cephem, 7-(benzyloxycarboxamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-raethoxybenzyl)tetrazol-5-yl ]-A3-cephem, 7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl )tetrazol-5-yl]-A - i -cephem, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol- 5-yl]-A3-cephem, 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A -cephem, 7 -(benzyloxy-carboxamido )-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[ 1-(p-methoxybenayl)tetrazol-5-yl]-A<3->cephem , 7-amino-3-methyl-4-(tetrazol-5-yl)-A 3 -cephem, 7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-α<3->cephem, 7 -amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tefcrazol-5-yl)-α<3->cephem, 7-amino-3-(l-methyltetrazol-5 -ylthiomethyl)-4-(tetrazol-5-yl)-a 3-cephem, 7-(2',2',2'-trichloroethoxy ycarboxamido)-3-methyl-4-(tetrazol-5-yl)-A 2-cephem, 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(methoxymethyl)tetrazole -5-yl]-A 2-cephem, 7-(2',2',2'-trichloroethokaycarboxamido)-3-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-A 2 -cephem, 7-amino-3-methyl-4-[1-(methoxymethyl)tetrazol-5-yl3-A -cephem, 7-amino-3-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-A <2->cephem, 7-amino-3-acetoxymethyl-4-t1-(methoxymethyl)tetrazol-5-yl]-A<2>-cephem, 7-amino-3-acetoxymethyl-4-[l-(methoxymethyl )tetrazol-5-yl]-A<2->cephem,
7-amino-3-(l-raetyltetrazol-5-yltiometyl)-4-[l-(metoksymetyl)-tetrazol-5-yl]-A 2-cefem, 7-amino-3-(l-metyltetrazol-5-yltiometyl)-4-[2-(metoksymetyl)tetrazol-5-yl]-A<2->cefem, 7-amino-3-(2-metyl-1,3,4-tiadiazol-5-yltiometyl)-4-[1-metoksymetyl)tetrazol-5-vl]-2 7-amino-3-(1-raethyltetrazol-5-ylthiomethyl)-4-[1-(methoxymethyl)-tetrazol-5-yl]-A 2-cephem, 7-amino-3-(1-methyltetrazol-5- ylthiomethyl)-4-[2-(methoxymethyl)tetrazol-5-yl]-A<2->cephem, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4 -[1-methoxymethyl)tetrazol-5-yl]-2
A -cefem, 7-amino-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-[2-(metoksymetyl)tetrazol-5-yl]-A<2->cefem, 7-(2',2"^'-trikloretoksykarboksamido )-3-brommetyl-4-[1-metoksymetyl)tetrazol-5-yl]- A -cephem, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[2-(methoxymethyl)tetrazol-5-yl]-A<2->cephem, 7-(2',2"^'-trichloroethoxycarboxamido)-3-bromomethyl-4-[1-methoxymethyl)tetrazol-5-yl]-
2 2
A -cefem og 7- (2',2 *,2'-trikloretoksykarboksamido)-3-brom-metyl-4-[2-(metoksymetyl)tetrazol-5-yl]-A 2-cefem. A -cephem and 7-(2',2*,2'-trichloroethoxycarboxamido)-3-bromo-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-A 2-cephem.
De foretrukne antibakterielle midler ifølge foreliggende oppfinnelse er 7-fenylacetamido-3-metyl-4-(tetrazol-5-yl)-A -cefem, 7-fenoksyacetamido-3-metyl-4-(tetrazol-5-yl)-A 3-cefem, 7-(2-tienylacetamido)-3-metyl-4-(tetrazol-5-yl)-A<3>-cefem, 7-fenylacetamido-3-metyl-4-[2-(pivaloyloksymetyl)tetrazol-5-yl]-A -cefem, 7-fenoksyacetamido-3-metyl-4-[2-(pivaloyloksymetyl)tetrazol-5-yl]-A<3->cefem og 7-(2-tienylacetamido)-3-metyl-4-[2-(pivaloyoksymetyl)-tetrazol-5-ylJ-A -cefem. The preferred antibacterial agents according to the present invention are 7-phenylacetamido-3-methyl-4-(tetrazol-5-yl)-A -cephem, 7-phenoxyacetamido-3-methyl-4-(tetrazol-5-yl)-A 3 -cephem, 7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-A<3>-cephem, 7-phenylacetamido-3-methyl-4-[2-(pivaloyloxymethyl)tetrazol- 5-yl]-A -cephem, 7-phenoxyacetamido-3-methyl-4-[2-(pivaloyloxymethyl)tetrazol-5-yl]-A<3->cephem and 7-(2-thienylacetamido)-3-methyl -4-[2-(pivaloyloxymethyl)-tetrazol-5-yl J-A -cephem.
Antimikrobielle data for en rekke forbindelser ifølge foreliggende oppfinnelse mot Streptomyces pyogenes er angitt i den følgende tabell. Disse forsøk ble utført under standardiserte betingelser hvor næringsbuljongen som inneholder forskjellige konsentrasjoner av forsøksaaateriale ble podet med den angitte organisme, og man bestemte minste konsentrasjon (MIC) hvor man ikke fikk noen vekst av mikroorganismen. Antimicrobial data for a number of compounds according to the present invention against Streptomyces pyogenes are given in the following table. These experiments were carried out under standardized conditions where the nutrient broth containing different concentrations of experimental material was inoculated with the indicated organism, and the minimum concentration (MIC) at which no growth of the microorganism was obtained was determined.
Do nye antibakterielle midler ifølge foreliggende oppfinnelse er bemerkelsesverdig effektive for behandlingen av en rekke infeksjoner som skyldes gram-negative og gram-positive bakterier i fjærkre og dyr, og også mennesker. For slike formål kan det anvendes rene materialer eller blandinger derav med andre antibiotika. De kan administreres alene eller i kombinasjon med en farmasøytisk bærer på basis av den valgte adminlstrasjonsvei og standard farmasøytisk praksis. De kan f.eks. administreres oralt 1 form av tabletter som inneholder slike eksiplenter som stivelse, melkesukker, visse typer av clay etc, eller bare i kapsler eller i blandinger med de samme eller ekvivalente eksiplenter. De kan også administreres oralt i form av eliksirer eller orale suspensjoner sem kan inneholde aromastoffer, ell©r fargestoffer, oller de kan injiseres parenteralt, dvs. intra-muskulært eller subkutant. For parénteral administrering anvendes de best i form av en steril vandig løsning som enten kan være vandig slik som vann, isotonisk saltløsning, isotonisk dekstrose, Ringers løsning, eller ikke-vandige, slik som fete oljer av vegetabilsk opprinnelse (bomullsfrøolje, peanøttolje, maisolje, sesamolje) og andre ikke-vandige løsningsformidlere som ikke for-styrrer den terapeutiske virkning ved fremstillingen og er ikke giftige i det anvendte volum eller mengde (glyoerol, propylenglykol, sorbitol). Dessuten kan fremstilles preparater som er egnet for fremstilling av preparater på bestilling fra løsninger før administreringen. Slike preparater kan omfatte flytende for-tynningsmidler, f.eks. propylenglykol, dietylkarbonat, glycerol, sorbitol, etc, buffermidler, såvel som lokale bedøvelsesmidler og uorganiske salter for å gi de ønskede farmakologiske egenskaper. The new antibacterial agents according to the present invention are remarkably effective for the treatment of a variety of infections caused by gram-negative and gram-positive bacteria in poultry and animals, and also humans. For such purposes, pure materials or mixtures thereof with other antibiotics can be used. They can be administered alone or in combination with a pharmaceutical carrier based on the chosen route of administration and standard pharmaceutical practice. They can e.g. administered orally 1 form of tablets containing such excipients as starch, milk sugar, certain types of clay etc, or only in capsules or in mixtures with the same or equivalent excipients. They can also be administered orally in the form of elixirs or oral suspensions which may contain flavoring substances, or coloring substances, or they can be injected parenterally, i.e. intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which can either be aqueous such as water, isotonic saline solution, isotonic dextrose, Ringer's solution, or non-aqueous, such as fatty oils of vegetable origin (cottonseed oil, peanut oil, corn oil, sesame oil) and other non-aqueous solvents that do not interfere with the therapeutic effect during preparation and are not toxic in the volume or quantity used (glyoerol, propylene glycol, sorbitol). In addition, preparations suitable for the preparation of preparations to order can be prepared from solutions prior to administration. Such preparations may comprise liquid diluents, e.g. propylene glycol, diethyl carbonate, glycerol, sorbitol, etc., buffering agents, as well as local anesthetics and inorganic salts to provide the desired pharmacological properties.
De følgende eksempler er gitt for å Illustrere oppfinnelsen. Infrarøde spektra (IR) er målt som kaliumbromidskiver (KBr-skiver) eller som Nujol-mull, og diagnostiske absorbsjonsbånd er angitt 1 bølgelengdetall (cm~^). Kjernemagnetiske resonansspektra (NMR) er målt ved 60 MHz for løsninger i deuterokloroform (CDCl3), perdeutorodimetylsulfoksyd (DMSO-dg) eller deuteriumoksyd (D20), og toppene er uttrykt i deler pr. million (ppm) "downfield a fra tetrametylsilan eller natrium-2,2-dimetyl-2-silapentan-5-sulfonat. De følgende forkortelser for formene av toppen er anvendt» The following examples are given to illustrate the invention. Infrared (IR) spectra are measured as potassium bromide disks (KBr disks) or as Nujol mulls, and diagnostic absorption bands are indicated by 1 wavelength number (cm~^). Nuclear magnetic resonance spectra (NMR) have been measured at 60 MHz for solutions in deuterochloroform (CDCl3), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (D2O), and the peaks are expressed in parts per million (ppm) "downfield a from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for the shapes of the peaks are used"
s, singlett, d, dublett, t, triplett, q, kvartett, m, multiplett. s, singlet, d, doublet, t, triplet, q, quartet, m, multiplet.
Eksempel 1 Example 1
7- (2 •, 2', 2'-trikloretoksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl) karbamoyl3~ A<3>- cefem 7-(2•,2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl3~ A<3>- cephem
A. 7-(2',2°, 2°-trikloretoksykarboksamido)-3-mety■ l-A 3-cefem^-karboksylsyre A. 7-(2',2°, 2°-trichloroethoxycarboxamido)-3-methyl 1-A 3-cephem^-carboxylic acid
Til en suspensjon av 553 g 7-amino-3-metyl~A3-cefem~4-karboksylsyre i 16,65 1 løsning av 1:2 aceton/vann tilsettes 600 g natriumbikarbonat og blandingen omrøres ved værelsestemperatur i 30 minutter. Til den resulterende løsningen tilsettes i løpet av 45 minutter 600 g 2,2,2-triklorotoksykarbonylklorid og reaksjonsblåndingen omrøres i ytterligere 18 timer» Blandingen ekstraheres med aetylonklorid og det vandig©skiktct adskilles og surgjøres til pH 2 med 5W saltsyre. Det surgjorte, vandige skikt ekstraheres med frisk metylenklorid (3 sc 1,51 og 2 x 500 ml) og de kombinerte organiske skikt vaskes i rekkefølge med 5N saltsyre (2 x 500 ml) og vann (3 x 500 ml) og tørkes over magnesiumsulfat. Den tykke oljen, som blir tilbake sftar at løsningsmidlet er fjernet i vakuum, oppløses 12 1 dietyleter og tilsettes dråpevis til 1,5 1 petroleter. Mellomproduktet krystalliserer langsomt fra løsningen (70% utbytte). To a suspension of 553 g of 7-amino-3-methyl~A3-cephem~4-carboxylic acid in 16.65 1 solution of 1:2 acetone/water, 600 g of sodium bicarbonate is added and the mixture is stirred at room temperature for 30 minutes. To the resulting solution, 600 g of 2,2,2-trichlorotoxycarbonyl chloride is added over 45 minutes and the reaction mixture is stirred for a further 18 hours. The mixture is extracted with ethyl chloride and the aqueous layer is separated and acidified to pH 2 with 5W hydrochloric acid. The acidified aqueous layer is extracted with fresh methylene chloride (3 sc 1.51 and 2 x 500 ml) and the combined organic layers are washed sequentially with 5N hydrochloric acid (2 x 500 ml) and water (3 x 500 ml) and dried over magnesium sulfate . The thick oil, which remains after the solvent has been removed in vacuo, is dissolved in 12 1 diethyl ether and added dropwise to 1.5 1 petroleum ether. The intermediate crystallizes slowly from the solution (70% yield).
NMR (DMSOdg)s 6 » 5,4 (q) 1H> 5,1 (d) 1H? 4,85 (s) IH?3,42 (s) 2H, 2,0 (a) 3H. , NMR (DMSOdg)s 6 » 5.4 (q) 1H> 5.1 (d) 1H? 4.85 (s) 1H?3.42 (s) 2H, 2.0 (a) 3H. ,
IR (KBr-skive) y maks: 1770 cm""<*>(3-laktam-karbonyl). IR (KBr disc) y max: 1770 cm""<*>(3-lactam carbonyl).
Produktet oppbevares i on dioksanløsning for anvendelse i de følgende reaksjoner uten ytterligere rensning. The product is stored in dioxane solution for use in the following reactions without further purification.
B. 7-(2',2•,2•-trikloretoksykarboksamido)-3-metyl-4-[N-(p-raetoksy-benzyl)- karbamoyl3- A<3>- cefem. B. 7-(2',2•,2•-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-ethoxy-benzyl)-carbamoyl3-α<3>-cephem.
En løsning som inneholder 1,34 g 2,4-dinitrofenol i 35 ml metylenklorid behandles med 4 g 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-A<3->cefem-4-karboksylsyre i en minst mulig mengde av dioksan, efterfulgt av en løsning av 2,1 g dicykloheksylkarbodiimid i 20 ml metylenklorid. Efter omrøring av reaksjonsblandingen i 30 minutter ved værelsestemperatur, filtreres dicyklohsksylurea, vaskes med metylenklorid, og filtratet og vaske-løsningene kombineres og behandles med 1,4 g p-metoksybenzylamin i 14 ml metylenklorid. A solution containing 1.34 g of 2,4-dinitrophenol in 35 ml of methylene chloride is treated with 4 g of 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-A<3->cephem-4-carboxylic acid in the smallest possible amount of dioxane, followed by a solution of 2.1 g of dicyclohexylcarbodiimide in 20 ml of methylene chloride. After stirring the reaction mixture for 30 minutes at room temperature, dicycloxylurea is filtered, washed with methylene chloride, and the filtrate and washing solutions are combined and treated with 1.4 g of p-methoxybenzylamine in 14 ml of methylene chloride.
Efter 30 minutter ved værelsestemperatur vaskes reaksjonsblandingen med mettet natriumkarbonatløsning og den organiske fasen tørkes over magnesiumsulfat. Den tykke oljen, som blir tilbake efter at løsningsmidlet er fjernet under redusert trykk, tritureres med petroleter. Det krystalliserte produkt filtreres og tørkes,<p>g man får 4,0 g av et svakt gulfarvet fast stoff. After 30 minutes at room temperature, the reaction mixture is washed with saturated sodium carbonate solution and the organic phase is dried over magnesium sulfate. The thick oil, which remains after the solvent has been removed under reduced pressure, is triturated with petroleum ether. The crystallized product is filtered and dried to give 4.0 g of a slightly yellow solid.
NMR (DMSOdg)s 6 => 8,5 (t) 1H, 7,0 (q) 4H, 5,3 (q) ogNMR (DMSOdg)s 6 => 8.5 (t) 1H, 7.0 (q) 4H, 5.3 (q) and
4,95 (d) 2H, 4,8 (s) 2H» 4,3 (d) 2H, 3,7 (s) 3H, 3,45 (bred) 2H 4.95 (d) 2H, 4.8 (s) 2H» 4.3 (d) 2H, 3.7 (s) 3H, 3.45 (broad) 2H
og 2 (s) 3Hoand 2 (s) 3Ho
IR (KBr-skive) y: 1770 cm""<1>(3-laktam-karbonyl).IR (KBr disc) y: 1770 cm""<1>(3-lactam carbonyl).
Eksempel 2 Example 2
7-(2<8>,2',2'-trikloretoksykarboksamido)-3-metyl-4-11-p-metoksy- 7-(2<8>,2',2'-trichloroethoxycarboxamido)-3-methyl-4-11-p-methoxy-
3 3
benzyltetrazol- 5- yl- A - °cefembenzyltetrazol-5-yl-A - °cephem
Til en suspensjon av 100 g 7-(2',2",2'-trikloretoksy-tarboksamido)-3-metyl-4-[N-(p-metoksybenzyl)karbamoyl]-A 3-cefem 12 1 kloroform tilsettes dråpevis 250 ml toluen som inneholder To a suspension of 100 g of 7-(2',2",2'-trichloroethoxy-tarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-A 3-cephem 12 1 chloroform is added dropwise 250 ml of toluene containing
30 g fosgen i løpet av 15 minutter. Efter ytterligere 15 minutter tilsettes dråpevis en løsning av 24 g tørr pyridin i 100 ml kloroform i løpet av 45 minutter, i løpet av denne tiden oppnås en løsning og det utvikles langsomt karbondioksyd. Løsningen omrøres i 90 minutter og konsentreres derefter til halve volumet i vakuum for å fjerne overskudd av fosgen. Det tilsettes kloroform (2 1) 30 g of phosgene within 15 minutes. After a further 15 minutes, a solution of 24 g of dry pyridine in 100 ml of chloroform is added dropwise over the course of 45 minutes, during which time a solution is obtained and carbon dioxide slowly evolves. The solution is stirred for 90 minutes and then concentrated to half the volume in vacuo to remove excess phosgene. Chloroform (2 1) is added
og til den omrørte løsningen tilsettes derefter 45 g tetrametyl-guanidiniumazid i 250 ml kloroform. Efter 2 timer vaskes kloroform-løsningen efter hverandre med vann (2 x 500 ml), mettet natrium-karbonatløsning (2 x 300 ml), 2,5E3 saltsyre og vann (1 x 250 ml). Den organiske fasen tørkes over magnesiurasulfat og konsentreres and 45 g of tetramethylguanidinium azide in 250 ml of chloroform are then added to the stirred solution. After 2 hours, the chloroform solution is washed successively with water (2 x 500 ml), saturated sodium carbonate solution (2 x 300 ml), 2.5E3 hydrochloric acid and water (1 x 250 ml). The organic phase is dried over magnesium sulphate and concentrated
i vakuum til et gummiaktig fast stoff, 102 g. Produktet renses ytterligere ved kromatografering på en kolonne av aluminiumoksyd (306 g) ved å anvende kloroform som løsningsmiddel (408 ml) og elueringsmiddel (1,5 1).Eluatet tilsettes under omrøring til 6 1 petroleter, og dette resulterer i utfelling av produktet som et lysebrunt, fast stoff, 79 g. in vacuo to a gummy solid, 102 g. The product is further purified by chromatography on a column of alumina (306 g) using chloroform as solvent (408 ml) and eluent (1.5 L). The eluate is added with stirring to 6 1 petroleum ether, and this results in precipitation of the product as a light brown solid, 79 g.
NMR (CDCl3)s 6 ■ 6,9 (q) 4Hr 5,4 (m) 3H, 4,9 (d) 1H,NMR (CDCl3)s 6 ■ 6.9 (q) 4Hr 5.4 (m) 3H, 4.9 (d) 1H,
4,7 (s) 2H, 3,7 (s) 3H, 3,3 (q) 3H og 1,4 (s) 3H. 4.7 (s) 2H, 3.7 (s) 3H, 3.3 (q) 3H and 1.4 (s) 3H.
IR (KBr-skive) y: 1770 cm"<*1>(fl-laktam-karbonyl) „ IR (KBr disc) y: 1770 cm"<*1>(fl-lactam carbonyl) „
På lignende måte gir 250 mg 7-(2',2•,2•-trikloretoksykarboksamido)-3-metyl-[N-(p-metoksybenzyl)karbamoyl]-A<3->cefem, 0,007 mé pyridin og 2,6 mg fosforpentaklorid i 6 ml kloroform det tilsvarende iminoklorid som ved behandling med tetrametylguanidinium-azid (lg) 12 ml kloroform, gir 220 mg av det ønskede tetrazol, som på alle måter er identisk med det som ble oppnådd ovenfor. Similarly, 250 mg of 7-(2',2•,2•-trichloroethoxycarboxamido)-3-methyl-[N-(p-methoxybenzyl)carbamoyl]-A<3->cephem, 0.007 me pyridine and 2.6 mg of phosphorus pentachloride in 6 ml of chloroform the corresponding imino chloride which, on treatment with tetramethylguanidinium azide (lg) in 12 ml of chloroform, gives 220 mg of the desired tetrazole, which is in all respects identical to that obtained above.
Eksempel 3 Example 3
7~amino-3-metyl-"4-[l-( p- metoksybenzyl) tetrazol- 5- yl]- A - cefem7~amino-3-methyl-"4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A-cephem
Til 73 g 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-El-(p-metoksybenzyl)tetrazol-5-yl]-Å 3-cefem i 500 ml 95% eddiksyre tilsettes 25 g sinkstøv, og blandingen omrøres. kraftig i 3 timer ved værelsestemperatur. Blandingen filtreres og filtratet tilsettes til et stort volum vann og ekstraheres med kloroform.» Det organiske skikt vaskes medneann og produktet ekstraheres fra den organiske fase med IN saltsyre. Den vandige fasen vaskes med kloroform, gjøres basisk med 2N natriumhy&rokGydløsning til pH 7 og ekstraheres med kloroform. Kloroformskiktet tørkes over magnesiumsulfat og konsentrerea under redusert trykk til et lite volum0 Ved tilsetning av konsentratet til petroleter, faller produktet ut. Det faste stoffet filtreres fra og tørkes, 30 g. 25 g of zinc dust, and the mixture is stirred. vigorously for 3 hours at room temperature. The mixture is filtered and the filtrate is added to a large volume of water and extracted with chloroform.' The organic layer is washed with water and the product is extracted from the organic phase with IN hydrochloric acid. The aqueous phase is washed with chloroform, basified with 2N sodium hydroxide solution to pH 7 and extracted with chloroform. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to a small volume. When the concentrate is added to petroleum ether, the product precipitates. The solid is filtered off and dried, 30 g.
NMR (DMSOdg): 6 « 7(2 q) 8H, 5,5(s) 2H, 5,4 (d) 1H, 5,05 (d) 1H, 3,7 (s) 3H, 3,6 (s) 2H, 2,2 (s) 3H og 1,4 (s) 3H»NMR (DMSOdg): 6 « 7(2q) 8H, 5.5(s) 2H, 5.4 (d) 1H, 5.05 (d) 1H, 3.7 (s) 3H, 3.6 ( s) 2H, 2.2 (s) 3H and 1.4 (s) 3H»
Eksempel 4 Example 4
7- amino- 3- metyl- 4-( tetrazol- 5- yl)- A 3- cefem7- amino- 3- methyl- 4-( tetrazol- 5- yl)- A 3- cephem
En blanding av 7,0 g 7-amino-3-metyl-4-(l-[p-metoksybenzyl]-tetrazol-5-yl)-A<3->cefem i 50ml trifluoreddiksyre/anisol (4sl) A mixture of 7.0 g of 7-amino-3-methyl-4-(1-[p-methoxybenzyl]-tetrazol-5-yl)-A<3->cephem in 50 ml of trifluoroacetic acid/anisole (4sl)
får lov til å stå ved 50°C i 5 timer. Løsningen helles derefterallowed to stand at 50°C for 5 hours. The solution is then poured
ned i et stort volum av omrørt dietyleter og utfelningen som dannes filtreres fra. Det faste stoffet oppløses i vann, som ekstraheres into a large volume of stirred diethyl ether and the precipitate that forms is filtered off. The solid is dissolved in water, which is extracted
en rekke ganger med etylacetat, justeres til pH 7,0 med 2N vandig natrlumhydroksyd og ekstraheres igjen. Den vandige løsningen som inneholder produktet frysetørros, og man får 3,2 g av den ønskede forbindelse (som inneholder noe natriumtrifluoracetat). several times with ethyl acetate, adjusted to pH 7.0 with 2N aqueous sodium hydroxide and extracted again. The aqueous solution containing the product is freeze-dried to give 3.2 g of the desired compound (which contains some sodium trifluoroacetate).
NMR (DMSOdg)s 6 =» 5,0 (d) 1H, 4,6 (d) 1H, 3,4 (q) 2H,NMR (DMSOdg)s 6 =» 5.0 (d) 1H, 4.6 (d) 1H, 3.4 (q) 2H,
1,9 (s) 3H og 1,3 (s) 3H.1.9 (s) 3H and 1.3 (s) 3H.
Eksempel 5Example 5
3 7-( benzyloksykarboksamido)- 3- metyl- A - cefem- 4~ karbok3ylsyre 3 7-( benzyloxycarboxamido)- 3- methyl- A - cephem- 4~ carboxylic acid
Natriumbikarbonat (500 g) tilsettes i porsjoner i løpet avSodium bicarbonate (500 g) is added in portions during
3 3
45 minutter til en omrørt suspensjon av 7-amlno-3-metyl-A -cefem-4-karboksylsyre (560 g) i koldt vann (5,6 liter) og aceton (5,6 liter). Når brusingen er opphørt tilsettes benzylklorformiat (490 g) og løsningen omrøres ved værelsestemperatur natten over. Reaksjonsblandingen ekstraheres derefter med etylacetat (2x1 liter), og pH av det adskilte vandige skikt justeres til 2 ved tilsetning av 2N saltsyre. Denne blandingen ekstraheres derefter med etylacetat 45 minutes to a stirred suspension of 7-amino-3-methyl-A-cephem-4-carboxylic acid (560 g) in cold water (5.6 liters) and acetone (5.6 liters). When the effervescence has ceased, benzyl chloroformate (490 g) is added and the solution is stirred at room temperature overnight. The reaction mixture is then extracted with ethyl acetate (2x1 liter), and the pH of the separated aqueous layer is adjusted to 2 by adding 2N hydrochloric acid. This mixture is then extracted with ethyl acetate
(2x1 liter) og løsningsmidlet fra det adskilte organiske skikt fjernes i vakuum. Det resulterende faste stoff oppløses i varm metanol (2 liter) og fortynnes med varmt vann (5 liter), og man får 7-(benzyloksykarboksamido)-3-metyl-A 3-cefem-4-karboksylsyre som et hvitt, fast stoff (750 g), som tørkes i vakuum ved 60°C. (2x1 liter) and the solvent from the separated organic layer is removed in vacuo. The resulting solid is dissolved in hot methanol (2 L) and diluted with hot water (5 L) to give 7-(benzyloxycarboxamido)-3-methyl-A 3-cephem-4-carboxylic acid as a white solid ( 750 g), which is dried in vacuum at 60°C.
NMR (DMSOdg): 6 = 8,3 (d) 1H, 7,3 (m) 5H, 5,4 (g) 1H,NMR (DMSOdg): δ = 8.3 (d) 1H, 7.3 (m) 5H, 5.4 (g) 1H,
5,1 (d) 1H, 5 (s) 2H, 3,4 (q) 2H og 2,1 (s) 3H, 5.1 (d) 1H, 5 (s) 2H, 3.4 (q) 2H and 2.1 (s) 3H,
Eksempel 6 Example 6
7-(benzyloksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl)-karbamoyl3- A 3- cefem 7-(Benzyloxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl3- A 3- cephem
En blanding av 7-(benzyloksykarboksamido)-3-metyl-A<3->cefem-4-karboksylsyre (34,8 g) og 2,4-dinitrofenol (18,4 g) A mixture of 7-(benzyloxycarboxamido)-3-methyl-A<3->cephem-4-carboxylic acid (34.8 g) and 2,4-dinitrophenol (18.4 g)
oppløses 1 tørr dioksan (700 ml). Det tilsettes derefter dicykloheksylkarbodiimid (20,6 g) og løsningen omrøres i 20 minutter ved værelsestearperatur. Derefter filtreres det utfalte dicykloheksylurea fra, og filtratet behandles med p-metoksybenzylamin (13,7 g) som tilsettes 1 løpet av 10 minutter. Efter ytterligere 15 minutter fortynnes reaksjonsblandlngen med tørr eter (1,4 liter). dissolve 1 dry dioxane (700 ml). Dicyclohexylcarbodiimide (20.6 g) is then added and the solution is stirred for 20 minutes at room temperature. The precipitated dicyclohexylurea is then filtered off, and the filtrate is treated with p-methoxybenzylamine (13.7 g) which is added 1 over 10 minutes. After a further 15 minutes, the reaction mixture is diluted with dry ether (1.4 litres).
Utfelningen filtreres fra, vaskes med tørr eter (500 ml), ogThe precipitate is filtered off, washed with dry ether (500 ml), and
tørkes i vakuum ved 50°C, og man får 40 g av produktet som et hvitt, dried in vacuum at 50°C, and 40 g of the product is obtained as a white,
fast stoff.solid.
NMR (DMSOdg): 6 =8,4(m) 2H, 7 (q) 4H, 5,3 (q) 1H,NMR (DMSOdg): 6 =8.4(m) 2H, 7 (q) 4H, 5.3 (q) 1H,
5,1 (s) 2H, 5 (d) 1H, 4,3 (d) 2H, 3,7 (s) 3H, 3,3 (s) 2H og 2 (s) 3H. 5.1 (s) 2H, 5 (d) 1H, 4.3 (d) 2H, 3.7 (s) 3H, 3.3 (s) 2H and 2 (s) 3H.
Eksempel 7 Example 7
7- amino- 3- metyl- 4-[ N- ( p- metoksybenzyl) karbamoyl 3- A^ r- cafem 7- amino- 3- methyl- 4-[ N-( p- methoxybenzyl) carbamoyl 3- A^ r-cafem
7-(benzyloksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl)-karbamoylQ-A 3-cefem (20 g) oppløses i hydrobromsyre/eddiksyre (200 ml) og løsningen omrøres ved værelsesteraperatur inntil gass-utviklingen opphører. Blandingen helles ned i et stort volum (ca. 2 liter) av omrørt eter og den resulterende utfeining oppsamles. Det faste stoffet oppløses i vann og den vandige løsningen vaskes med etylacetat (2 ganger)* Den vandige løsningen justeres til 7-(Benzyloxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoylQ-A 3-cephem (20 g) is dissolved in hydrobromic acid/acetic acid (200 ml) and the solution is stirred at room temperature until gas evolution ceases . The mixture is poured into a large volume (about 2 liters) of stirred ether and the resulting skimming is collected. The solid is dissolved in water and the aqueous solution is washed with ethyl acetate (2 times)* The aqueous solution is adjusted to
pH 7,5 med natriumbikarbonat og suspensjonen ekstraheres med kloroform. Kloroformekstrakten tørkes (MgSO^) og fordampes under redusert trykk, og man får produktet som et svakt gult, fast stoff (7,7 g). pH 7.5 with sodium bicarbonate and the suspension is extracted with chloroform. The chloroform extract is dried (MgSO4) and evaporated under reduced pressure, and the product is obtained as a pale yellow solid (7.7 g).
NMR (DMSOdg)l6 - 8,0 (t) 1H, 7,0 (q) 4H, 4,8 (d) 1H,NMR (DMSOdg)16 - 8.0 (t) 1H, 7.0 (q) 4H, 4.8 (d) 1H,
4,6 (d) IK, 4,4 (d) 2H, 3,7 (s) 3H, 3,2 (q) 2H, 2,1 (s) 2H og 2,0 (s) 3H<4.6 (d) IK, 4.4 (d) 2H, 3.7 (s) 3H, 3.2 (q) 2H, 2.1 (s) 2H and 2.0 (s) 3H<
Eksempel 8 Example 8
7-(N-tri fenyImety1amino)-3-metyl-4-[N-(p-metoksybénzyl)karbamoyl]-A3- cefem Til 24 g 7-amino-3-metyl-4~[N-(p-metoksybenzyl)karbamoyl]-A 3-cefem i kloroform (etanolfri, 300 ml) tilsettes trifenylmetyl-klorid (21,0 g) og trietylamin (7,64 g). Blandingen står ved værelsesteraperatur under utelukkelse av lys i 15 timor. Løsningen fortynnes derefter til det flerdoble volum med kloroform og vaskes to ganger med vann. Den organiske løsningen tørkes (MgSO^) og 7-(N-triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-A3-cephem To 24 g 7-amino-3-methyl-4~[N-(p-methoxybenzyl) carbamoyl]-A 3-cephem in chloroform (ethanol-free, 300 ml) is added triphenylmethyl chloride (21.0 g) and triethylamine (7.64 g). The mixture stands at room temperature under the exclusion of light for 15 hours. The solution is then diluted to multiple volumes with chloroform and washed twice with water. The organic solution is dried (MgSO^) and
fordampes til tørrhet, og man får produktet som et skum»evaporates to dryness, and you get the product as a foam"
Triturering med lett petroleter gir et svakt gult, fast stoff (40 g). Trituration with light petroleum ether gives a pale yellow solid (40 g).
NMR (CDCl3)s 6«7,2, 9H, (q) 1H, 4,4 (d) 2H, 4,1 (d) 1H, 3,7 (s) 3H, 3,0 3H og 2,0 (s) 3H. NMR (CDCl3)s 6«7.2, 9H, (q) 1H, 4.4 (d) 2H, 4.1 (d) 1H, 3.7 (s) 3H, 3.0 3H and 2.0 (s) 3H.
Eksempel 9 Example 9
7-(N-trifenylmetylamino)-3-metyl-4-[l-(p-metoksybenzyl)-tetrazol-5- yl]- A<3>- cefem 7-(N-triphenylmethylamino)-3-methyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]- A<3>- cephem
7-(N-trifenylmetylamino)-3-metyl-4-[N-(p-metoksybenzyl)-karbamoyl]-A 3-cefem (2,8 g) i etanolfri kloroform (7,5 ml) som inneholder pyridin (0,6 g) behandles med fosgen i kloroform (3,7 ml, 1,7M). Reaksjonsblandingen omrøres i 30 minutter ved værelsestearperatur, Overskudd av fosgen fjernes under redusert trykk og ytterligere kloroform tilsettes inntil volumet av løsningen er 10 ral. Det tilsettes tetrametylguanidinhydrogenazid (2,4 g) i kloroform (5 ml) til den ovenfor fremstilte løsningen og reaksjonsblandingen omrøres ved værelsesteraperatur i 20 minutter. Løsningen vasfees med vann, tørkes (MgSO^) og fordampes under redusert trykk, og man får en oljo. Triturering med lett petroleter gir 2,2 g av produktet. 7-(N-triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl]-A 3-cephem (2.8 g) in ethanol-free chloroform (7.5 mL) containing pyridine (0 .6 g) is treated with phosgene in chloroform (3.7 ml, 1.7M). The reaction mixture is stirred for 30 minutes at room temperature. Excess phosgene is removed under reduced pressure and further chloroform is added until the volume of the solution is 10 ral. Tetramethylguanidine hydrogenazide (2.4 g) in chloroform (5 ml) is added to the solution prepared above and the reaction mixture is stirred at room temperature for 20 minutes. The solution is washed with water, dried (MgSO^) and evaporated under reduced pressure, and an oil is obtained. Trituration with light petroleum ether gives 2.2 g of the product.
NMR (CDC13): .6 =» 7,2 19 H, 5,3 (s) 2H, 4,4 (q) 1H, 4,2 (d) lH, 3,6 (3) 3H, 3,0 3H og 1,2 (s) 3H. NMR (CDCl 3 ): .6 =» 7.2 19 H, 5.3 (s) 2 H, 4.4 (q) 1 H, 4.2 (d) 1 H, 3.6 (3) 3 H, 3.0 3H and 1.2 (s) 3H.
Eksempel 10 Example 10
7- amino- 3- metyl- 4-[ l-( p- metoksybenzyl) tetrazol- 5- yl]- A 3- cefem 7-(N-trifenylmetylamino)-3-metyl-4-[l-(p-metoksyb©nzyl)-tetrazol-5-yl]-A 3-cefem (1,5 g) behandles med maursyre (30 ml) og løsningen får stå ved vsrelsestemperatur i 30 minutter* Løsningen helles ned i vann (100 ml) og den vandige suspensjonen vaskes med etylacetat. Den vandige løsningen justeres til pH 7,5 med 2N vandig natriumhydroksyd og blandingen ekstraheres med kloroform. Den organiske løsningen tørkes (MgSO^) og fordampes under redusert 7-amino-3-methyl-4-[l-(p-methoxybenzyl)tetrazol-5-yl]- A 3-cephem 7-(N-triphenylmethylamino)-3-methyl-4-[l-(p-methoxyb ©nzyl)-tetrazol-5-yl]-A 3-cephem (1.5 g) is treated with formic acid (30 ml) and the solution is allowed to stand at room temperature for 30 minutes* The solution is poured into water (100 ml) and the aqueous the suspension is washed with ethyl acetate. The aqueous solution is adjusted to pH 7.5 with 2N aqueous sodium hydroxide and the mixture is extracted with chloroform. The organic solution is dried (MgSO^) and evaporated under reduced
trykk, og man får et skum. Triturering med lett petroleter gir 400 mg av produktet som et fast stoff. pressure, and you get a foam. Trituration with light petroleum ether gives 400 mg of the product as a solid.
NMR (CDCl3)i 6 » 7,0 (q) 4H, 5,4 (s) 2H, 4,9 (d) 1H, 4,6 (d) 1H, 3,7 (s) 3H, 3,3 (q) 2H, 2,0 (s) 2H og 1,4 (s) 3H. NMR (CDCl3)i 6 » 7.0 (q) 4H, 5.4 (s) 2H, 4.9 (d) 1H, 4.6 (d) 1H, 3.7 (s) 3H, 3.3 (q) 2H, 2.0 (s) 2H and 1.4 (s) 3H.
Eksempel 11 7-[ D~( a- amino- g- fenyl) acetamido]~ 3- metyl- 4-( tetrazol- 5- yl)- A3- cefem Example 11 7-[D~(a-amino-g-phenyl)acetamido]~ 3-methyl-4-(tetrazol-5-yl)-A3-cephem
A. 7~[D-a-t-butoksykarboksainido-o-fenyl)acetamido]-3-*metyl-4-( tetrazol- 5- yl)- A 3- cefem A. 7~[D-α-t-butoxycarboxainido-o-phenyl)acetamido]-3-*methyl-4-(tetrazol-5-yl)- A 3-cephem
D-(a-t-butoksykarboksamldo-H-fenyl)eddiksyre (0,251 g) i tetrahydrofuran (2 ml) behandles med trietylamin (0,101 g) og D-(α-t-butoxycarboxyldo-H-phenyl)acetic acid (0.251 g) in tetrahydrofuran (2 ml) is treated with triethylamine (0.101 g) and
etylklorformiat (0,108 g) ved -10°C. Efter 15 minutter ved denne temperatur tilsettes under omrøring i en porsjon natriumsaltet av 7-amino-3-mety1-4-(tetrazol-5-yl)-A -cefem (0,400 g) i vann (3 ml). Blandingen fortynnes med tetrahydrofuran (2 ml) og får lov til å varmes opp til værelsestemperatur. Efter 1 time justeres løsningen til pH 2 med 2N saltsyre og suspensjonen ekstraheres med etylacetat. Etylacetatløsningen vaskes med vann, tørkes (MgS04), konsentreres under redusert trykk og helles ned i et stort volum av lett petroleter, og man får et hvitt, fast stoff. Forbindelsen rekrystalliseres fra kloroform (316 ml). ethyl chloroformate (0.108 g) at -10°C. After 15 minutes at this temperature, the sodium salt of 7-amino-3-methyl-4-(tetrazol-5-yl)-A-cephem (0.400 g) in water (3 ml) is added with stirring in one portion. The mixture is diluted with tetrahydrofuran (2 ml) and allowed to warm to room temperature. After 1 hour, the solution is adjusted to pH 2 with 2N hydrochloric acid and the suspension is extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried (MgSO 4 ), concentrated under reduced pressure and poured into a large volume of light petroleum ether, and a white solid is obtained. The compound is recrystallized from chloroform (316 mL).
NMR (DMSOdg): 6 » 7,6 (d) 1H, 7,2 5H, 6,0 (d) 1H, 5,6 (q) 1H, 5,2 (d) 1H, 4,9 (d) 1H, 3,3 (q) 2H, »,0 (s) 3H.bg 1,2 (s) 9H. NMR (DMSOdg): 6 » 7.6 (d) 1H, 7.2 5H, 6.0 (d) 1H, 5.6 (q) 1H, 5.2 (d) 1H, 4.9 (d) 1H, 3.3 (q) 2H, »,0 (s) 3H.bg 1.2 (s) 9H.
B. 7-[D-(a-ajnino-q-fenyl)acetamido]-3-metyl-4-(tetrazol-5ryl)-A B. 7-[D-(α-ajnino-q-phenyl)acetamido]-3-methyl-4-(tetrazol-5ryl)-A
cefem- trifluoracetat 7-[D-(a-t-butoksykarboksamido-o-fenyl)acetamido]-3-metyl-4-(tetrazol-i-yl)-A<3->cefem (26 mg) oppløses i trifluoreddiksyre Cepheme trifluoroacetate 7-[D-(a-t-butoxycarboxamido-o-phenyl)acetamido]-3-methyl-4-(tetrazol-i-yl)-A<3->cepheme (26 mg) is dissolved in trifluoroacetic acid
(0,5 ml) og får lov til å stå ved væreIsestemperatur i 20 minutter.. (0.5 ml) and allowed to stand at room temperature for 20 minutes.
Til løsningen tilsettes eter og utfelningen oppsamles (24 mg).Ether is added to the solution and the precipitate is collected (24 mg).
NMR (DMSOd6-D20) t 6 * 7,4(s) 5B, 5,6(d) 1H, 5,1(d) lH, 5,0(s) 1H, 3,4, 2H og 2,0(s) 3H. NMR (DMSOd 6 -D 2 O) t 6 * 7.4(s) 5B, 5.6(d) 1H, 5.1(d) 1H, 5.0(s) 1H, 3.4, 2H and 2.0 (s) 3H.
Eksempel 12 7-[D-o-amino-a-(p-hydroksyfenyl)acetamido]-3-metyl-4-(tetrazol-5- yl)- A3- cefem Example 12 7-[D-o-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-α3-cephem
Fremgangsmåten i eksempel 11 Ac?og B gjentas ved å gå ut fra defc nødvendige D-[o-t-butoksykarboksamido-a-(p-hydroksyfenyl)]-eddiksyre i stedet for D-(a-t-butoksykarboksamido-o-fenyl)eddiksyre, og man får produktet. The procedure in example 11 Ac?and B is repeated by starting from the necessary D-[o-t-butoxycarboxamido-a-(p-hydroxyphenyl)]-acetic acid instead of D-(a-t-butoxycarboxamido-o-phenyl)acetic acid, and you get the product.
IR (CH2C<1>2)<:><Y>najt8« 1780cm"<1>(p-laktam-karbonyl)» 1660 cm"1 IR (CH2C<1>2)<:><Y>najt8« 1780 cm"<1>(p-lactam-carbonyl)" 1660 cm"1
(-C0NH-). (-C0NH-).
Eksempel 13 7-( D- a- hydroksvfenylacetamldo)- 3- metyl- 4-( tetrazol- 5- yl)- A3- cefem A. 7-(D-o-formyloksyfenylacetamido)-3-metyl-4-(tetrazol-5-yl)-A - Example 13 7-(D-α-hydroxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-α3-cephem A. 7-(D-o-formyloxyphenylacetamido)-3-methyl-4-(tetrazol-5- yl)-A -
cefemcephem
D-O-formylmandelsyre (1,8 g) i eter (15 ml) behandles med oksalylklorid (2,5 ml) og en dråpe dimetylformamid. Efter at den kraftige reaksjonen har stilnet av (30 min.) fjernes eteren under redusert trøkk og resten i THF (10 ml) tilsettes til en omrørt løsning av 7-amino-3-metyl-4-(tetrazol-5-yl)-A -cefem (1 g) i en blanding av vann/THF (lii, 20 ml) som inneholder et overskudd av natriumbikarbonat. Efter omrøring i ytterligere 1 time ved værelsestemperatur justeres blandingen til pH 2 med 2N saltsyre og blandingen ekstraheres med etylacetat. Den organiske løsningen vaskes med vann, tørkes (MgSO^) og fordampes under redusert trykk, og man får det ønskede produkt som et fast stoff (350 mg). D-O-formylmandelic acid (1.8 g) in ether (15 ml) is treated with oxalyl chloride (2.5 ml) and a drop of dimethylformamide. After the vigorous reaction has subsided (30 min.), the ether is removed under reduced pressure and the residue in THF (10 ml) is added to a stirred solution of 7-amino-3-methyl-4-(tetrazol-5-yl)- A -cephem (1 g) in a mixture of water/THF (lii, 20 ml) containing an excess of sodium bicarbonate. After stirring for a further 1 hour at room temperature, the mixture is adjusted to pH 2 with 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The organic solution is washed with water, dried (MgSO4) and evaporated under reduced pressure, and the desired product is obtained as a solid (350 mg).
NMR (DMSOdg)» 6 - 8,2 (s) 1H, 7,2(s) 5H, 6,0(s) 1H, 5,5(q)NMR (DMSOdg)» 6 - 8.2 (s) 1H, 7.2(s) 5H, 6.0(s) 1H, 5.5(q)
1H, 5,1(d) 1H, 3,5(s) 2H og 2,0, 3H. 1H, 5.1(d) 1H, 3.5(s) 2H and 2.0, 3H.
B. 7-( D- g- hydroksyfenylacetamido)- 3- metyl- 4-( tetrazol- 5- yl)- A 3- cefem B. 7-( D- g- hydroxyphenylacetamido)- 3- methyl- 4-( tetrazol- 5- yl)- A 3- cephem
7-(D-a-formyloksyfenylacetamldo)-3-metyl-4-(tetrazol-5-yl)-A3-cefem (0,34 g) oppløses i et overskudd av vandig natriumbikarbonat og får lov til å stå ved 30°C i 3 timer. Løsningen justeres til pH 2 med 2N saltsyre og suspensjonen ekstraheres med etylacetat. Den organiske løsningen tørkes (MgSO^) og fordampes under redusert trykk, og man får produktet som et fast stoff (0,26 g). 7-(D-a-formyloxyphenylacetamldo)-3-methyl-4-(tetrazol-5-yl)-A3-cephem (0.34 g) is dissolved in an excess of aqueous sodium bicarbonate and allowed to stand at 30°C for 3 hours. The solution is adjusted to pH 2 with 2N hydrochloric acid and the suspension is extracted with ethyl acetate. The organic solution is dried (MgSO4) and evaporated under reduced pressure, and the product is obtained as a solid (0.26 g).
NMR (DMSOdg): 6 » 9,0, 1H, 7,3(s) 5H, 5,6(q) 1H, 5,2(d) 1H, 5,l(s) 1H, 3,6(8) 2H og 2,0(s) 3H. NMR (DMSOdg): 6 » 9.0, 1H, 7.3(s) 5H, 5.6(q) 1H, 5.2(d) 1H, 5.1(s) 1H, 3.6(8 ) 2H and 2.0(s) 3H.
Eksempel 14Example 14
'3 '3
7-( 2- cyanoacetamido)- 3- metyl- 4-( tetrazol- 5- yl)- A - cefem 7-( 2- cyanoacetamido)- 3- methyl- 4-( tetrazol- 5- yl)- A - cephem
Til en omrørt suspensjon av 7-amino-3-metyl-4-(tetrazol-5-yl)-A 3-cefem-tosylatsalt (576 mg) i metylenklorid (20 ml) under nitrogen, ble tilsatt trietylamin (450 mg). Efter omrøring i 20 minutter ved værelsestemperatur behandles denne løsningen med N-hydroksy-succinimidester av cyanoeddiksyre (470 mg), alt i en porsjon. Efter omrøring natten over under nitrogen, helles reaksjonsblandingen ned 1 vann (30 ml) og pH av den vandige fasen justeres til 8,0. Metylenkloridskiktet adskilles. Den vandige fasen surgjøres til To a stirred suspension of 7-amino-3-methyl-4-(tetrazol-5-yl)-α 3-cephemtosylate salt (576 mg) in methylene chloride (20 mL) under nitrogen was added triethylamine (450 mg). After stirring for 20 minutes at room temperature, this solution is treated with N-hydroxy-succinimide ester of cyanoacetic acid (470 mg), all in one portion. After stirring overnight under nitrogen, the reaction mixture is poured into 1 water (30 ml) and the pH of the aqueous phase is adjusted to 8.0. The methylene chloride layer is separated. The aqueous phase is acidified
pH 2 og ekstraheres derefter med etylacetat. Etylacetatskiktet vaskes med vann, tørkes (natriumsulfat) og løsningsmidlet fjernes pH 2 and then extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried (sodium sulfate) and the solvent is removed
under vakuum* Triturering av resten med tørr eter, gir produktet som et svakt gulfarget, fast stoff (55 mg)• under vacuum* Trituration of the residue with dry ether gives the product as a faint yellow solid (55 mg)•
NMR (DMSOdg)i 6 » 5,7 (q) 1H, 5,2 (d) 1H, 3,8 (s) 2H,NMR (DMSOdg)i 6 » 5.7 (q) 1H, 5.2 (d) 1H, 3.8 (s) 2H,
3,6 (s) 2H og 2,0 (d) 6H.3.6 (s) 2H and 2.0 (d) 6H.
Eksempel 15 7-(2-karboksyfenylacetamido)-3-raetyl-4-(tetrazol-5<-yl)-A3-cefem-natriumsalt Example 15 7-(2-Carboxyphenylacetamido)-3-ethyl-4-(tetrazol-5<-yl)-A3-cephem sodium salt
Fenylmalonsyre (0,79 g) oppløses i destillert vann (25 ml) og pB av løsningen justeres til 6,0 ved å tilsettes 2N natrium-hydroksydløsning. En løsning av 7-amino-3-metyl-4-(tetrazol-5-yl)-A<3>-cefem (0,65 g) i 10 ml destillert vann (pH justeres til 6 ved tilsetning av 2N natriumhydrokaydløsning) tilsettes derefter, og reaksjonsblandingen avkjøles til 0°C. bet tilsettes l<->etyl-3-(3-dimetylaminoprop-l-yl)karbodiimid (1,6 g) og løsningen omrøres i 3,5 timer, og 1 løpet avddenne tiden holdes pH i området 6,1-6,3 ved dråpevis tilsetning av fortynnet saltsyre. Derefter heves pH til 7,3 ved tilsetning av mettet natriumbikarbonatløsning, og reaksjonsblandingen ekstraheres med etylacetat. Ekstrakten kastes. Den vandige fasen surgjøres derefter til pH 3 ved å anvende Phenylmalonic acid (0.79 g) is dissolved in distilled water (25 ml) and the pB of the solution is adjusted to 6.0 by adding 2N sodium hydroxide solution. A solution of 7-amino-3-methyl-4-(tetrazol-5-yl)-A<3>-cephem (0.65 g) in 10 ml of distilled water (pH adjusted to 6 by addition of 2N sodium hydroxide solution) is added then, and the reaction mixture is cooled to 0°C. 1<->ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide (1.6 g) is then added and the solution is stirred for 3.5 hours, and during this time the pH is kept in the range 6.1-6, 3 by the dropwise addition of dilute hydrochloric acid. The pH is then raised to 7.3 by adding saturated sodium bicarbonate solution, and the reaction mixture is extracted with ethyl acetate. The extract is discarded. The aqueous phase is then acidified to pH 3 by using
0,4M fosforsyre, og ekstraheres igjen med etylacetat (to 50 ml porsjoner). Det sistnevnte ekstrakt tørkes, og konsentreres til et volum på ca. 25 ml. Til denne løsningen tilsettes derefter en løsning av natrium-2-etylheksanoat (1 g) i 20 ml etylacetat. Utfeiningen som dannes filtreres, og man får 0,75 g av dinatrium-saltet av 7-(2-karboksy-2-fenylacetamido)-3-metyl-4-(tetrazol-5-yl)-A 3-cefem. Det infrarøde spektrum av produktet (KBr-skive) viser absorpsjoner ved 1760 cm"""<*>(3-laktam-karbonyl), 1660 cm 1 (amid X bånd) og 1600 cm""<1>(karboksylat-karbonyl). 0.4M phosphoric acid, and extracted again with ethyl acetate (two 50 ml portions). The latter extract is dried and concentrated to a volume of approx. 25 ml. A solution of sodium 2-ethyl hexanoate (1 g) in 20 ml of ethyl acetate is then added to this solution. The precipitate that forms is filtered, and 0.75 g of the disodium salt of 7-(2-carboxy-2-phenylacetamido)-3-methyl-4-(tetrazol-5-yl)-A 3-cephem is obtained. The infrared spectrum of the product (KBr disc) shows absorptions at 1760 cm""<*>(3-lactam carbonyl), 1660 cm 1 (amide X band) and 1600 cm""<1>(carboxylate carbonyl) .
NMR (D20)i 6 - 7,4 (m) 5H, 5,7 (d) 1H, 5,2 (d) 1H, 3,4(ra) 2H og l,9(s) 3H. NMR (D 2 O)i 6 - 7.4 (m) 5H, 5.7 (d) 1H, 5.2 (d) 1H, 3.4(ra) 2H and 1.9(s) 3H.
Eksempel 16Example 16
Ved å anvende 2-tienylmalonsyre i stedet for fenylmalonsyre ved fremgangsmåten 1 eksempel 15 får man 7-ta-(2-tienyl)-a-karboksyacetamido]-3-metyl-4-(tetrazol-5-yl)-<3->cefem. By using 2-thienylmalonic acid instead of phenylmalonic acid in method 1 example 15, 7-ta-(2-thienyl)-a-carboxyacetamido]-3-methyl-4-(tetrazol-5-yl)-<3-> cephem.
NMR (DMSOdg)t 6 - 2,1 (s) 3H, 3,3( ) 2H, 5(s) 1H, 5,6 (m) 1H, 6,8-7,5(m) 3H. NMR (DMSOdg)t 6 - 2.1 (s) 3H, 3.3( ) 2H, 5(s) 1H, 5.6 (m) 1H, 6.8-7.5(m) 3H.
IR (KBr-ski<ve>)<Tm>aks1770cm""<1>(3-laktam-karbonyl),IR (KBr-ski<ve>)<Tm>ax1770cm""<1>(3-lactam-carbonyl),
1670 cm<**1>(-C0NH-). 1670 cm<**1>(-C0NH-).
Eksempel 17Example 17
7- f enylacetamldo- 3- metyl~ 4- ( tetrazol- 5- yl) - »A3- cef em 7- f enylacetamldo- 3- methyl~ 4- (tetrazol- 5- yl)- »A3- cef em
Fenaoetylklorid (2,3 g) i aceton (5 ml) tilsettes dråpevis til en omrørt løsning av 7-amino-3-metyl-4-(tetrazol-S-yl)-A<3->cefem-natriumsalt (1,31 g) i vandig aceton (20 ml) i 20 minutter ved værelsestemperatur. Det tilsettes samtidig natriumhydroksyd (2N) for å holde pH ved 8 ± 0,5. Efter tilsetningen omrøres løsningen i ytterligere 15 minutter. Aceton fjernes under redusert trykk og pH av den vandige løsningen justeres til 2 med 2N saltsyre. Suspensjonen ekstraheres med etylacetat, den organiske løsningen tørkes (MgSOj) og fordampes under redusert trykk, og man får en olje som størkner efter triturering med eter (440 mg). Phenoethyl chloride (2.3 g) in acetone (5 ml) is added dropwise to a stirred solution of 7-amino-3-methyl-4-(tetrazol-S-yl)-A<3->cephem sodium salt (1.31 g) in aqueous acetone (20 ml) for 20 minutes at room temperature. Sodium hydroxide (2N) is added at the same time to keep the pH at 8 ± 0.5. After the addition, the solution is stirred for a further 15 minutes. Acetone is removed under reduced pressure and the pH of the aqueous solution is adjusted to 2 with 2N hydrochloric acid. The suspension is extracted with ethyl acetate, the organic solution is dried (MgSO 4 ) and evaporated under reduced pressure, and an oil is obtained which solidifies after trituration with ether (440 mg).
NMR (DMSOdg)i6 - 9,0(d) 1H, 7,2(s) 5H, 5,6(q) 1H, 5,2(d) lH, 3,5(a) 4H og 2,0(s) 3H. NMR (DMSOdg)i6 - 9.0(d) 1H, 7.2(s) 5H, 5.6(q) 1H, 5.2(d) 1H, 3.5(a) 4H and 2.0( s) 3H.
Eksempel 18 Example 18
7- fenoksyacetamido- 3- metyl- 4-( tetrazol- 5- yl)- A3- cefem 7- phenoxyacetamido- 3- methyl- 4-( tetrazol- 5- yl)- A3- cephem
Fenokayacetylklorid (2,56 g) 1 aceton (5 ml) tilsettes Fenokay acetyl chloride (2.56 g) 1 acetone (5 ml) is added
dråpevis til en omrørt løsning av 7-amino-3-raetyl-4-(tetrazol-5-yl)-A 3-cefem-natriumsalt (1,31 g) i vandig aceton (30 ml) i løpet av 20 minutter ved værelsestemperatur. Det tilsettes samtidig natriumhydroksyd (2N) for å holde pH ved 8 * 0,5. Løsningen omrøres derefter 1 ytterligere 15 minutter. Acetonet fjernes under redusert trykk og pH av den vandige løsningen justeres til 2 med saltsyre (2N). Suspensjonen ekstraheres med etylacetat og den organiske løsningen tørkes (MgS04)• Fordampning og triturering av resten gir produktet som et fast stoff (370 mg). dropwise to a stirred solution of 7-amino-3-raethyl-4-(tetrazol-5-yl)-A 3-cephem sodium salt (1.31 g) in aqueous acetone (30 mL) over 20 min at room temperature . Sodium hydroxide (2N) is added at the same time to keep the pH at 8 * 0.5. The solution is then stirred for a further 15 minutes. The acetone is removed under reduced pressure and the pH of the aqueous solution is adjusted to 2 with hydrochloric acid (2N). The suspension is extracted with ethyl acetate and the organic solution is dried (MgSO4)• Evaporation and trituration of the residue gives the product as a solid (370 mg).
NMR (DMSOdg)t 6 - 9,0<d) lH, 7,0(m) 5H, 5,6(q) 1H, 5,2(d) lH, 4,6(s) 2H, 3,8(s) 2H og 2,0(s) 2H. NMR (DMSOdg)t 6 - 9.0<d) 1H, 7.0(m) 5H, 5.6(q) 1H, 5.2(d) 1H, 4.6(s) 2H, 3.8 (s) 2H and 2.0(s) 2H.
Eksempel 19Example 19
Ved å anvende fremgangsmåten i eksempftene 17 og 18 og ved å gå ut fra de nødvendige reagenser, får man de følgende A 3-forbindelsen By applying the procedure in examples 17 and 18 and starting from the required reagents, the following A 3 compound is obtained
7-bromacetamido-3-metyl-4-(tetrazol-5-yl)-A<3->cefem,7-bromoacetamido-3-methyl-4-(tetrazol-5-yl)-A<3->cephem,
NMR (DMSOdg)t 6 - 2,15(s) 3K, 3,7(m) 2H, 4,1 (s) 2H, 5,4(d) lH og 5,2 (m) lH, NMR (DMSOdg)t 6 - 2.15(s) 3K, 3.7(m) 2H, 4.1(s) 2H, 5.4(d) 1H and 5.2(m) 1H,
7-(o-azido-o-fenylacetamido)-3-metyl-4-(tetrazol-5-yl)-A 3-cefem,7-(o-azido-o-phenylacetamido)-3-methyl-4-(tetrazol-5-yl)-A 3-cephem,
NMR (DMSOdg)s 6°9,2(s) 1H, 7,35(s) 5H, 5,6 (s) lH, 5,15(q) 2H, 3,58(s) 2H og 1,98(a) 3H. NMR (DMSOdg)s 6° 9.2(s) 1H, 7.35(s) 5H, 5.6 (s) 1H, 5.15(q) 2H, 3.58(s) 2H and 1.98 (a) 3H.
7-Co-(tetrazol-5-yl)acetamido]-3-metyl-4-(tetrazol-5-yl)-A<3->cefem, 7-Co-(tetrazol-5-yl)acetamido]-3-methyl-4-(tetrazol-5-yl)-A<3->cephem,
NMR (DMSOdg)j 6 - 2,0(s) 3H, 3,6(s) 2H, 5,05-5,15(d) IR, 5,15(3) 2H, 5,5-5,8(q) 1H og 9,5(a) lH, NMR (DMSOdg)j 6 - 2.0(s) 3H, 3.6(s) 2H, 5.05-5.15(d) IR, 5.15(3) 2H, 5.5-5.8 (q) 1H and 9.5(a) 1H,
7-(a-fenyltioacetamldo)-3-raetyl~4-(tetrazol-5-yl)-A<3->ce£em,7-(α-phenylthioacetamido)-3-ethyl~4-(tetrazol-5-yl)-α<3->ce£em,
NMR (DMSOdg)i 6 - 9,18(d) LR, 7,23(ra) 5H, 5,63(q) LH, 5,35(d) 1H, 3,77(8) 2B, 3,6(m) 2B og 2,03(s) 3R, NMR (DMSOdg)i 6 - 9.18(d) LR, 7.23(ra) 5H, 5.63(q) LH, 5.35(d) 1H, 3.77(8) 2B, 3.6 (m) 2B and 2.03(s) 3R,
7-[o- (2,6-dimetoksyfenyl)karboksamido]~3-raetyl-4-(tetrazol-5-yl)-7-[o-(2,6-dimethoxyphenyl)carboxamido]~3-ethyl-4-(tetrazol-5-yl)-
3 3
A -cefem,A-cephem,
NMR (DMSOdg) t 6 - 2,0(s) 3H, 3,6(a) 2H, 3,7 (s) 6H, 5,05-5,15(d) LH, 5,5-5,8(q) lB, 6,5-6,7(d) 2B og 7,0-7,3(ra) IB, NMR (DMSOdg) t 6 - 2.0(s) 3H, 3.6(a) 2H, 3.7 (s) 6H, 5.05-5.15(d) LH, 5.5-5.8 (q) 1B, 6.5-6.7(d) 2B and 7.0-7.3(ra) IB,
7-(2-tienyigLyoksyLamido)-3-met<y>L-4-(tetrazoL-5-yL)-A<3>-cefem,7-(2-thienyigLyoxyLamido)-3-met<y>L-4-(tetrazoL-5-yl)-A<3>-cephem,
NMR (DMSOdg)i 6 - 2,0(s) 3H, 3,6(s) 2H, 5,l-5,15(d) lH, 5,4-5,7(q) 1H, 7,05-7,15(m) IB og 7,8-8,1 (m) 2H, og 7-Co-(2-tienyl)acetamido]-3-metyl-4-(tetrazol-5-yl)-A 3-cefem, NMR (DMSOdg)i 6 - 2.0(s) 3H, 3.6(s) 2H, 5.1-5.15(d) 1H, 5.4-5.7(q) 1H, 7.05 -7,15(m) IB and 7,8-8,1 (m) 2H, and 7-Co-(2-thienyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-A 3 -cephem,
NMR (DMSOdg)t 6 « 2,0(s) 3H, 3,6(s) 2B, 3,8 (a) 2B, 5,1-5,15(d) lH, 5,5-5,8(q) lH, 6,95-7,0(d) 2H og 7,1-7,2 (m) 1H. NMR (DMSOdg)t 6 « 2.0(s) 3H, 3.6(s) 2B, 3.8 (a) 2B, 5.1-5.15(d) 1H, 5.5-5.8 (q) 1H, 6.95-7.0(d) 2H and 7.1-7.2 (m) 1H.
Eksempel 20Example 20
7-[a-hydroksy-c-(2-tienyl)acetamido]-3-mety1-4-(tetrazol-5-yl)-A<3->cefem 7-[α-hydroxy-c-(2-thienyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-α<3->cephem
7-(2-tlenylglyoksylamido)-3-metyl-4-(tetrazol-5-yl)-A - cefem (1,50 g) i vann (30 ml) overføres til natriurasaltat med 2N natriumhydroksyd. Denne løsningen avkjøles i is og tilsettes vannfritt natriumacetat (1,53 g). Det tilsettes i små porsjoner natrlumborhydrid (276 mg) 1 løpet av 45 minutter. pH holdes ved 8 ved tilsetning av vekselsvis iseddik og natrlumborhydrid. Efter tilsetningene holdes pB ved 8 i 45 minutter med isbadet fjernet. Løsningen skiktes med etylacetat og pB justeres til 2 med 40% fosforsyre. Det organiske skiktet adskilles, vaskes med vann, tørkes (Na2S04), filtreres og konsentreres i vakuum inntil det faste stoffet krystalliserer. Produktet filtreres, vaskes med tørr eter og tørkes under vakuum, 360 mg. 7-(2-thlenylglyoxylamido)-3-methyl-4-(tetrazol-5-yl)-α-cephem (1.50 g) in water (30 ml) is transferred to sodium urate with 2N sodium hydroxide. This solution is cooled in ice and anhydrous sodium acetate (1.53 g) is added. Sodium borohydride (276 mg) is added in small portions over 45 minutes. The pH is maintained at 8 by alternately adding glacial acetic acid and sodium borohydride. After the additions, the pH is kept at 8 for 45 minutes with the ice bath removed. The solution is layered with ethyl acetate and the pB is adjusted to 2 with 40% phosphoric acid. The organic layer is separated, washed with water, dried (Na 2 SO 4 ), filtered and concentrated in vacuo until the solid crystallizes. The product is filtered, washed with dry ether and dried under vacuum, 360 mg.
NMR (DMSOdg)t 6 7,2 (ra) lH, 7,0, 2H, 5,4(m) 1H, 5,0(s) 2H, 3,5, 2H og 2,0(s) 3H. NMR (DMSOdg)t 6 7.2 (ra) 1H, 7.0, 2H, 5.4(m) 1H, 5.0(s) 2H, 3.5, 2H and 2.0(s) 3H.
Eksempel 21 7-[2-(2-metyl-l,3,4-tiadiazol-5-yl-tio-acetamido)]-3-metyl-4-(tetrazol-5-yl)-A 3- cefem Example 21 7-[2-(2-methyl-1,3,4-thiadiazol-5-yl-thio-acetamido)]-3-methyl-4-(tetrazol-5-yl)-A 3-cephem
Trietylamin (0,2 ml) tilsettes til en kald, 0°C suspensjon Triethylamine (0.2 ml) is added to a cold, 0°C suspension
av 1-(2-bromacetamido)-3-metyl-4-(tetrazol-5°yl)-A 3-cefem (0,5 g)of 1-(2-bromoacetamido)-3-methyl-4-(tetrazol-5°yl)-A 3-cephem (0.5 g)
1 metylenklorid (15 ral). Til den resulterende svakt gule løsningen tilsettes en suspensjon av 2-metyl-l,3,4-tiadiazol-5-tiol (0,19 g) og løsningen omrøres ved 0°C. Efter 2 timer oppsamles det utfelte produkt v@d filtrering (0,3 g). 1 methylene chloride (15 ral). To the resulting slightly yellow solution is added a suspension of 2-methyl-1,3,4-thiadiazole-5-thiol (0.19 g) and the solution is stirred at 0°C. After 2 hours, the precipitated product is collected by filtration (0.3 g).
NMR (DMSOdg)a 6 - 9,3(d) lH, 5,6(m) lH, 5,2(d) lH, 4,15(s) 2H, 3,6(s) 2H, 2,7(s) 3H og 2,05(s) 3H. NMR (DMSOdg)a 6 - 9.3(d) 1H, 5.6(m) 1H, 5.2(d) 1H, 4.15(s) 2H, 3.6(s) 2H, 2.7 (s) 3H and 2.05(s) 3H.
Eksempel 22Example 22
Fremgangsmåten 1 eksempel 21 gjentas, ved å gå ut fra 7-(2-broraacetamido)-3-metyl-4-(tetrazol-5-yl)-A 3-cefem og l-m@tyl-5-merkaptotetrazol (Lieber, et al., Can. J. Chem. 37 101 (1959)), og man får The procedure 1 example 21 is repeated, starting from 7-(2-broaacetamido)-3-methyl-4-(tetrazol-5-yl)-A 3-cephem and 1-m@tyl-5-mercaptotetrazole (Lieber, et al ., Can. J. Chem. 37 101 (1959)), and one gets
7-Ca-(l-metyltetrasol-5-yltlo)acetamido]-3-metyl-4-(tetrasol-5-yl)-zP-cefem. 7-Ca-(1-methyltetrazol-5-ylthio)acetamido]-3-methyl-4-(tetrazol-5-yl)-zP-cephem.
NMR (DMSOdg)s 6 » 9,28(d) lH, 5,6(q) lH, 5,24(d) IB, 4,13(s) 2H, 3,95(s) 3H, 3,59(m) 2H og 2,01(©) 3H. NMR (DMSOdg)s 6 » 9.28(d) 1H, 5.6(q) 1H, 5.24(d) 1B, 4.13(s) 2H, 3.95(s) 3H, 3.59 (m) 2H and 2.01(©) 3H.
Eksempel 23Example 23
Fremgangsmåten 1 eksempel 21 gjentas ved å anvende 4-merkapto-pyridin og 7-(2-bromacetamido)-3-metyl-4-(tetrazol-5-yl)-A 3-cefem, får man 7-[2-<4-pyridyltio)acetamido]-3-metyl-4-(tetrasol-5-yl)-A 3-cefem. The procedure 1 example 21 is repeated by using 4-mercapto-pyridine and 7-(2-bromoacetamido)-3-methyl-4-(tetrazol-5-yl)-A 3-cephem, you get 7-[2-<4 -pyridylthio)acetamido]-3-methyl-4-(tetrazol-5-yl)-A 3-cephem.
NMR (DMSOdg)86 « 9,32(d) 1H, 8,41(m) 2H, 7,33(m) 2H, 5,7-5,6(q) 1H, 5,25(d) lH, 3,95(d) 2B, 3,6 (m) 2H og 2,03(c) 3H. NMR (DMSOdg)86 « 9.32(d) 1H, 8.41(m) 2H, 7.33(m) 2H, 5.7-5.6(q) 1H, 5.25(d) 1H, 3.95(d) 2B, 3.6(m) 2H and 2.03(c) 3H.
Eksempel 24 Example 24
7-(2 *,2',2'-trikloretoksykarboksamido)-3-acetoksymetyl-4-[N-(p-metoksybensyl) karbamoyl]- A 3- cefem 7-(2*,2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]- A 3- cephem
A. 7-(2•,2',2 1-trikloretoksykarboksamido)-3-acetoksymetyl-A 3-cefem-4- karboksylsyre A. 7-(2•,2',2 1-trichloroethoxycarboxamido)-3-acetoxymethyl-A 3-cephem-4-carboxylic acid
Det tilsettes natriumbikarbonat (300 g) porsjonsvis til en omrørt suspensjon av 7-amino-cefaiosporaneyr©(408 g) i vandig aceton (2.1, 5 11 tert 2,5 liter). 2 ,*, 2', 2'-trikloretylklorf ormiat (350 g) tilsettes derefter dråpevis 1 løpet av 45 minutter og blandingen omrøres i ytterligere 5 timer ved værelsestemperatur. Sodium bicarbonate (300 g) is added portionwise to a stirred suspension of 7-amino-cefaiosporaneyr© (408 g) in aqueous acetone (2.1, 5 11 tert 2.5 liters). 2,*, 2', 2'-trichloroethyl chloroformate (350 g) is then added dropwise over 45 minutes and the mixture is stirred for a further 5 hours at room temperature.
Acetonet fjernes i vakuum og den vandige løsningen fortynnes derefter til 10 li tes r med destillert vann. pH av løsningen justeres til 2 med 50% saltsyre, og blandingen ekstraheres med etylacetat (5 at 1,5 liter). De kombinerte organiske skikt valakes med vann (2x2 liter), tørkes (MgSO^) og løsningen konsentreres til et volum på 1,5 liter. The acetone is removed in vacuo and the aqueous solution is then diluted to 10 liters with distilled water. The pH of the solution is adjusted to 2 with 50% hydrochloric acid, and the mixture is extracted with ethyl acetate (5 at 1.5 litres). The combined organic layers are washed with water (2x2 litres), dried (MgSO 4 ) and the solution is concentrated to a volume of 1.5 litres.
Konsentratet tilsettes langsomt til petroleter (k.p. 60-80°C, 15 liter) og det utfalte faste materiale vaskes med petroleter (k.p, 30-40°C, 2x2 liter). Utfeiningen tørkes i vakuum ved 45°C, og man får 7-(2•,2<1>,2•^trikloretoksykarbonyl)-amino-3-acetoksymetyl-A 3-cefem-4-karboksylsyre som @t hvitt fast stoff (490 g). The concentrate is added slowly to petroleum ether (b.p. 60-80°C, 15 litres) and the precipitated solid material is washed with petroleum ether (b.p. 30-40°C, 2x2 litres). The separation is dried in vacuum at 45°C, and 7-(2•,2<1>,2•^trichloroethoxycarbonyl)-amino-3-acetoxymethyl-A 3-cephem-4-carboxylic acid is obtained as a white solid ( 490 g).
NMR (DMSOdg)t. 6 - I0(d) lH, 5,5(q) lH, 5,1(d) lH, 4,8(q) 2H, 4,8(3) 2H, 3,5(s) 2H og 2,0(s) 3H. NMR (DMSO dg )t. 6 - I0(d) 1H, 5.5(q) 1H, 5.1(d) 1H, 4.8(q) 2H, 4.8(3) 2H, 3.5(s) 2H and 2, 0(s) 3H.
B. 7- (2' ,2 • ,2 '-trikloretoksykarboksamido) -3-acetoksy-4-EN- (p-metoksybanzyl) - karbamoyl ]-A 3-cofora ' B. 7-(2',2•,2'-trichloroethoxycarboxamido)-3-acetoxy-4-EN-(p-methoxybanzyl)-carbamoyl]-A 3-cofora'
Ved å gå ut fra syren i eksempel 24A og følge fremgangsmåten By starting from the acid in example 24A and following the procedure
i eksempel IB, får man det ønskede produkt i et moderat utbytte. in example IB, the desired product is obtained in a moderate yield.
NMR (CDC13) : 6"2, 0{ a) 3H, 3,4(s) 2H, 3,8(s) 3H, 4,45(d) 2H, 4,75(S) 2H, 4,9(m) 3H, 5,5(q) 1H, 6,2(b) 1H og 7,l(q) 4B2. NMR (CDCl 3 ) : 6"2, 0{ a) 3H, 3.4(s) 2H, 3.8(s) 3H, 4.45(d) 2H, 4.75(S) 2H, 4.9 (m) 3H, 5.5(q) 1H, 6.2(b) 1H and 7.1(q) 4B2.
Eksempel 25 Example 25
7-(2',2•,2•-trikloretoksykarboksamido)-3-(2-m©tyl-l,3,4-tiadiazol-5- yltiometyl)- 4°[ N-( p- metoksybenzyl) karbamoyl3- A - cefem A. 7-(2<1>,2<9>,2'-trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tia-diazol- 5- yltlQmetyl)- A 3- cefem- 4- karboksylsyre 7-(2',2•,2•-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)- 4°[ N-( p -methoxybenzyl)carbamoyl3- A - cephem A. 7-(2<1>,2<9>,2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thia-diazol-5-yl 1Qmethyl)- A 3- cephem- 4- carboxylic acid
Ved å gå frem som angitt i eksempel 24A, men ved å anvende cefemderivatet 7-amino-3-(2-metyl-l,3,4-tiadlazol~5-yltiometyl)-A - cefem-4-karboksylsyre (U.S.-patent 3.641.021) får man dot Ønskede produkt. By proceeding as indicated in Example 24A, but using the cephem derivative 7-amino-3-(2-methyl-1,3,4-thiadlazol~5-ylthiomethyl)-A-cephem-4-carboxylic acid (U.S. Pat. 3.641.021) you get the desired product.
NMR (CDCl3)s 6 • 5,4(m) 2H, 5,l(d) lH, 4,85(s) 2H, 4,4(q) 2H, 3,7 (s) 2H og 2,7 (s) 3H. NMR (CDCl3)s 6 • 5.4(m) 2H, 5.1(d) 1H, 4.85(s) 2H, 4.4(q) 2H, 3.7 (s) 2H and 2.7 (s) 3H.
B. 7-(2',2<8>,2•-trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tladiazol- 5- yltiometyl)- 4-[ N-( p- metoksybenzyl) karbamoyl]- A 3- cefem Ved å anvende produktet fra eksempel 25A og anvende fremgangsmåten angitt i eksempel 24B og IB kan man syntetisere detønskede mellomprodukt. B. 7-(2',2<8>,2•-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thladiazol-5-ylthiomethyl)-4-[ N-( p -methoxybenzyl)carbamoyl ]- A 3- cefem By using the product from example 25A and applying the method indicated in examples 24B and IB, the desired intermediate product can be synthesized.
NMR (CDC13):6 «= 7,0(q) 2H, 6,l(m) 1H, 5,4(q) lH, 4,9(d) lH, 4,7(s) 2H, 4,4 (m) 4H, 3,75(s) 3H og 3,6(s) 2H. NMR (CDCl 3 ): 6 = 7.0(q) 2H, 6.1(m) 1H, 5.4(q) 1H, 4.9(d) 1H, 4.7(s) 2H, 4, 4 (m) 4H, 3.75(s) 3H and 3.6(s) 2H.
Eksempel 26 Example 26
7-(2',2',2'-trikloretoksykarboksamido)-3-aoetoksymetyl-4-£l-(p-metoksybenzyl) tetrazol- 5- yl 3-A -cefem 7-(2',2',2'-trichloroethoxycarboxamido)-3-aoethoxymethyl-4-£1-(p-methoxybenzyl)tetrazol-5-yl 3-A-cephem
Fos forpantaklorid (1,68 g, 8 mmol) tilsettes til en omrørt løsning av 7-(2* ,2* ,2'-trikloretoksykarlK>ksamido)-3^acatoksymetyl-4-[N-(p-metoksybenzyl9karbamoyl]-A 3-cefem (2,26 g, 4 mmol) og Fos forpantochloride (1.68 g, 8 mmol) is added to a stirred solution of 7-(2*,2*,2'-trichloroethoxycarylxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl-9carbamoyl]-A 3-cephem (2.26 g, 4 mmol) and
pyridin (0,64 g, 8 mmol) i tørr etanolfri kloroform (30 ml)pyridine (0.64 g, 8 mmol) in dry ethanol-free chloroform (30 mL)
ved 0-5 CV Efter 30 minutter indikerer kjernemagnetisk resonansspektrum at amidet er fullstendig omsatt (de to protondubléttene ved 6 4,45 er forsvunnet). Det tilsettes dråpevis en løsning av tetrametylguanldinlumazid (6,3 g, 40 mmol) i tørr etanolfri kloroform (20 ml) i løpet av 10 minutter til den avkjølte løsningen. Efter ytterligere 10 minutter fjernes Isbadet og reaksjonsblandingen omrøres ved omgivelsestemperatur i 30 minutter. Reaksjonsblandingen vaskes med vann, vandig natriumbikarbonatløsning (3 x), 6N saltsyre (3 x), vann og tørkes over raagnesiumsulfat. Fordampningen av løsningsmidlet gir urenset produkt som et lysebrunt fast stoff (1,5 g)• Kolonnekromatografi på silikagel som til å begynne med anvender heksan som eluaringsmiddel og gradvis til-setter økend© mengder av oter, og til slutt eluere med 100% oter, gir det rensede produkt (ved tynnskiktskromatografi)• at 0-5 CV After 30 minutes, the nuclear magnetic resonance spectrum indicates that the amide has been completely converted (the two proton doublets at 6 4.45 have disappeared). A solution of tetramethylguanldinlumazide (6.3 g, 40 mmol) in dry ethanol-free chloroform (20 ml) is added dropwise over 10 minutes to the cooled solution. After a further 10 minutes, the ice bath is removed and the reaction mixture is stirred at ambient temperature for 30 minutes. The reaction mixture is washed with water, aqueous sodium bicarbonate solution (3 x), 6N hydrochloric acid (3 x), water and dried over magnesium sulfate. Evaporation of the solvent gives impure product as a light brown solid (1.5 g)• Column chromatography on silica gel which initially uses hexane as eluent and gradually adds increasing amounts of otter, and finally elutes with 100% otter, gives the purified product (by thin-layer chromatography)•
NMR (DMSOdg) 6 » 1,8(8) 3H, 3,6(q) 2H, 3,9(s) 3H, 4,2(q) 2H, 4,8(s) 2H, 5,1(d) 1H, 5,6(m) 3H, 6,3(d) lHog 7,4(q) 4H. NMR (DMSOdg) 6 » 1.8(8) 3H, 3.6(q) 2H, 3.9(s) 3H, 4.2(q) 2H, 4.8(s) 2H, 5.1( d) 1H, 5.6(m) 3H, 6.3(d) 1H and 7.4(q) 4H.
Eksempel 27 7-(2',2•,2<1->trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tiadlazol-5- yltiometyl)- 4-[ l-( p- metoksybenzyl) tetrazol- 5- yl3- A •3- cefem Example 27 7-(2',2•,2<1->trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadlazol-5-ylthiomethyl)-4-[1-( p -methoxybenzyl) tetrazole - 5- yl3- A •3- cephem
Når man går ut fra cefemforbindelsen i eksempel 25B og When starting from the cephem compound in example 25B and
følger fremgangsmåten i eksempel 26, får man det ønskede produkt. following the procedure in example 26, the desired product is obtained.
NMR (CDCl3)s 6°7,0(q) 4H, 5,5(s) 2H, 5,4(m) 2H, 4,7(s) 2H, 4,l(m) 2H, 5,75(a) 3Hog5,65(m) 2H. NMR (CDCl 3 )s 6° 7.0(q) 4H, 5.5(s) 2H, 5.4(m) 2H, 4.7(s) 2H, 4.1(m) 2H, 5.75 (a) 3Hog5.65(m) 2H.
Eksempel 28 Example 28
7- amino- 3- aoetokaymety1- 4-[ 1-( p- metoksybenzyl) tetrazol- 5- yl)- A3- befem 7- amino- 3- aoethokaymethyl- 4-[ 1-( p- methoxybenzyl) tetrazol- 5- yl)- A3-befem
Aktivert sinkstøv (300 mg) tilsettes til en omrørt løsning av 7-(2',2',2 *-trikloretoksykarboksamido-3-acetoksymotyl-4-[1-(p-metoksybenzyl)t©trazol-5-yl]-A -cefem (300 mg, 0,5 mmol) i 90% eddiksyre (3 ml) og suspensjonen omrøres ved omgivelsestemperatur i 30 minutter. Reaksjonsblandingen filtreres og fordampes tiltørrhet. Det resulterende gule skum oppløses i kloroform og løsningen ekstraheres to ganger med fortynnet saltsyre. De vandige ekstraktene blandes med kloroform, og fortynnet natriumhydroksyd tilsettes til den omrørt©blanding til pH 7,0. Blandingen filtreres for å fjerne utfelte uorganiske salter, skiktene adskilles og den vandige løsningen ekstraheres to ganger med kloroform. De kombinerte organiske ekstrakter vaskes med vann og tørkes over magnesiumsulfat. Fordampning av løsningsmidlet gir Activated zinc dust (300 mg) is added to a stirred solution of 7-(2',2',2*-trichloroethoxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-A -cephem (300 mg, 0.5 mmol) in 90% acetic acid (3 mL) and the suspension is stirred at ambient temperature for 30 min. The reaction mixture is filtered and evaporated to dryness. The resulting yellow foam is dissolved in chloroform and the solution is extracted twice with dilute hydrochloric acid. The aqueous extracts are mixed with chloroform, and dilute sodium hydroxide is added to the stirred mixture to pH 7.0. The mixture is filtered to remove precipitated inorganic salts, the layers are separated, and the aqueous solution is extracted twice with chloroform. The combined organic extracts are washed with water and dried over magnesium sulfate Evaporation of the solvent gives
produktet som et svakt gulfarvet fast stoff (110 mg), som rensesthe product as a faint yellow solid (110 mg), which is purified
ved tynnskiktskromatografi, by thin-layer chromatography,
NMR (CDC13): 6 • l,9(s) lH, 2,0(s) 3H, 3/45(q) 2H, 3,8(s) 3H, 4,3(q) 2H, 3,8(s) 3H,4,3(q) 2H, 4,65(d) 1H, 4,95(d) lH, S,5(s) 2H og 7, l(q) 4H*NMR (CDCl 3 ): 6 • 1.9(s) 1H, 2.0(s) 3H, 3/45(q) 2H, 3.8(s) 3H, 4.3(q) 2H, 3.8 (s) 3H,4,3(q) 2H, 4.65(d) 1H, 4.95(d) 1H, S,5(s) 2H and 7, 1(q) 4H*
iPå lignendé måte får man ved å gå ut fra 7-(2',2',2<*->trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tiadlazol-5-yltiometyl)-4- [1-(p-metoksybenzyl) tetrazol-5-yl]-A -cefem og følge fremgangsmåten i eksempel 28 ovenfor, 7-amino-3-(2-metyl-l,3,4-tiadiazol-5- yltiometyl)-4-[1-(p-metoksybenzyl)tetraz' ol-5-yl]-A 3-cefem. In a similar way, starting from 7-(2',2',2<*->trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadlazol-5-ylthiomethyl)-4- [ 1-(p-methoxybenzyl)tetrazol-5-yl]-A-cephem and following the procedure in Example 28 above, 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4 -[1-(p-Methoxybenzyl)tetraz'ol-5-yl]-A 3-cephem.
NMR (CDCl3)i 6 « 7,0(q) 4H, 5,55(s) 2H, 4,9(d) lH, 4,6(m) lH, 3,8(s) 3H, 3,65(m) 2H og 2,7(s) 3H. NMR (CDCl3)i 6 « 7.0(q) 4H, 5.55(s) 2H, 4.9(d) 1H, 4.6(m) 1H, 3.8(s) 3H, 3.65 (m) 2H and 2.7(s) 3H.
Eksempel 29 Example 29
7-amino-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-tetrazol-5-yl)-' A3- cefem 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-tetrazol-5-yl)-' A3-cephem
7-amino-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-[1-(p-metoksybenzyl)totrazol-5-yl3-A 3-cefem (125 mg) oppløses i aceton (2 ml) og tilsatt p-toluensulfonsyre (60 mg) i aceton (1 ml). 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)totrazol-5-yl3-A 3-cephem (125 mg) is dissolved in acetone (2 ml) and added p-toluenesulfonic acid (60 mg) in acetone (1 ml).
Saltet faller ut som en brun olje efter tilsetning av eter til blandingen. Løsningsmidlet dekanteres dgrresten vaskes (3 x) med The salt precipitates as a brown oil after adding ether to the mixture. The solvent is decanted and the residue is washed (3 x) with
eter (30 ml). Den resterende oljen oppløses i trifluoreddlksyre/- anisol (4:1 v/v, 2 ml) og oppvarmes på et vannbad, i en lukket kolbe (25 ml) i 3 timer ved 38°C. ether (30 ml). The remaining oil is dissolved in trifluoroacetic acid/anisole (4:1 v/v, 2 ml) and heated on a water bath, in a closed flask (25 ml) for 3 hours at 38°C.
Derefter helles reaksjonsblcndingén ned i tørr eter, de organiske løsningsmidler dekanteres fra den dannede utfeining og The reaction mixture is then poured into dry ether, the organic solvents are decanted from the resulting slurry and
de resterende faste stoffer vaskes med ytterligere porsjoner av eter (3 x 30 ml). Det urensede, ikke beskyttede materiale tas opp i aceton/vann (pH 2,5), ekstraheres med etylacetat, pH av den the remaining solids are washed with further portions of ether (3 x 30 ml). The crude, unprotected material is taken up in acetone/water (pH 2.5), extracted with ethyl acetate, the pH of the
vandige fasen justeres til 7,6 med vandig natriumhydroksyd (2N) og ekstraheres igjen med etylacetat. Konsentrering av den vandige fasen i vakuum til tørrhet, gir et fast stoff. Denne forbindelse karakteriseres ved acylering av natriumsaltet ovenfor med 2',2',2'-trikloretoksykarbonylklorid ved å anvende fremgangsmåten i the aqueous phase is adjusted to 7.6 with aqueous sodium hydroxide (2N) and extracted again with ethyl acetate. Concentration of the aqueous phase in vacuo to dryness gives a solid. This compound is characterized by acylation of the above sodium salt with 2',2',2'-trichloroethoxycarbonyl chloride using the method in
eksempel IA, og man får 7-(2',2',2'-trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(tetrazol-5-yl)-A -cefem example IA, and one obtains 7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl) -A -cephem
NMR (CDCl3)i 6 « 4,7(d) lH, 4,2(m) 1H, 5,l(s) 2H, 5,35(s) 3H, 6,0(m) 2H og 7,2(s) 3H. NMR (CDCl3)i 6 « 4.7(d) 1H, 4.2(m) 1H, 5.1(s) 2H, 5.35(s) 3H, 6.0(m) 2H and 7.2 (s) 3H.
Eksempel 30Example 30
Det tilsettes gradvis natriumbikarbonat (42 g, 0,5 mol)Sodium bicarbonate (42 g, 0.5 mol) is gradually added
til en kraftig omrørt suspensjon av 7-amino-3-acetoksymetyl-A3--eefem-4-karboksylsyre (50 g, 0,18 mol) i aceton/vann (250/500 ml). to a vigorously stirred suspension of 7-amino-3-acetoxymethyl-A3--eefem-4-carboxylic acid (50 g, 0.18 mol) in acetone/water (250/500 mL).
En løsning av benzylklorformiat (36 g, 0,21 mol) i aceton (70 ml) tilsettes dråpevis til en omrørt løsning i løpet av 45 minutter. Efter omrøring i 6 timer fjernes aceton ved hjelp av rotasjons-fordamper og den vandige resten vaskes med etylacetat for å fjerne forurensninger. Den vandige løsningen overskiktes med etylacetat og surgjøras til pH 4,0. De kombinerte etylacetatløsninger fra ekstraksjonene av den vandige løsningen vaskes med vann og tørkes over magneslumsulfat. Fordampning av etylacetat gir produktet 7-benzyloksykarboksamido-3-acetoksymetyl-A 3-céfem-4-karboksylsyre, som et nesten hvitt, fast stoff (56 g), som renses ved tynnskiktskromatograf i. A solution of benzyl chloroformate (36 g, 0.21 mol) in acetone (70 mL) is added dropwise to a stirred solution over 45 minutes. After stirring for 6 hours, acetone is removed using a rotary evaporator and the aqueous residue is washed with ethyl acetate to remove impurities. The aqueous solution is covered with ethyl acetate and acidified to pH 4.0. The combined ethyl acetate solutions from the extractions of the aqueous solution are washed with water and dried over magnesium sulfate. Evaporation of ethyl acetate gives the product 7-benzyloxycarboxamido-3-acetoxymethyl-A 3-cephem-4-carboxylic acid as an almost white solid (56 g), which is purified by thin-layer chromatography.
NMR (DMSOdg): 6 2,0(s) 3H, 3,5(s) 2H, 4,8-5,2(m) 5H og NMR (DMSOdg): δ 2.0(s) 3H, 3.5(s) 2H, 4.8-5.2(m) 5H and
7,3(s) 5H. 7.3(s) 5H.
På lignende måte fremstilles 7-benzylokBykarboksamido-3-(l-m©tylt©trazol-5-yltiometyl)-A 3-cefem-4-karboksylsyre, In a similar way, 7-benzyloxycarboxamido-3-(1-methyltrazol-5-ylthiomethyl)-A 3-cephem-4-carboxylic acid is prepared,
NMR (DMSOdg)s 6 « 7,5(s) 5B, 6,6(d) lH, 6,2(s) 3B, 4,4(b)NMR (DMSOdg)s 6 « 7.5(s) 5B, 6.6(d) 1H, 6.2(s) 3B, 4.4(b)
2H, 4,04(s) 3H og 3,8(fl) 2R.2H, 4.04(s) 3H and 3.8(fl) 2R.
Eksempel 31 7-benzyloksykarboksamido-3-acetoksymetyl-4-[N-(p-metoksybensyl)-ftarbamoyl.- A 3- cefem Example 31 7-benzyloxycarboxamido-3-acetoxymethyl-4-[N-(p-methoxybenzyl)-ftarbamoyl.- A 3-cephem
En løsning av 2,4-dinitrofenol (22 g, 0,1 mol) i metylenklorid (100 ml) tilsettes til en løsning av 7-benzyloksykarboks-araido-3-acetoksymetyl-• A -3-cefem-4-karboksylsyre (41 g, 0,lmol) i tørr dioksan (400 ml). Til den omrørte løsningen tilsettes en løsning av dicykloheksylkarbodiimid (21 g, 0,1 mol) i dioksan (100 ml). Efter 1,5 tim®fjernes utfeiningen av dicykloheksylurea ved filtrering. Til filtratet tilsettes en løsning av p-metoksybenzyl-arain (13,7 g, 0,1 mol) i dioksan (ICO ml). Efter omrøring i 6 timer filtreres det utfelte, faste materiale, vaskes med etar og etylacetat og tørkes, og man får produktet som et hvitt, fast stoff (30 g), som renses ved tynnskiktskromatografi. A solution of 2,4-dinitrophenol (22 g, 0.1 mol) in methylene chloride (100 ml) is added to a solution of 7-benzyloxycarbox-araido-3-acetoxymethyl-• A -3-cephem-4-carboxylic acid (41 g, 0.1mol) in dry dioxane (400 ml). To the stirred solution is added a solution of dicyclohexylcarbodiimide (21 g, 0.1 mol) in dioxane (100 ml). After 1.5 hours, the dicyclohexylurea is removed by filtration. To the filtrate is added a solution of p-methoxybenzyl-araine (13.7 g, 0.1 mol) in dioxane (ICO ml). After stirring for 6 hours, the precipitated solid material is filtered, washed with ether and ethyl acetate and dried, and the product is obtained as a white solid (30 g), which is purified by thin-layer chromatography.
NMR (DMSOdg): 6 - 2,0(s) 3H, 3,4(s) 2H, 3,7 (s) 3H, 4,3(d) 2H, 4,9(d) 2H, 5,0(m) 4H, 5,4(q) lH og 7,0(m) 9H*NMR (DMSOdg): 6 - 2.0(s) 3H, 3.4(s) 2H, 3.7 (s) 3H, 4.3(d) 2H, 4.9(d) 2H, 5.0 (m) 4H, 5.4(q) 1H and 7.0(m) 9H*
På lignende måte fremstilles 7-benzyloksykarboksamido-3-(l-m©ty1-tetrazol-5-yltiomet<y>l)-4-[N-(p-metoks<y>benz<y>l)karbamo<y>l]-A3-cofem. 7-Benzyloxycarboxamido-3-(1-methyl-tetrazol-5-ylthiometh<y>l)-4-[N-(p-methoxy<y>benz<y>l)carbamo<y>l] is prepared in a similar manner -A3 cofem.
NMR (CDC13); 6 » 7,4 (s) 5H, 7,1 (q) 4H, 7,7 (ia) 2H, 5,25 (s) 2H, 5,45 (d) lH, 4,5(m) 4H, 4,0(s) 3H, 5,9(s) 3H og 5,79(3) 2H. NMR (CDCl 3 ); 6 » 7.4 (s) 5H, 7.1 (q) 4H, 7.7 (ia) 2H, 5.25 (s) 2H, 5.45 (d) lH, 4.5(m) 4H, 4.0(s) 3H, 5.9(s) 3H and 5.79(3) 2H.
Eksempel 32Example 32
Fosforpentaklorid (4,2 g, 20 mmol) tilsettes til en suspensjon av 7-benzyloksykarboksamido-3-acetoksymetyl-4-[N-(p-metoksybenzyl)karbamoyl3-A 3-cefem (5,3 g, 10 mmol) i tørr etanolfri kloroform (100 ml) som inneholder pyridin (1,7 g, 20 mmol). Efter 30 minutter indikerer det kjernemagnetiske resonansspektrum at reaksjonen er avsluttet. Phosphorus pentachloride (4.2 g, 20 mmol) is added to a suspension of 7-benzyloxycarboxamido-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl3-A 3-cephem (5.3 g, 10 mmol) in dry ethanol-free chloroform (100 mL) containing pyridine (1.7 g, 20 mmol). After 30 minutes, the nuclear magnetic resonance spectrum indicates that the reaction has ended.
Løsningen avkjøles i et isbad og en løsning av tetrametyl-guanidiniumazid (16,0 g, 100 mmol) i tørr etanolfri kloroform tilsettes dråpevis i løpet av 20 minutter. Efter ytterligere 10 minutter fjernes isbadet og omrøringen fortsetter i 30 minutter ved omgivelsestemperatur. Løsningen vaskes med vann, natrium-bikarbonatløsning (3 x), 6N saltsyre (3 x), vann og tørkes over magnesiumsulfat. Fordampningen av løsningsmidlet gir det urensede produkt som et brunt, fast stoff (3,7 g), som renses ved kolonnekromatografi på silisiumdioksyd. Eluerlng med diklormetansheksan (1:1) og derefter med eter:diklormetansheksan (2:lsl) fjerner forurensninger. Eluering med eter gir produktet, 7-benzyloksy-karboksamido-3-acetoksymetyl-4-[1-(p-metoksybenzyl)tetrasol-5-yl3-A - cefem, som et hvitt, fast materiale, som renses ved tynnsiktskromatografi. The solution is cooled in an ice bath and a solution of tetramethylguanidinium azide (16.0 g, 100 mmol) in dry ethanol-free chloroform is added dropwise over 20 minutes. After a further 10 minutes, the ice bath is removed and stirring is continued for 30 minutes at ambient temperature. The solution is washed with water, sodium bicarbonate solution (3 x), 6N hydrochloric acid (3 x), water and dried over magnesium sulfate. Evaporation of the solvent gives the crude product as a brown solid (3.7 g), which is purified by column chromatography on silica. Elution with dichloromethanehexane (1:1) and then with ether:dichloromethanehexane (2:1) removes impurities. Elution with ether gives the product, 7-benzyloxy-carboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrasol-5-yl3-α-cephem, as a white solid, which is purified by thin-screen chromatography.
NMR (DMSOdg): 6 « l,9(s) 3H, 3,65(s) 2H, 3,8(s) 3H, 4,3(s) 2H, 5,15(s) 2H, 5,35(d) lH, 5,6(m) 3H, 7,2(m) 9H og 8,6(d) 1H. NMR (DMSOdg): 6 « 1.9(s) 3H, 3.65(s) 2H, 3.8(s) 3H, 4.3(s) 2H, 5.15(s) 2H, 5.35 (d) 1H, 5.6(m) 3H, 7.2(m) 9H and 8.6(d) 1H.
På lignende måte fremstilles 7-benzyloksykarboksamido-3-(l-metyltetrazol-5-yltiometyl)-4-[1-(p-metoksybenzyl)tetrazol-5-yl3-3 In a similar way, 7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl3-3 is prepared
A -cefem.A -cephem.
NMR (DMSOdg) i 6 » 7,3(s) 5H, 7,05(q) 4H, 6,5(s) 3H, 6,2(d) 1H, 5,05(s) 2H, 3,S5(s) 3H, 3,7(s) 3H, 3,5-4 (m) 2H og 3,3(s) 2H„ NMR (DMSOdg) in 6 » 7.3(s) 5H, 7.05(q) 4H, 6.5(s) 3H, 6.2(d) 1H, 5.05(s) 2H, 3.S5 (s) 3H, 3.7(s) 3H, 3.5-4 (m) 2H and 3.3(s) 2H„
Eksempel 33 Example 33
7- amino- 3- acetoksymetyl- 4-( tetrazol- S- yl)- A 3- cefem 7- amino- 3- acetoxymethyl- 4-( tetrazol- S- yl)- A 3- cephem
7-benzyloksykarboksamido-3-acetoksymetyl-4-[1-(p-m©toksy-benzyl)tetrazol-5-yl3-A 3-cefem (100 mg) oppløses i trifluoreddiksyre/anisol (4il v/v),(0,5 ml) og til denne rødlig-brune løsningen tilsettes trifluormetansulfonsyre fra en Pasteur-pipette (25 dråper)• Man får øyeblikkelig brusning og løsningen blir kirsebærrød. 7-Benzyloxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxy-benzyl)tetrazol-5-yl3-A 3-cephem (100 mg) is dissolved in trifluoroacetic acid/anisole (4 ul v/v), (0.5 ml) and to this reddish-brown solution trifluoromethanesulfonic acid is added from a Pasteur pipette (25 drops) • Effervescence is immediately obtained and the solution becomes cherry red.
Efter 3 minutter ved værelsestemperatur stoppes reaksjonsblandingen ved tilsetning av eter (som er tørket ned natrium). Det faller ut en brun gummi, overliggende væske dekanteres og resten vaskes igjen med eter. After 3 minutes at room temperature, the reaction mixture is stopped by the addition of ether (which has been dried down to sodium). A brown gum falls out, the overlying liquid is decanted and the residue is washed again with ether.
Den viskøse gummien oppløses igjen i et minst mulig volumThe viscous rubber dissolves again in the smallest possible volume
av metylenklorid som inneholder 1% trietylamin og løsningen kromatograferes på siiisiumdioksyd (2 mm, 20 x 20 Kieselgel 6 F2S4) ved å anvende acetonitril/vann (6il v/v) som elueringsmiddel. of methylene chloride containing 1% triethylamine and the solution is chromatographed on silica (2 mm, 20 x 20 Kieselgel 6 F2S4) using acetonitrile/water (6 ul v/v) as eluent.
Båndet ved r.f. 0,4 ble fjernet og ekstrahert med 1% trietylamin/metylenklorid (3 x 150 ml). De organiske ekstraktene ble fordampet til tørrhet i vakuum, og man får et hvitt, fast stoff, en blanding av 7-amino-3-acetoksymetyl-4-(tetrasol-5-yl)-A<3->cefem og trietylaminhydrogenklorid. The band at r.f. 0.4 was removed and extracted with 1% triethylamine/methylene chloride (3 x 150 mL). The organic extracts were evaporated to dryness in vacuo to give a white solid, a mixture of 7-amino-3-acetoxymethyl-4-(tetrasol-5-yl)-A<3->cephem and triethylamine hydrogen chloride.
NMR (CDC13)s 6 o 5,25(d) 1H, 4,9 (ra) 2H og 2,05(s) 3H. NMR (CDCl 3 )s 6 o 5.25(d) 1H, 4.9 (ra) 2H and 2.05(s) 3H.
Eksempel 34 Example 34
7- amino- 3-( 1- metyltetrazol- 5- yltiometyl)- 4-( tetrazol- 5- yl)- A3~ cefem 7- amino- 3-( 1- methyltetrazol- 5- ylthiomethyl)- 4-( tetrazol- 5- yl)- A3~ cephem
Ved å gå ut fra 7-benzyloksykarboksamido-3-(1-metyltetrazol-5-yltiometyl)-4-[1-(p-metoksybenzyl)tetrazol»5-yl)-A 3=cefem slik som i eksempel 33, får man det urensede produkt. Starting from 7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol»5-yl)-A 3=cephem as in example 33, one obtains the uncleaned product.
Zwitterionet isoleres ved krystallisasjon av den urensede reaksjonsblandingen, efter utfeining med tørr eter, fra et minst mulig volum av kaliumhydrogenfosfat pH 7 buffer. Efter opp-løsningen av den urensede reaksjonsblandingen faller zwitterionet ut som et kremgult, fast stoff og renses ved tynnskiktskromatografi. The zwitterion is isolated by crystallization of the impure reaction mixture, after sweeping with dry ether, from the smallest possible volume of potassium hydrogen phosphate pH 7 buffer. After the dissolution of the impure reaction mixture, the zwitterion precipitates as a creamy yellow solid and is purified by thin-layer chromatography.
NMR (DMSOdg): 6 » 5,l(d) 1H, 4,8(d) 1H, 4,3(q) 2H, 3„9(s) 3H og 3,7 (s) 2H. NMR (DMSOdg): 6 » 5.1(d) 1H, 4.8(d) 1H, 4.3(q) 2H, 3„9(s) 3H and 3.7 (s) 2H.
Eksempel 35 Example 35
7-(2•,2 *,20-trikloretoksykarboksamido)-3-metyl-A2~cef©m-4- karboksylsyre 7-(2•,2*,20-trichloroethoxycarboxamido)-3-methyl-A2~cef©m-4- carboxylic acid
7- (2 *,211,2 • -trikloretoksykarboksamido)-3-metyl-A3-cefem-4-karboksylsyre (66,6 g) og N-hydroksysuccinimid (21,6 g) i dioksan (200 ml) ved værelsestemperatur behandles med dicykloheksylkarbodiimid (35,6 g) og blandingen omrøres i 1 time ved værelsestemperatur. Blandingen filtreres og filtratet fordampes under redusert trykk, og man får sn olje som oppløses i pyridin (400 ml) ved 7°C og som derefter behandles med vandig natriumhydroksyd (7,5 g i 100 ml) under kraftig omrøring. Blandingen får lov til å varmes opp til 25°C og omrøringen fortsetter i ytterligere 1,75 timer. Pyridinet fordampes under redusert trykk 7-(2*,211,2 • -trichloroethoxycarboxamido)-3-methyl-A3-cephem-4-carboxylic acid (66.6 g) and N-hydroxysuccinimide (21.6 g) in dioxane (200 ml) at room temperature are treated with dicyclohexylcarbodiimide (35.6 g) and the mixture is stirred for 1 hour at room temperature. The mixture is filtered and the filtrate is evaporated under reduced pressure, and a solid oil is obtained which is dissolved in pyridine (400 ml) at 7°C and which is then treated with aqueous sodium hydroxide (7.5 g in 100 ml) with vigorous stirring. The mixture is allowed to warm to 25°C and stirring is continued for an additional 1.75 hours. The pyridine is evaporated under reduced pressure
og resten helles ned på is. pH justeres til 2 med 6N saltsyre og and the rest is poured over ice. The pH is adjusted to 2 with 6N hydrochloric acid and
. utf einingen ekstraheres til etylacetat.' Den organiske, løsningen vaskes med IN saltsyre, vann og fordampes under redusert trykk. Resten oppløses i vandig natriumkarbonatløsning og den resulterende løsningen vaskes med etylacetat. Den vandige løsningen behandles . med trekull, filtreres og pH av filtratet justeres til 2 med . the solution is extracted into ethyl acetate.' The organic solution is washed with IN hydrochloric acid, water and evaporated under reduced pressure. The residue is dissolved in aqueous sodium carbonate solution and the resulting solution is washed with ethyl acetate. The aqueous solution is treated. with charcoal, is filtered and the pH of the filtrate is adjusted to 2 med
6N saltsyre. Utfeiningen ekstraheres med etylacetat og den organiske løsningen behandles med trekull, filtreres og tørkes (MgSO^). Løsningen fordampes derefter under redusert trykk, og man 6N hydrochloric acid. The skimming is extracted with ethyl acetate and the organic solution is treated with charcoal, filtered and dried (MgSO 4 ). The solution is then evaporated under reduced pressure, and
får produktet som et skum, som størkner ved triturering med petroleter (48,0 g) og som er rent nok efter kromatografi. obtains the product as a foam, which solidifies on trituration with petroleum ether (48.0 g) and which is pure enough after chromatography.
NMR (CDC13): 6 - 7,5(d) lH, 6,0(q) lH, 5,2(m) 2H, 4,7(s) 2H, 4,6 (s) 1H og 1,9(8) 3K. NMR (CDCl 3 ): 6 - 7.5(d) 1H, 6.0(q) 1H, 5.2(m) 2H, 4.7(s) 2H, 4.6 (s) 1H and 1.9 (8) 3K.
Eksempel 36 7- (2', 2', 2'rtrikloretoksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl) karbamoyl3- A - cefem Example 36 7-(2',2',2'trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl3-A-cephem
7-(2 *,2',2'-trikloretoksykarboksamido)-3-metyl-A 2-cefem-4-karboksylsyre (46,0 g) og N-hydroksysuccinimid (14,3 g) i dioksan (750 ml behandles efter 1 time med dicykloheksylkarbodiimid (24,3 g) ved værelsestemperatur under omrøring. Til den omrørte løsningen tilsettes p-metoksybenzylamin (32,8 g) i dioksan (200 ral) og blandingen omrøres i ytterligere 1 time ved værelsestemperatur. 7-(2*,2',2'-trichloroethoxycarboxamido)-3-methyl-A 2-cephem-4-carboxylic acid (46.0 g) and N-hydroxysuccinimide (14.3 g) in dioxane (750 ml) are treated after 1 hour with dicyclohexylcarbodiimide (24.3 g) at room temperature with stirring.To the stirred solution is added p-methoxybenzylamine (32.8 g) in dioxane (200 ral) and the mixture is stirred for a further 1 hour at room temperature.
Blandingen filtreres og løsningen omrøres i ytterligere 1 time ved værelsestemperatur. Blandingen filtreres og løsningen konsentreres til 300 ml under redusert trykk. Konsentratet helles ned på en mettet, vandig NågCOj-løsning (2 liter) og utfeiningen oppsamles. Utfeiningen vaskes méd vann, IN HC1 og The mixture is filtered and the solution is stirred for a further 1 hour at room temperature. The mixture is filtered and the solution is concentrated to 300 ml under reduced pressure. The concentrate is poured onto a saturated, aqueous NågCOj solution (2 litres) and the skimming is collected. The removal is washed with water, IN HC1 and
til slutt med vann. Det faste stoffet tørkes under redusert trykk ved 100°C 1 16 timer, og man får 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl)-karbamoyl3-A 2 -cefem (58,6 g). En prøve rekrystallisert fra aceton (sm.p. 219-220°C). NMR (DMSOdg): 6 » 7,0(q) 4H, 6,0(q) lH, 5,2(m) 2H, 4,7(s) 2H, 4,6(s) 1H, 4,2(d) 2H, 3,7(s) 3H og 1,7(s) 3H. finally with water. The solid is dried under reduced pressure at 100°C for 116 hours, and 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl3- A 2 -cephem (58.6 g). A sample recrystallized from acetone (m.p. 219-220°C). NMR (DMSOdg): 6 » 7.0(q) 4H, 6.0(q) 1H, 5.2(m) 2H, 4.7(s) 2H, 4.6(s) 1H, 4.2 (d) 2H, 3,7(s) 3H and 1,7(s) 3H.
Eksempel 37 7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-[lr(p-metoksybenzyl)- tetrazol- 5- yl3- A 2- cefem ' , i Example 37 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1r(p-methoxybenzyl)-tetrazol-5-yl3-A 2-cephem', i
7-(2',2',2•-trikloretoksykarboksamido)-3-metyl-4-[N-(p-metoksybenzyl)karbamoyl3-A 2-pefem (44,2 g) og pyridin (14,06 g) 7-(2',2',2•-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl3-A 2-pefem (44.2 g) and pyridine (14.06 g)
i kloroform (300 ml, etanolfri) ved 40°C behandles med fosfor- in chloroform (300 ml, ethanol-free) at 40°C is treated with phosphorus-
pentaklorid (27,5 g) og blandingen omrøres ved 40°C i 3 timer. Løsningen avkjøles til værelsestemperatur og tilsettes tetrametyl-guanidiniumazid (87,9 g), og løsningen omrøres ved værelsestemperatur i 2 timer. Løsningen vaskes derefter med vann, vandig natriumbikarbonat, IN saltsyre, vann og tørkes (MgSO^). Den organiske løsningen fordampes under redusert trykk, og man får en gummi som oppløses i etylacetat (200 ml) og som føres gjennom en kolonne av aluminiumoksyd. Fraksjonen som inneholder produktet oppsamles Og løsningen fordampes til tørrhet under redusert trykk, og man får produktet som et svakt oransjefarvet fast stoff (42,4 g). pentachloride (27.5 g) and the mixture is stirred at 40°C for 3 hours. The solution is cooled to room temperature and tetramethylguanidinium azide (87.9 g) is added, and the solution is stirred at room temperature for 2 hours. The solution is then washed with water, aqueous sodium bicarbonate, 1N hydrochloric acid, water and dried (MgSO 4 ). The organic solution is evaporated under reduced pressure, and a gum is obtained which is dissolved in ethyl acetate (200 ml) and which is passed through a column of aluminum oxide. The fraction containing the product is collected and the solution is evaporated to dryness under reduced pressure, and the product is obtained as a slightly orange colored solid (42.4 g).
NMR (CDC13): 6 = 7,0(q) 4H, 6,1(d) lH, 6,0(s) lH, 5,6(q) 2H, 5,4(s) 1H, 5,2(q) 1H, 4,8(d) 1H, 4,7(s) 2H, 3,7(s) 3H og l,5(s) 3H. NMR (CDCl 3 ): δ = 7.0(q) 4H, 6.1(d) 1H, 6.0(s) 1H, 5.6(q) 2H, 5.4(s) 1H, 5.2 (q) 1H, 4.8(d) 1H, 4.7(s) 2H, 3.7(s) 3H and 1.5(s) 3H.
Eksempel 38 Example 38
7-(2<«>,2<»>,2'-trikloretoksykarboksamido)-3-metyl-4-(tetrasol-5-yl)-A2- e9Zem 7-(2<«>,2<»>,2'-trichloroethoxycarboxamido)-3-methyl-4-(tetrasol-5-yl)-A2-e9Zem
7-(2',2•,2 *-trikloretoksykarboksamido)-3-metyl-4- 11-(p-metoksybenzyl)tetrazol-5-yl]-A<2->cefem (40,7 g) i trifluoreddiksyre 7-(2',2•,2*-trichloroethoxycarboxamido)-3-methyl-4-11-(p-methoxybenzyl)tetrazol-5-yl]-A<2->cephem (40.7 g) in trifluoroacetic acid
(280 ml) som inneholder anisol (70 ml) får lov til å stå ved 50°C (280 ml) containing anisole (70 ml) is allowed to stand at 50°C
i 6 timer. Løsningen helles ned på vann (1 liter) og suspensjonen ekstraheres med etylacetat. Den organiske løsningen ekstraheres med mettet, vandig natriumbikarbonat og den vandige løsningen justeres til pH 2 med IN saltsyre, og utfeiningen ekstraheres med etylacetat. Den organiske løsningen tørkes (MgSO^) og fordampes under redusert trykk, og man får 7-(2<*>,2',2<1->trikloretoksykarboksamido)-3-metyl-4-(tetrazol-5-yl)-A 2-cefem som et svakt brunfarvet, fast stoff (23,2 g). En prøve som rekrystalliseres fra kloroform (etanolfri) sm.p. 165-167°C. for 6 hours. The solution is poured onto water (1 litre) and the suspension is extracted with ethyl acetate. The organic solution is extracted with saturated aqueous sodium bicarbonate and the aqueous solution is adjusted to pH 2 with 1N hydrochloric acid, and the supernatant is extracted with ethyl acetate. The organic solution is dried (MgSO4) and evaporated under reduced pressure, and 7-(2<*>,2',2<1->trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)- A 2-cephem as a faint brown solid (23.2 g). A sample recrystallized from chloroform (ethanol-free) m.p. 165-167°C.
NMR (DMSOdg): 6 = 6,4(q* lH, 5,8(s) 1H, 5,2(m) 2H, 4,8(s) 2H og 1,8(s) 3H. NMR (DMSOdg): δ = 6.4(q* 1H, 5.8(s) 1H, 5.2(m) 2H, 4.8(s) 2H and 1.8(s) 3H).
Eksempel 39 7-(2 *,2 *,2'-trikloretoksykarboksamido)-3-metyl-4-(metoksymetyl- Example 39 7-(2*,2*,2'-trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyl-
2 2
tetrazol- 5- yl)- A - cefemtetrazol-5-yl)- A - cephem
Til en suspensjon av 7-(2',2',2•-trikloretoksykarboksamido)-3-metyl-4-(tetrazol-5-yl)-A<2->cefem (8,27 g) i metylenklorid (50 ml) tilsettes trietylamin (2,22 g) og klormetyl-metyleter (1,76 g) og To a suspension of 7-(2',2',2•-trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-A<2->cephem (8.27 g) in methylene chloride (50 ml ) triethylamine (2.22 g) and chloromethyl methyl ether (1.76 g) are added and
løsningen omrøres ved værelsestemperatur i 30 minutter. Løsningen vaskes derefter med vann, vandig natriumbikarbonat og tørkes (MgSOj. Fordampningen under redusert trykk gir 7-(2',2',2'-trikloretoksykarboksamido)-3-raetyl-4-(metoksymetyltetrazol-5-yl)-A 2- the solution is stirred at room temperature for 30 minutes. The solution is then washed with water, aqueous sodium bicarbonate and dried (MgSOj. The evaporation under reduced pressure gives 7-(2',2',2'-trichloroethoxycarboxamido)-3-raethyl-4-(methoxymethyltetrazol-5-yl)-A 2-
cefem (7,3 g) som et kremfarvet, fast stoff.cefem (7.3 g) as a cream-colored solid.
NMR-(CDClj) s 6°6,4(d) lH, 6,0(q) lH, 5,8(s) 2H, 4,7{s) 2H, 3,4(m) 3H og 1,7(s) 3H. NMR-(CDCl1) s 6° 6.4(d) 1H, 6.0(q) 1H, 5.8(s) 2H, 4.7(s) 2H, 3.4(m) 3H and 1, 7(s) 3H.
Eksempel 40 Example 40
7- (211,2 • ,2 "-trikloretoksykarboksamido)-3- (1-metyltetrasol-5=yl-tiometyl)- 4- ( metoksymetyltetrazol- 5~ yl)- A - cefem 7- (211,2 • ,2 "-trichloroethoxycarboxamido)-3- (1-methyltetrazol-5=yl-thiomethyl)- 4-( methoxymethyltetrazol-5~ yl)- A - cephem
7-(2<*>,2",2'-trikloretoksykarboksamido)-3-metyl-4-(metoksy-metyltetraaol-5-yl)-A 2-cefem (8,0 g) i karbontetraklorid (160 ml) og kloroform (16 ml) ble deokeygenert. Det ble tilsatt N-bromsuccinimid (3,20 g) og benzoylperoksyd (200 mg) og den omrørte blandingen ved 10-15°C ble belyst (250 watt, wolframlampe) i 2 timer. I løpet av denne tiden ble tilsatt ytterligere kloroform for å bibeholde en klar overliggende væske, og en ytterligere mengde av benzoylperoksyd (200 mg) ble tilsatt 30 minutter efter at man begynte med belysningen. 7-(2<*>,2",2'-trichloroethoxycarboxamido)-3-methyl-4-(methoxy-methyltetraaol-5-yl)-A 2-cephem (8.0 g) in carbon tetrachloride (160 ml) and chloroform (16 mL) was deoxygenated. N-bromosuccinimide (3.20 g) and benzoyl peroxide (200 mg) were added and the stirred mixture at 10-15°C was illuminated (250 watts, tungsten lamp) for 2 hours. During of this time additional chloroform was added to maintain a clear supernatant, and an additional amount of benzoyl peroxide (200 mg) was added 30 minutes after starting the illumination.
Succinimidet ble filtrert fra og filtratet ble behandles med trietylaminsaltet av 5-merkapto-l-metyltetrazol (3,40 g) i 2,5 timer ved 45 oC. Den organiske løsningen ble derefter vasket med vann, vandig natriumbikarbonat, vann og til slutt tørket (MgS0A). Den organiske løsningen ble fordampet til tørrhet under redusert trykk. Resten ble renset ved hjelp av kolonnekromatografi (silikagel, etylacetat, lett petroleter, 1:1), og man får produktet (3,0 g). The succinimide was filtered off and the filtrate was treated with the triethylamine salt of 5-mercapto-1-methyltetrazole (3.40 g) for 2.5 hours at 45°C. The organic solution was then washed with water, aqueous sodium bicarbonate, water and finally dried (MgSOA). The organic solution was evaporated to dryness under reduced pressure. The residue was purified by means of column chromatography (silica gel, ethyl acetate, light petroleum ether, 1:1), and the product (3.0 g) is obtained.
NMR (CDC13): 6 « 6,6(s) lH, 6,2(d) lH, 6,0(s) 1H, 5,9(s) 2H, 5,4(m) 2H, 4,8(s) 2H, 4,2(q) 2H, 4,0(s) 3H og 3,5(s) 3H. NMR (CDCl 3 ): 6 « 6.6(s) 1H, 6.2(d) 1H, 6.0(s) 1H, 5.9(s) 2H, 5.4(m) 2H, 4.8 (s) 2H, 4.2(q) 2H, 4.0(s) 3H and 3.5(s) 3H.
Eksempel 41 Example 41
7-(2 *,2 *,2'-trikloretoksykarboksamido)-3-(2-metyl-l,3,4-tiadiazol-5- yltiometyl) - 4- metoksymetyltetrazol- 5- yl)- A 2- cefem 7-(2*,2*,2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4- methoxymethyltetrazol-5-yl)- A 2- cephem
7-(2',2',2'-trikloretoksykarboksamido)-3-metyl-4-(metoksymetyltetrazol-5-yltiometyl)-A 2-cefem (4,0 g) i karbontetraklorid (60 ml) og kloroform (8 ml) ble behandlet med N-bromsuccinimid og benzoylperoksyd som i eksempel 40. Produktet ble behandlet på lignende måte med trietylaminsaltet av 5-merkapto-2-metyltiadiazol (2 g) g og man får, efter kolonnekromatograf! (silisiumdioksyd, etylacetat/lett petroleter 1:1), 7-(2',2•,2 *-trikloretoksykarboksamido) -3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A<2->cefem (1,1 g). 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-ylthiomethyl)-A 2 -cephem (4.0 g) in carbon tetrachloride (60 ml) and chloroform (8 ml ) was treated with N-bromosuccinimide and benzoyl peroxide as in example 40. The product was treated in a similar way with the triethylamine salt of 5-mercapto-2-methylthiadiazole (2 g) g and one obtains, according to column chromatography! (silicon dioxide, ethyl acetate/light petroleum ether 1:1), 7-(2',2•,2*-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-( methoxymethyltetrazol-5-yl)-A<2->cephem (1.1 g).
NMR (CDC13): 6 ■ 6,6 (a) 1H, 6,3(d) lH, 6,1(s) 1H, 5,9 (s) 2H, 5,3-5,7 (m) 2H, 4,8(s) 2H, 4,l(q) 2H, 3,5(s) 3H og 2,7 (s) 3H. NMR (CDCl 3 ): 6 ■ 6.6 (a) 1H, 6.3(d) 1H, 6.1(s) 1H, 5.9 (s) 2H, 5.3-5.7 (m) 2H , 4.8(s) 2H, 4.1(q) 2H, 3.5(s) 3H and 2.7(s) 3H.
Eksempel 42 Example 42
7-(2',2',2•-trikloretoksykarboksamido)-3-(l-aretyltetrazol~5-yltiometyl)-4-(metoksymetyltetrazol~5-yl)-A<2->cefem (2,0 g) i en ' 7-(2',2',2•-trichloroethoxycarboxamido)-3-(1-arethyltetrazol~5-ylthiomethyl)-4-(methoxymethyltetrazol~5-yl)-A<2->cephem (2.0 g) in a'
blanding av eddiksyre-vann (7:3, 20 ml) ved 0°C ble behandlet med aktivert sinkstøv (2,0 g) under omrøring. Efter 1 time ble blandingen filtrert og filtratet fortynnet med vann (100 ml). mixture of acetic acid-water (7:3, 20 ml) at 0°C was treated with activated zinc dust (2.0 g) with stirring. After 1 hour, the mixture was filtered and the filtrate diluted with water (100 ml).
pH av blandingen ble justert til 2 med IN saltsyre og ble derefter vasket to ganger med etylacetat. pH av den klare, vandige løsningen ble justert til 6 med natriumbikarbonat og blandingen ble ekstrahert med kloroform. Den organiske løsningen ble vasket mod pH 7 buffer, tørket (MgSO^) og til slutt fordampet under redusert trykk, og man får 7~amino~3-(1-metyltetraaol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A 2-cefem (0,9 g) som et skum, som renses ved kromatografi. The pH of the mixture was adjusted to 2 with 1N hydrochloric acid and was then washed twice with ethyl acetate. The pH of the clear aqueous solution was adjusted to 6 with sodium bicarbonate and the mixture was extracted with chloroform. The organic solution was washed against pH 7 buffer, dried (MgSO^) and finally evaporated under reduced pressure, and 7~amino~3-(1-methyltetraaol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl) is obtained )-A 2-cephem (0.9 g) as a foam, which is purified by chromatography.
NMR (CDC13): 6 6,6(s) 1H, 5,95(s) lH, 5,85(s) 2H, 5,25(d) lH, NMR (CDCl 3 ): δ 6.6(s) 1H, 5.95(s) 1H, 5.85(s) 2H, 5.25(d) 1H,
4,70(d) 1H, 4,l(q) 2H, 3,95(s) 3H og 3,5(s) 3H. 4.70(d) 1H, 4.1(q) 2H, 3.95(s) 3H and 3.5(s) 3H.
På lignende måte fremstilles 7-amino-3-(2-metyl-l,3,4-2 tiadiazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A -cefem. In a similar manner, 7-amino-3-(2-methyl-1,3,4-2-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A-cephem is prepared.
NMR (CDCl3)s 6 » 6,8(s) lH, €>,4(s) 1H, 6,0(s) 2H, 5,4(d) lH, 4,8(d) 1H, 4,2(q) 2H, 3,7(s) 3H og 3,2(s) 2H. NMR (CDCl3)s 6 » 6.8(s) 1H, €>.4(s) 1H, 6.0(s) 2H, 5.4(d) 1H, 4.8(d) 1H, 4, 2(q) 2H, 3.7(s) 3H and 3.2(s) 2H.
Eksempel 43 7-(tetrazol-1-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4- ( tetrazol- 5- yl)- A 3- cefem Example 43 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-A 3-cephem
A. 7-(tetrazol-1-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yl-tlometyl) - 4- ( metoksymetyltetrazol- 5- yl)- A<2>- cefem A. 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl-thlomethyl)-4-(methoxymethyltetrazol-5-yl)-A<2>-cephem
7-aroino-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A 2-cefem (430 mg) og tetrasol-l-yl-eddiksyra (133 mg) i tetrahydrofuran (10 ml) og acetonitril (10 ml) behandles med dlcykloheksylkarbodilmid (215 mg) og blandingen får lov til å stå ved værelsestemperatur i 1 time. Blandingen filtreres og fordampes under redusert trykk, og man får 7-(tetrazol-1-ylacetamido) -3- (2-aietyl-l, 3,4-tiadiaool-5-yltiometyl) -4- (metoksy-matyltetrasol-5-yl)~A 2-cefem (520 mg), som et kremfarvet, fast stoff, som renses ved tynnskiktskromatograf!. 7-aroino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A 2-cephem (430 mg) and tetrazol-1-yl-acetic acid (133 mg) in tetrahydrofuran (10 ml) and acetonitrile (10 ml) is treated with dlcyclohexylcarbodylimide (215 mg) and the mixture is allowed to stand at room temperature for 1 hour. The mixture is filtered and evaporated under reduced pressure, and 7-(tetrazol-1-ylacetamido)-3-(2-ethyl-1,3,4-thiadiaol-5-ylthiomethyl)-4-(methoxy-methyltetrazol-5- yl)~A 2-cephem (520 mg), as a cream-colored solid, which is purified by thin-layer chromatography!.
NMR (CDC13): 6 « 9,1(s) 1H, 6,6(s) lH, 6,0(s) lH, 5,9(s) 2H, 5,4(s) 2H, 5,4(s) lH, 5,2(d) lH, 4,0(q) 2H, 3,4(s) 3H og 2,6(s) 3H. NMR (CDCl 3 ): 6 « 9.1(s) 1H, 6.6(s) 1H, 6.0(s) 1H, 5.9(s) 2H, 5.4(s) 2H, 5.4 (s) 1H, 5.2(d) 1H, 4.0(q) 2H, 3.4(s) 3H and 2.6(s) 3H.
B. 7-(tetrazol-l-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltio-3 ^ metyl)- 4-( metoksymetyltetrazol- 5- yl) rA ^ cefem- l- oksyd 7-(tetrazol-l-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A -rcefém (500 mg) i kloroform (20 ml) behandles med m-klorperbenzoesyre (219 mg) ved 0°G under omrøring. Efter 1 time ved 0°C tilsettes pyridin B. 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-3^methyl)-4-(methoxymethyltetrazol-5-yl)rA^cefem-1 - oxide 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A-recefem (500 mg) in chloroform (20 ml) is treated with m-chloroperbenzoic acid (219 mg) at 0°G with stirring. After 1 hour at 0°C, pyridine is added
(40 mg) og blandingen får lov til å oppvarmes til værelsestemperatur » Efter ytterligere 1 time konsentreres blandingen under redusert trykk og dietyleter tilsettes til konsentratet. Det kremfarvede, faste stoffet som felles ut oppsamles, tørkes under redusert trykk og produktet (410 mg) oppnås som etickrem-farvet, fast stoff, som renses ved kromatografi. (40 mg) and the mixture is allowed to warm to room temperature » After a further 1 hour, the mixture is concentrated under reduced pressure and diethyl ether is added to the concentrate. The cream-colored solid that precipitates is collected, dried under reduced pressure and the product (410 mg) is obtained as an ethyl-cream-colored solid, which is purified by chromatography.
NMR (DMSOdg/aceton dg) t 6°8,9(s) lH, 6,0(s) 2H, 6,0, lH, 5,6(s) 2H, 5,2(d) lH, 4,5(q) 2H, 4,0(s) 2H, 3,5(s) 3H og 2,7(s) 3H. NMR (DMSOdg/acetone dg) t 6°8.9(s) 1H, 6.0(s) 2H, 6.0, 1H, 5.6(s) 2H, 5.2(d) 1H, 4, 5(q) 2H, 4.0(s) 2H, 3.5(s) 3H and 2.7(s) 3H.
C. 7-(tetrazol-1-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltio-metyl)- 4-( metokaymetyltetrazol- 5~ yl)- A 3- cefem C. 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl)- 4-(methocaylmethyltetrazol-5-yl)- A 3- cephem
7-(tetrazol-l-ylacetamido)-3-(2-metyl-l,3,4-tiadiasol?-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A 3-cefem-l-oksyd (400 mg) i dimetylformamid (10 ml) behandles med vannfri stannoklorid (400 mg) og acetylklbrid (200 mg) ved 0°C under omrøring. Blandingen omrøres i 1 time og helles derefter ned i et overskudd av vann. Den vandige blandingen ekstraheres emrcekke ganger med kloroform og den organiske løsningen vaskes en rekke ganger med vann. 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol?-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A 3-cephem-1-oxide ( 400 mg) in dimethylformamide (10 ml) is treated with anhydrous stannous chloride (400 mg) and acetyl chloride (200 mg) at 0°C with stirring. The mixture is stirred for 1 hour and then poured into an excess of water. The aqueous mixture is extracted several times with chloroform and the organic solution is washed several times with water.
Kloroformløsningen tørkes (MgSO^) og fordampes under redusert trykk, og man får forbindelsen som et skum (250 mg), som renses ved tynnskiktskromatograf1. The chloroform solution is dried (MgSO^) and evaporated under reduced pressure, and the compound is obtained as a foam (250 mg), which is purified by thin-layer chromatography1.
NMR (CDC13)36 « 9,0(s) lH, 8,7(d) lH, 6,0(s) 2H, 6,0, 1H, 5,4(s) 2H, 5,2(d) 1H, 4,4(q) 2H, 3,7(s) 2H, 3,4(s) 3H og 2,7(s) 2H. NMR (CDCl 3 ) 36 « 9.0(s) 1H, 8.7(d) 1H, 6.0(s) 2H, 6.0, 1H, 5.4(s) 2H, 5.2(d) 1H, 4,4(q) 2H, 3,7(s) 2H, 3,4(s) 3H and 2,7(s) 2H.
D. 7-(tetrazol-l-ylacetaraido)-3-(2-metyl-l,3,4-tiadiazol-5-yltio-metyl)- 4-( tetrazol- 5- yl)- A 3- cefem D. 7-(tetrazol-1-ylacetaraido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio-methyl)-4-(tetrazol-5-yl)- A 3- cephem
7-(tetrazol-l-ylacetamido)-3-(2-metyl-l,3,4-tiadiazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A -cefem (70 mg) i trifluoreddiksyre (2 ml) og anisol (0,5 ml) får lov til å stå ved 20°C i 6 timer. Efter dette fjernes trifluoreddiksyren under redusert trykk og man får en olje. Denne resten fortynnes med etylacetat og den resulterende organiske løsningen ekstraheres med 7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A-cephem (70 mg) in trifluoroacetic acid ( 2 ml) and anisole (0.5 ml) is allowed to stand at 20°C for 6 hours. After this, the trifluoroacetic acid is removed under reduced pressure and an oil is obtained. This residue is diluted with ethyl acetate and the resulting organic solution is extracted with
mettet, vandig natrlumbikarbonatløsning. Den vandige løsningen surgjøres til pH 2 med 2N saltsyre og løsningen ekstraheres med etylacetat. Den organiske løsningen tørkes (MgSO^) og fordampes under redusert trøkk, og man får en olje som krystalliseres ved tilsetning av dietyleter, og man får produktet som farveløse saturated aqueous sodium bicarbonate solution. The aqueous solution is acidified to pH 2 with 2N hydrochloric acid and the solution is extracted with ethyl acetate. The organic solution is dried (MgSO^) and evaporated under reduced pressure, and an oil is obtained which is crystallized by the addition of diethyl ether, and the product is obtained as colorless
nåler (35 mg), som renses ved kromatografi• needles (35 mg), which are purified by chromatography•
NMR (trif luoreddiksyre-d) t 6 «= 9,5 (o) 1H, 5,8 (d) lH, 5,5 (s) 2H, 5,2(d) 1H, 4,5(s) 2H, 3,6(s) 2H og 2,8(s) 3H. NMR (trifluoroacetic acid-d) t 6 «= 9.5 (o) 1H, 5.8 (d) 1H, 5.5 (s) 2H, 5.2(d) 1H, 4.5(s) 2H , 3.6(s) 2H and 2.8(s) 3H.
Eksempel 44 Example 44
7-D™ (a-hydroksy-a-f enylacetamido) -3- (1-metyltetrazol-5-yltiometyl) - 4-( tetrazol- 5- yl)- A 3- cefem 7-D™ (α-hydroxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)- A 3- cephem
A. 7-D-(e-formyloksy-a-fenylacetamido)-3-(l-metyltetraaol-5-yl-tiometyl)- 4-( roetoksymetyltetrazol- 5- yl)- A 2- cefem A. 7-D-(e-formyloxy-a-phenylacetamido)-3-(1-methyltetraaol-5-yl-thiomethyl)- 4-(roethoxymethyltetrazol-5-yl)- A 2- cephem
Ved å anvende egnede reagenser og anvende fremgangsmåten i eksempel 43A, fremstilles detønskede mellomprodukt» By using suitable reagents and applying the procedure in example 43A, the desired intermediate product is prepared"
NMR (CDCl3)t 6 «= 8,2 (s) 1H, 7,3(s) 5E, 6,4(s) lH, 6,2(s) lH, 5,9 (s) 1H, 5,7(s) 2H, 5,5(q) 1H, 5,2(d) lH, 4,0(q) 2H, 3,9(s) 3H og 3,4(s) 3H. NMR (CDCl3)t 6 «= 8.2 (s) 1H, 7.3(s) 5E, 6.4(s) 1H, 6.2(s) 1H, 5.9 (s) 1H, 5, 7(s) 2H, 5.5(q) 1H, 5.2(d) 1H, 4.0(q) 2H, 3.9(s) 3H, and 3.4(s) 3H.
B. 7-D- (ci-formyloksy-a-fenylacetamido) -3- (l-rmetyltetrazol-5-yl-tiometyl)- 4-( metoksymetyltetra20l- 5- yl)- A 3- cefem- l^- oksyd B. 7-D-(ci-formyloxy-a-phenylacetamido)-3-(1-methyltetrazol-5-yl-thiomethyl)-4-(methoxymethyltetra20l-5-yl)- A 3-cephem-1^-oxide
Ved å anvende mellomproduktet ovenfor fra eksempel 44A og følge fremgangsmåten i eksempel 43B, isoleres den ønskede forbindelse og anvendes i den følgende reaksjon ufcéa ytterligere rensing. By using the above intermediate from Example 44A and following the procedure in Example 43B, the desired compound is isolated and used in the following reaction for further purification.
C. 7-D-(ct-formyloksy-os-fenylacetamido)-3-(1-metyltetrazol-5-yl-tiometyl)- 4-( metoksymetyltetrazol- 5- yl)-A 3- cefem C. 7-D-(ct-formyloxy-os-phenylacetamido)-3-(1-methyltetrazol-5-yl-thiomethyl)- 4-(methoxymethyltetrazol-5-yl)-A 3- cephem
Det anvendes fremgangsmåten i eksempel 4 3C pg man gåt ut fra den egnede forbindelse fra eksempel 44B, og man får det ønskede produkt. The method in example 4 3C is used because the suitable compound from example 44B was used as the starting point, and the desired product is obtained.
NMR (CDCl3)s 6 = 8,3(s) 1H, 7,4(o) 5H, 6,3(s) 1H, 6,0(s) 2H, 6,0, 1H, 5,2(d) 1H, 4,5(q) 2H, 4,0(s) 3H, 3,8(s) 2H og 3,5(s) 3H. NMR (CDCl3)s 6 = 8.3(s) 1H, 7.4(o) 5H, 6.3(s) 1H, 6.0(s) 2H, 6.0, 1H, 5.2(d ) 1H, 4.5(q) 2H, 4.0(s) 3H, 3.8(s) 2H and 3.5(s) 3H.
D. 7-D-(ci-formyloksy-ot-fenylacetamido)-3-(l-metyltetrazol-5-yl-D. 7-D-(ci-formyloxy-ot-phenylacetamido)-3-(1-methyltetrazol-5-yl-
3 3
tiometyl) - 4° ( tetrazol- 5- yl) - A - cefem thiomethyl) - 4° (tetrazol-5-yl) - A - cephem
Trifluoreddiksyre-anisol-bohandlingen i eksempel 43D gjentas ved å gå ut fra produktet i eksempel 44C, og man får det ønskede produkt. _ The trifluoroacetic acid-anisole reaction in example 43D is repeated starting from the product in example 44C, and the desired product is obtained. _
NMR (aceton-d6/D20)t 6 » 8,3(s) 1H, 7,5(m) 5H, 6,2(s) lH, 5,9(d) lH, 5,3(d) 1H, 4,4(s) 2H og 4,0 (HOD). NMR (acetone-d6/D2O)t 6 » 8.3(s) 1H, 7.5(m) 5H, 6.2(s) 1H, 5.9(d) 1H, 5.3(d) 1H , 4.4(s) 2H and 4.0 (HOD).
(aceton-dg/D20/trifluoreddiksyre-d)s 6 = 4,4(s) 2H, 4,0(s) 3H og 3,9 (s) 2H. (acetone-dg/D 2 O/trifluoroacetic acid-d)s 6 = 4.4(s) 2H, 4.0(s) 3H and 3.9 (s) 2H.
E. 7-D-(a-hydroksy-o-fenylacetamido)-3-(l-metyltetrazol-5-yltlo-3 metyl) - 4- ( tetrazol- 5- yl) - A - cefem E. 7-D-(a-hydroxy-o-phenylacetamido)-3-(1-methyltetrazol-5-yltholo-3 methyl)-4-(tetrazol-5-yl)-A-cephem
7-D-(a-formyloksy-a-fenylacetamido)-3-(1-metyltetrazol-5-yltiometyl)-4-(tetrazol-5-yl)-A -cefem (100 mg) 1 vandig natrium-bikarbonatløsning (5 ml) får lov til å stå ved værelsestemperatur i 3 timero pH av reaksjonsblandingen justeres til 2 med 2N saltsyre og ekstraheres med etylacetat. Den organiske løsningen 7-D-(a-formyloxy-a-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-A -cephem (100 mg) 1 aqueous sodium bicarbonate solution (5 ml) is allowed to stand at room temperature for 3 hours, the pH of the reaction mixture is adjusted to 2 with 2N hydrochloric acid and extracted with ethyl acetate. The organic solution
tørkes (MgSO^) og fordampes ander redusert trykk, og man får det ønskede produkt som et kremfarvet, fast materiale (35 rag)„ som efter rensning ved hjelp av tynnskiktskromatografi er hovedsakelig rent.. is dried (MgSO^) and evaporated under reduced pressure, and the desired product is obtained as a cream-coloured, solid material (35 rag)„ which, after purification by means of thin-layer chromatography, is mainly pure..
Eksempel 45 Example 45
7-D-(a-amino-æ-fenylacetamido)-3-(1-metyltetrazol-5-yltiometyl)-4- ( tetrazol- 5- yl)- A 3- cefem- trifluoracetat 7-D-(α-amino-ε-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-( tetrazol-5-yl)- A 3- cephem- trifluoroacetate
A. 7-[D-o-(t-butoksykarbonylamino)-fenylacetamido]-3-(1-mety1-tetrazol- 5- yltiometyl)- 4-( metoksymetyltetrazol- 5- yl)- A 2- cefem 7-amino-3-(l-metyltetrazol-5-yltioraetyl)-4-(metoksymetyltetrazol-5-yl)-A<2>-cefem (100 mg) og N-t-butoksykarbonylfenylglycin (63,4 mg) i etylacetat-acetonitril (1:1, 2 ml) behandles med dicykloheksylkarbodiimid (52 mg) ved 15°C. Efter 1 time filtreres blandingen og filtratet fortynnes med etylacetat (10 ml) og den resulterende løsningen vaskes med IN saltsyre, vandig natriumbikarbonat og til slutt med vann. Tørking (MgSO^) og fordampning under redusert trykk gir produktet (152 rag) som et svakt gulfarvet, fast stoff. A. 7-[D-o-(t-butoxycarbonylamino)-phenylacetamido]-3-(1-methyl-tetrazol-5-ylthiomethyl)- 4-(methoxymethyltetrazol-5-yl)- A 2-cephem 7-amino-3- (1-methyltetrazol-5-ylthioraethyl)-4-(methoxymethyltetrazol-5-yl)-A<2>-cephem (100 mg) and N-t-butoxycarbonylphenylglycine (63.4 mg) in ethyl acetate-acetonitrile (1:1, 2 ml) is treated with dicyclohexylcarbodiimide (52 mg) at 15°C. After 1 hour, the mixture is filtered and the filtrate is diluted with ethyl acetate (10 ml) and the resulting solution is washed with 1N hydrochloric acid, aqueous sodium bicarbonate and finally with water. Drying (MgSO^) and evaporation under reduced pressure gives the product (152 mg) as a faint yellow solid.
NMR (CDC13): 6 « 7,25(s) 5H, 6,5(s) lH, 6,0(s) lH, 5,3(s) 2H, 5,6(m) 2H, 5,3(m) 2H, 4,l(g) 2H, 3,9(s) 3H, 3,5(s) 3H og l,4(s) 9H. NMR (CDCl 3 ): 6 « 7.25(s) 5H, 6.5(s) 1H, 6.0(s) 1H, 5.3(s) 2H, 5.6(m) 2H, 5.3 (m) 2H, 4.1(g) 2H, 3.9(s) 3H, 3.5(s) 3H and 1.4(s) 9H.
B. 7-[D-a™ (t-butoksykarbonylamino) f enylacetamido j ~ 3- (1-raetyl-B. 7-[D-α™ (t-butoxycarbonylamino)phenylacetamido j ~ 3-(1-raethyl-
3 tetrazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A -cefem-1- oksyd . 3 tetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A-cephem-1-oxide.
7-[D-ci- (t-butoksykarbonylamino) £enylacetamido]~3- (1-metyltetrazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A 2-cefem (140 mg, 0,22 mmol) i kloroform (2 ml) behandles med m-klorperbenzoesyre (51 mg, 85%) ved 0°C under omrøring. Løsningen holdes ved 0°c i 1 time og derefter tilsettes pyridin (20 mg) og løsningen oppvarmes til værelsestemperatur og holdes ved den temperatur i ytterligere 2 timer. 7-[D-ci-(t-butoxycarbonylamino)phenylacetamido]~3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A 2-cephem (140 mg, 0.22 mmol ) in chloroform (2 ml) is treated with m-chloroperbenzoic acid (51 mg, 85%) at 0°C with stirring. The solution is kept at 0°c for 1 hour and then pyridine (20 mg) is added and the solution is heated to room temperature and kept at that temperature for a further 2 hours.
Reaksjonsblandingen fortynnes med kloroform og vaskes méd IN saltsyre, vandig natriumbikarbonat og tørkes (MgSO^). Fordampning under redusert trykk gir det ønskede produkt som et kremfarvet, fast stoff (120 mg). The reaction mixture is diluted with chloroform and washed with 1N hydrochloric acid, aqueous sodium bicarbonate and dried (MgSO 4 ). Evaporation under reduced pressure gives the desired product as a cream solid (120 mg).
Dette materiale anvendes direkte i neste reaksjon uten ytterligere rensning. This material is used directly in the next reaction without further purification.
C. 7 " i D-a- (t-butoksykarbonylamino) f enylacetamido 3*-3- (1-metyltetrazol- 5- yl- tiomatyl)-4-( metoksymetyltetrazol- S- yl)- A 3- cefem 7-[D-a-(t-butoksykarboksylaarino)f©nylacatamido3-3-(1-metyltetrazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A 3-cefem-1-oksyd (120 mg) ble suspendert i dimetylformamid (0,3 ml) og acetonitril (0,75 ml) og blandingen behandles med acetylklorid (60 mg) og vannfri stannoklorid (33 mg) under omrøring ved 0°C C. 7 " i D-a-(t-butoxycarbonylamino)phenylacetamido 3*-3-(1-methyltetrazol-5-yl-thiomatyl)-4-(methoxymethyltetrazol-S-yl)- A 3-cephem 7-[D-a- (t-butoxycarboxylarino)phenylacatamido3-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-α 3-cephem-1-oxide (120 mg) was suspended in dimethylformamide (0, 3 ml) and acetonitrile (0.75 ml) and the mixture is treated with acetyl chloride (60 mg) and anhydrous stannous chloride (33 mg) with stirring at 0°C
i 1 time. Blandingen får derefter lov til å oppvarmes til værelsestemperatur og omrøres ytterligere 1 time. Blandingen konsentreres under redusert trykk og fortynnes derefter med etylacetat. Den organiske løsningen vaskes med vann og vandig natriumbikarbonat og tørkes til slutt (MgSO^). Fordampning under redusert trykk gir en olje som ble renset ved preparativ tynnsiktskromatografi (silioiumdioksyd, etylacetat-lett petroleter, 3:2), og man får det ønskede produkt som et svakt gulfarvet skum (60 mg). for 1 hour. The mixture is then allowed to warm to room temperature and stirred for a further 1 hour. The mixture is concentrated under reduced pressure and then diluted with ethyl acetate. The organic solution is washed with water and aqueous sodium bicarbonate and finally dried (MgSO 4 ). Evaporation under reduced pressure gives an oil which was purified by preparative thin-screen chromatography (silicon dioxide, ethyl acetate-light petroleum ether, 3:2), and the desired product is obtained as a faint yellow foam (60 mg).
NMR (CDC13): 6 «= 7,4 (s) 5H, 7,2 (d) lH, 5,8 (m) 4H, 5,3 (d) lH, 5,2(d) 1H, 4,5(q) 2H, 4,0(s) 3E, 3,8 (s) 2H, 3,6(s) 3H og 1,5 (s) 9H. NMR (CDCl 3 ): 6' = 7.4 (s) 5H, 7.2 (d) 1H, 5.8 (m) 4H, 5.3 (d) 1H, 5.2(d) 1H, 4, 5(q) 2H, 4.0(s) 3E, 3.8(s) 2H, 3.6(s) 3H and 1.5(s) 9H.
D. 7-D-(a-amino-a-fenylacetamido)-3-(1-metyltetrazol-5~yltiom©tyl-4- ( tetrazol- 5- yl)- A<3>~ceferg-trifluoracetat D. 7-D-(α-amino-α-phenylacetamido)-3-(1-methyltetrazol-5~ylthiomethyl-4-(tetrazol-5-yl)-α<3>~ceferg trifluoroacetate
7-tD-(a-t-butoksykarbonylamino-o-fenyl)acetamido]-3-(1-metyltetrazol-5-yltiometyl)-4-(metoksymetyltetrazol-5-yl)-A<3>-cefem (55 mg) i trifluoreddiksyre (2 ml) og anisoi (0,5 ml) får lov til å stå ved 20°C i 6 timer. Trifluoreddiksyren fordampes under redusert trykk og resten behandles med eter. Det resulterende faste stoffet oppsamles og vaskes med porsjoner av tørr eter. 7-tD-(a-t-butoxycarbonylamino-o-phenyl)acetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-A<3>-cephem (55 mg) in trifluoroacetic acid (2 ml) and aniseed (0.5 ml) are allowed to stand at 20°C for 6 hours. The trifluoroacetic acid is evaporated under reduced pressure and the residue is treated with ether. The resulting solid is collected and washed with portions of dry ether.
Det faste stoffet tørkes under høyvakuum, og man får det Ønskede produkt som trifluoreddiksyresalt. The solid is dried under high vacuum, and the desired product is obtained as a trifluoroacetic acid salt.
NMR (D20/DMS0d6/trifluoreddiksyr©-d): 6 - 7,4(s) 5H, 5,8(d) lH, 5,2(d) 1H, 5,l(s) lH, 4,2(s) 2K, 4,0(3) 3H og 3,6(s) 2H. NMR (D2O/DMS0d6/trifluoroacetic acid©-d): 6 - 7.4(s) 5H, 5.8(d) 1H, 5.2(d) 1H, 5.1(s) 1H, 4.2( s) 2K, 4.0(3) 3H and 3.6(s) 2H.
Eksempel 46Example 46
De følgende ingredienser blandes sammen i de angitte vekt-mengder. The following ingredients are mixed together in the specified amounts by weight.
Efter at man har oppnådd god blanding fremstilles After a good mixture has been achieved, it is prepared
tabletter av blandingen og hver tablett er av en slik størrelse at den inneholder 100 mg av cefemforbindelsen. tablets of the mixture and each tablet is of such a size as to contain 100 mg of the cephem compound.
Det fremstilles også tabletter som inneholder henholdsvis 50 og 250 mg av den virksomme bestanddel, ved å velge passende mengder av cefemforbindelsen og eksipientblandingen i hvert tilfelle . Tablets containing respectively 50 and 250 mg of the active ingredient are also prepared, by selecting appropriate amounts of the cephem compound and the excipient mixture in each case.
Eksempel 47Example 47
De følgende ingredienser blandes sammen 1 de angitte vekt-mengder. The following ingredients are mixed together in the indicated amounts by weight.
Den godt blandede farmasøytiske blanding fylles i bløte gelatinkapsler, slik at hver kapsftft inneholder 100 mg av virksom bestanddel. The well-mixed pharmaceutical mixture is filled into soft gelatin capsules, so that each capsule contains 100 mg of active ingredient.
Det fremstilles også kapsler som inneholder henholdsvisCapsules containing respectively are also produced
50 og 250 mg av virksom bestanddel ved å variere mengden av cefemforbindelsen og eksipientblandingen. 50 and 250 mg of active ingredient by varying the amount of the cephem compound and the excipient mixture.
Eksempel 48Example 48
Natriumsaltet av 7-(2-tienylacetamido)-3-metyl-4-(tetrazol-5-yl)-A -cefem blandes godt og males med natriumcitrat (4 vekt%). Den malte, tørre blandingen steriliseres og pakkes i sterile, The sodium salt of 7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-A-cephem is mixed well and ground with sodium citrate (4% by weight). The ground, dry mixture is sterilized and packaged in sterile,
små medisinglass, som lukkes igjen med serumkapsler under sterile betingelser* Når dette preparatet skal anvendes injiseres tilstrekkelig sterilt vann ned i de små medisinglassene for å opp-løse innholdet, og man får en løsning som inneholder 25 mg/ml av virksom bestanddel. For parénteral anvendelse trekkes løsningen ut av de små medisinglassene ved å anvende en sprøyte. small medicinal vials, which are sealed with serum capsules under sterile conditions* When this preparation is to be used, sufficient sterile water is injected into the small medicinal vials to dissolve the contents, and a solution containing 25 mg/ml of active ingredient is obtained. For parenteral use, the solution is withdrawn from the small medicinal vials using a syringe.
På lignende måte ved å variere mengden av tilsatt vann får man henholdsvis løsninger som inneholder 10, 50, 100 og 200 mg/ml av virksom bestanddel. Eksempel 49 7-[D-(a-amino-a-fenyl)acetamido]-3-metyl-4-(tetrazol-5-yl)-A<3->cefem- kaliumsalt In a similar way, by varying the amount of added water, solutions containing 10, 50, 100 and 200 mg/ml of active ingredient are obtained respectively. Example 49 7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-α<3->cephem potassium salt
Til en omrørt løsning av 1,94 g 7-[D-(a-amino-a-fenyl)-acetamido]-3-metyl-4-(tetrazol-5-yl)-A 3-cefem i 100 ml metanol, avkjølt til -30°C, tilsettes dråpevis tilstrekkelig 1,0N løsning av kallumhydroksyd i metanol slik at det tilsettes 1 ekvivalent av base. Blandingen får lov til å oppvarmes til 0°C og tilsettes derefter dråpevis under omrøring til 700 ml eter. Det faste stoffet som utfelles fjernes ved filtrering og tørkes under høy-vakuum. Dette gir kaliumsaltet av sluttproduktet i godt utbytte. To a stirred solution of 1.94 g of 7-[D-(a-amino-a-phenyl)-acetamido]-3-methyl-4-(tetrazol-5-yl)-A 3-cephem in 100 ml of methanol, cooled to -30°C, a sufficient 1.0N solution of potassium hydroxide in methanol is added dropwise so that 1 equivalent of base is added. The mixture is allowed to warm to 0°C and is then added dropwise with stirring to 700 ml of ether. The solid that precipitates is removed by filtration and dried under high vacuum. This gives the potassium salt of the final product in good yield.
Når fremgangsmåten ovenfor gjentas, bortsett fra at det anvendte kallumhydroksyd erstattes av en ekvimolar mengde av natriumhydroksyd, er produktet natriumsaltet av 7-[D-(a-amino-a-fenyl)acetamido]-3-mety1-4-(tetrazol-5-yl)-A 3-cefem. When the above procedure is repeated, except that the calcium hydroxide used is replaced by an equimolar amount of sodium hydroxide, the product is the sodium salt of 7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazole-5 -yl)-A 3-cephem.
Eksempel 50 Example 50
7-[D-a-amino-a-(p-hydroksyfenyl)acetamido]-3-metyl-4-(tetrazol-5- yl)- A<3>- cefem- kalslumsalt 7-[D-a-amino-a-(p-hydroxyphenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)- A<3>- cephem- calcium salt
Til en omrørt løsning av 3,87 g 7-[D-a-amino-a-(p-hydroksy-fenyl)acetamido]-3-mety1-4-(tetrazol-5-yl)-A 3-cefem i 40 ml dimetylformamid tilsettes en uklar løsning av 370 mg kalsium-hydroksyd i løpet av 5 minutter. Blandingen oppvarmes ved 35-40°C i 1 time og tilsettes derefter ytterligere 30 ml dimetylformamid. Oppvarmingen ved 35-40°C fortsetter i ytterligere 30 minutter, og deh avkjølte løsningen tilsettes dråpevis til 700 ml eter. Det faller ut en olje. Løsningsmidlet dekanteres fra og til resten tilsettes 100 ml etanol, efterfulgt av 400 ml eter. Oljen størkner langsomt og oppnås derefter ved filtrering og tørkes under høyvakuum. Dette gir kalsiumsaltet av sluttproduktet. To a stirred solution of 3.87 g of 7-[D-a-amino-a-(p-hydroxy-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-A 3-cephem in 40 ml of dimethylformamide a cloudy solution of 370 mg calcium hydroxide is added over the course of 5 minutes. The mixture is heated at 35-40°C for 1 hour and then a further 30 ml of dimethylformamide is added. The heating at 35-40°C is continued for a further 30 minutes, and the cooled solution is added dropwise to 700 ml of ether. An oil falls out. The solvent is decanted from and until the residue is added 100 ml of ethanol, followed by 400 ml of ether. The oil solidifies slowly and is then obtained by filtration and dried under high vacuum. This gives the calcium salt of the final product.
Eksempel 51 7-[D-(a-amino-a-fenyl)acetamido]-3-metyl-4-(tetrazol-5-yl)-A<3->cefem- hydrogenkloridsalt Example 51 7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-α<3->cephem hydrochloride salt
En suspensjon av 50 mg 7-[D-(a-amino-a-fenyl)acetamido]-3-metyl-4-(tetrazol-5-yl)-A 3-cefem i 2 ml deionisert vann omrøres i 5 minutter ved omgivelsestemperatur. pH justeres til 2,45 ved å anvende fortynnet saltsyre og den oppnådde løsningen lyofiliseres umiddelbart. Dette gir hydrogenklorldsaltet av forbindelsen som et hvitt, fast stoff. A suspension of 50 mg of 7-[D-(a-amino-a-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-A 3-cephem in 2 ml of deionized water is stirred for 5 minutes at ambient temperature. The pH is adjusted to 2.45 by using dilute hydrochloric acid and the resulting solution is immediately lyophilized. This gives the hydrogen chloride salt of the compound as a white solid.
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JP6006201B2 (en) * | 2011-04-28 | 2016-10-12 | 塩野義製薬株式会社 | Novel cephem compounds having catechol or pseudo-catechol structure |
CN103619853A (en) | 2011-06-27 | 2014-03-05 | 盐野义制药株式会社 | Cephem compound having pyridinium group |
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1974
- 1974-10-07 SE SE7412602A patent/SE429342B/en unknown
- 1974-10-11 NO NO743667A patent/NO743667L/no unknown
- 1974-10-14 GB GB22872/76A patent/GB1481809A/en not_active Expired
- 1974-10-14 GB GB22873/76A patent/GB1481810A/en not_active Expired
- 1974-10-14 GB GB44350/74A patent/GB1481807A/en not_active Expired
- 1974-10-14 GB GB22871/76A patent/GB1481808A/en not_active Expired
- 1974-10-14 IL IL45849A patent/IL45849A0/en unknown
- 1974-10-14 IE IE2113/74A patent/IE40745B1/en unknown
- 1974-10-15 MW MW41/74A patent/MW4174A1/en unknown
- 1974-10-15 MW MW40/74A patent/MW4074A1/en unknown
- 1974-10-15 ZA ZA00746544A patent/ZA746544B/en unknown
- 1974-10-16 DD DD181737A patent/DD114266A5/xx unknown
- 1974-10-16 ES ES431069A patent/ES431069A1/en not_active Expired
- 1974-10-16 DK DK542174A patent/DK542174A/da not_active Application Discontinuation
- 1974-10-16 CA CA211,504A patent/CA1064019A/en not_active Expired
- 1974-10-16 AR AR256116A patent/AR209283A1/en active
- 1974-10-16 DE DE19742449834 patent/DE2449834A1/en not_active Ceased
- 1974-10-17 LU LU71128A patent/LU71128A1/xx unknown
- 1974-10-17 NL NL7413643A patent/NL7413643A/en not_active Application Discontinuation
- 1974-10-17 PL PL1974174893A patent/PL95747B1/en unknown
- 1974-10-17 FR FR7435015A patent/FR2257298B1/fr not_active Expired
- 1974-10-17 JP JP49118743A patent/JPS50121293A/ja active Pending
- 1974-10-17 BE BE1006235A patent/BE821164A/en unknown
- 1974-10-18 OA OA55326A patent/OA04935A/en unknown
- 1974-11-04 ZM ZM161/74A patent/ZM16174A1/en unknown
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1975
- 1975-08-18 AR AR260031A patent/AR213726A1/en active
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1976
- 1976-08-02 ES ES450399A patent/ES450399A1/en not_active Expired
- 1976-08-02 ES ES450397A patent/ES450397A1/en not_active Expired
- 1976-08-02 ES ES450398A patent/ES450398A1/en not_active Expired
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1977
- 1977-09-23 SE SE7710697A patent/SE7710697L/en not_active Application Discontinuation
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1978
- 1978-06-28 SU SU782377452A patent/SU974936A3/en active
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1982
- 1982-01-20 JP JP57007361A patent/JPS5822480B2/en not_active Expired
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1983
- 1983-01-17 JP JP58005766A patent/JPS58131988A/en active Pending
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