NO862107L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES. - Google Patents
ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES.Info
- Publication number
- NO862107L NO862107L NO862107A NO862107A NO862107L NO 862107 L NO862107 L NO 862107L NO 862107 A NO862107 A NO 862107A NO 862107 A NO862107 A NO 862107A NO 862107 L NO862107 L NO 862107L
- Authority
- NO
- Norway
- Prior art keywords
- thiomethyl
- oxadethia
- cephem
- mixture
- methyltetrazol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 11
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 title 1
- -1 1-methyltetrazol-5-yl Chemical group 0.000 claims description 79
- 150000001875 compounds Chemical class 0.000 claims description 38
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 229940124587 cephalosporin Drugs 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 231
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 225
- 239000000203 mixture Substances 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 123
- 125000005982 diphenylmethyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 103
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 101
- 239000000243 solution Substances 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 58
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 37
- 238000003756 stirring Methods 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 30
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 29
- 238000001816 cooling Methods 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000843 powder Substances 0.000 description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 239000006260 foam Substances 0.000 description 21
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- 150000001408 amides Chemical class 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 9
- 229930186147 Cephalosporin Natural products 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 9
- 150000001780 cephalosporins Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 7
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Natural products CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000005042 acyloxymethyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 125000005633 phthalidyl group Chemical class 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 241000589516 Pseudomonas Species 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 3
- 239000008227 sterile water for injection Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 125000002221 trityl group Chemical class [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- FFRWASKHRZIKNT-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanide Chemical compound ClC(Cl)(Cl)C(=O)[N+]#[C-] FFRWASKHRZIKNT-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- AVBHHECXXFKOHS-UHFFFAOYSA-N 3-benzhydryloxy-3-oxo-2-phenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 AVBHHECXXFKOHS-UHFFFAOYSA-N 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000006178 methyl benzyl group Chemical group 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical class [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av arylmalonamido 1-oksadetiacefalosporiner med den generelle formel The present invention relates to a process for the production of arylmalonamido 1-oxadethiacephalosporins with the general formula
hvori Ar er eller (hvori acyl er organisk eller uorganisk4cyl), COB 1 og COB<2>hver er karboksy eller beskyttet karboksy, wherein Ar is or (where acyl is organic or inorganic4cyl), COB 1 and COB<2> are each carboxy or protected carboxy,
(hvori COB^ er karboksy eller beskyttet karboksy), (where COB^ is carboxy or protected carboxy),
og and
Y er hydrogen eller metoksy,Y is hydrogen or methoxy,
med den betingelse at når Y er metoksy er Het with the proviso that when Y is methoxy, Het
og farmasøytisk tålbare salter derav, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at et amin med den generelle formel hvori COB 2, Het og Y har den- ovennevnte betydning, omsettes med en arylmalonsyre med den generelle formel hvori Ar og COB 1 har den ovennevnte betydning, eller reaktive derivater derav, eller for fremstilling av en forbindelse med den generelle formel hvori COB 1 , COB 2, Het og Y har den ovennevnte betydning, fjernes den beskyttende gruppe i Ar' i en forbindelse med formel and pharmaceutically acceptable salts thereof, and the distinctive feature of the method according to the invention is that an amine with the general formula in which COB 2 , Het and Y have the above meaning is reacted with an arylmalonic acid with the general formula in which Ar and COB 1 have the above meaning, or reactive derivatives thereof, or for the preparation of a compound of the general formula in which COB 1 , COB 2 , Het and Y have the above meaning, the protecting group in Ar' is removed in a compound of formula
hvori Ar' er para-beskyttet hydroksyfenyl og wherein Ar' is para-protected hydroxyphenyl and
COB 1 , COB 2, Het og Y har den ovennevnte betydning, men er ikke nbdvendigvis den samme som i utgangsmaterialet, eller for fremstilling av en forbindelse med formel COB 1 , COB 2 , Het and Y have the above meaning, but are not necessarily the same as in the starting material, or for the preparation of a compound of formula
hvori COB 1 , COB 2, Het og Y har den ovennevnte betydning, acyleres en forbindelse med formel wherein COB 1 , COB 2 , Het and Y have the above meaning, a compound of formula is acylated
hvori COB 1 , COB 2, Het og Y har den ovennevnte betydning, med et acylerende reagens for innforing av en acylgruppe, og eventuelt fremstilles farmasøytisk tålbare salter derav på i og for seg kjent måte. in which COB 1 , COB 2 , Het and Y have the above-mentioned meaning, with an acylating reagent for the introduction of an acyl group, and optionally pharmaceutically acceptable salts thereof are prepared in a manner known per se.
Disse trekk ved oppfinnelsen fremgår av patentkravene. These features of the invention appear from the patent claims.
Cefalosporin-analoge med oksygen i stedet for svovelatom i kjernen er beskrevet i Journal of Heterocyclic Chemistry, bind 55Cephalosporin analogues with oxygen instead of sulfur atom in the core are described in Journal of Heterocyclic Chemistry, Volume 55
side 779 (1968) av J.C. Sheehan og M. Dadic; tysk Offenlegungs-schrift nr. 2.219.601 (1972); Canadian Journal of Chemistry, bind 52, side 3996 0 97^0 av Saul Wolfe et al; og Journal of American Chemical Society, bind 96, side 7582 (197<*>+) av B.G. Christensen et al. page 779 (1968) by J.C. Sheehan and M. Dadic; German Offenlegungsschrift No. 2,219,601 (1972); Canadian Journal of Chemistry, Volume 52, Page 3996 0 97^0 by Saul Wolfe et al; and Journal of American Chemical Society, Volume 96, Page 7582 (197<*>+) by B.G. Christensen et al.
Det er nå fremstilt forskjellige 1-oksadetiacefalosporiner som ■ er nær beslektet med kjente (l-tia)cefalosporiner. I motsetning til det som er angitt av B.G. Christensen et air. som antok at racemiske 1 -oksacefalosporiner fremviste omtrent den halve potens av (1-tia)cefalosporiner, var de optisk aktive produkter fremstilt i henhold til oppfinnelsen omtrent<*>f til 8 ganger så aktive som de tilsvarende (1-tia)cefalosporiner med hensyn til antibakterielle egenskaper. Imidlertid var B-laktamringen i 1-oksadetiacefalosporiner mindre stabile enn nodvendig for kliniske legemidler, i motsetning til (1-tia)cefalosporiner. Various 1-oxadethia cephalosporins have now been prepared which are closely related to known (1-thia) cephalosporins. Contrary to what is stated by B.G. Christensen and air. which assumed that racemic 1-oxacephalosporins exhibited approximately half the potency of (1-thia)cephalosporins, the optically active products prepared according to the invention were about <*>f to 8 times as active as the corresponding (1-thia)cephalosporins with regard to antibacterial properties. However, the B-lactam ring in 1-oxadethiacephalosporins was less stable than required for clinical drugs, in contrast to (1-thia)cephalosporins.
Forbindelsene (I) valgt fra 'de optisk aktive forbindelser fremstilt i henhold til oppfinnelsen overvant den nevnte mangel med 1-oksadetiacefalosporiner. The compounds (I) selected from the optically active compounds prepared according to the invention overcame the aforementioned deficiency with 1-oxadethiacephalosporins.
Videre hadde forbindelsene (I) folgende egenskaper i sammenligning med andre 1-oksadetiacefalosporiner: 1) mer potent antibakteriell virkning mot gram-negative bakterier, Furthermore, the compounds (I) had the following properties in comparison with other 1-oxadethiacephalosporins: 1) more potent antibacterial action against gram-negative bacteria,
2) hbyere stabilitet av B-laktamringen,2) higher stability of the B-lactam ring,
3) nærmere minimal inhiberende konsentrasjon mellom bakterieproduserende og ikke-produserende B-laktamase, 3) closer to minimum inhibitory concentration between bacteria-producing and non-producing B-lactamase,
k) mindre avhengighet av inokulum-storrelse,k) less dependence on inoculum size,
5) hoyere effektivitet mot bakterier som er resistente mot andre cefalosporiner, f.eks. enterobacteria, Serratia, indol-positiv proteus, 5) higher effectiveness against bacteria that are resistant to other cephalosporins, e.g. enterobacteria, Serratia, indole-positive proteus,
6) hoyere bidrag av baktericid karakter, og6) higher contributions of a bactericidal nature, and
7) hoyere blodnivå.7) higher blood level.
Ytterligere har forbindelser (I) hvori Y er metoksy folgende overlegne egenskaper: a) bredere antibakterielle spektra (f.eks. 3>6y/ml eller mer overfor pseudomonas sp. anaerobisk bakterie (Bacteroid Furthermore, compounds (I) in which Y is methoxy have the following superior properties: a) wider antibacterial spectra (e.g. 3>6y/ml or more against pseudomonas sp. anaerobic bacteria (Bacteroid
fragilis),fragilis),
b) hoyere potens mot bakterier som frembringer B-laktamase b) higher potency against bacteria that produce B-lactamase
c) hoyere stabilitet i blod, ogc) higher stability in blood, and
d) lavere binding til serumproteiner.d) lower binding to serum proteins.
I formel (I) er foretrukket Ar 3_tienyl, p-hydrøksyfenyl og In formula (I), preferred are Ar 3_thienyl, p-hydroxyphenyl and
p-acyloksyfenyl, hvori acyl er 1-5C alkanoyl, karbamoyl, 2-6C N-alkylkarbamoyl, eller ureinokarbonyl. p-acyloxyphenyl, wherein acyl is 1-5C alkanoyl, carbamoyl, 2-6C N-alkylcarbamoyl, or ureinocarbonyl.
Gruppen acyl i definisjonen av Ar kan være uorganiske eller organiske acylgrupper inneholdende opptil 8 karbonatomer, spesielt 1-5C alkanoyl, 8-12C aralkanoyl, 7-9C-aroyl, 2-5C alkoksykarbonyl, 8-20C aralkoksykarbonyl, karbamoyl, 2-6C N-alkylkarbamoyl, og ureidokarbonyl. The group acyl in the definition of Ar can be inorganic or organic acyl groups containing up to 8 carbon atoms, in particular 1-5C alkanoyl, 8-12C aralkanoyl, 7-9C-aroyl, 2-5C alkoxycarbonyl, 8-20C aralkoxycarbonyl, carbamoyl, 2-6C N -alkylcarbamoyl, and ureidocarbonyl.
Spesifikke eksempler på acylgrupper omfatter formyl, acetyl, propionyl, butyryl, isobutyryl, enantoyl, fenylacetyl, fenyl-propionyl, benzoyl, toluoyl, karbetoksykarbonyl, benzyloksykarbonyl, karbamoyl, N-metylkarbamoyl, N-etylkarbamoyl, N-propylkarbamoyl, N-isobutylkarbamoyl, N,N-dimetylkarbamoyl, karbamoylkarbamoyl, Na<->metylureidokarbonyl og lignende acylgrupper . Specific examples of acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, enantoyl, phenylacetyl, phenyl-propionyl, benzoyl, toluoyl, carbethoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isobutylcarbamoyl, N ,N-dimethylcarbamoyl, carbamoylcarbamoyl, Na<->methylureidocarbonyl and similar acyl groups .
Gruppe COB<1>, COB<2>og COB^ kan være karboksy eller beskyttet karboksy som konvensjonelt innenfor kjemien til penicilliner og cefalosporiner, vanligvis inneholdende opptil 15 karbonatomer. De beskyttende grupper kan være like eller forskjellige for hver karboksygruppe i molekylet. Vanligvis fjernes de beskyttende grupper til å gi fri karboksygrupper eller salter i hvilket som helst trinn av syntesen av forbindelsene (I). Strukturene av de karboksybeskyttende grupper kan derfor variere sterkt uten å endre rammen for oppfinnelsen. Med andre ord kan deres strukturer'alene bestemmes på basis av beskyttelse, fjernelse og eventuelt ved saltdannelse. Group COB<1>, COB<2> and COB^ may be carboxy or protected carboxy as conventional in the chemistry of penicillins and cephalosporins, usually containing up to 15 carbon atoms. The protecting groups can be the same or different for each carboxyl group in the molecule. Generally, the protecting groups are removed to give free carboxy groups or salts in any step of the synthesis of the compounds (I). The structures of the carboxy protecting groups can therefore vary greatly without changing the scope of the invention. In other words, their structural properties can be determined on the basis of protection, removal and possibly by salt formation.
Spesifikke eksempler på de nevnte beskyttende grupper er estere (inklusive eventuelt substituerte alkylestere som f;eks. Specific examples of the protective groups mentioned are esters (including optionally substituted alkyl esters such as
t-butyl, mono-hydroksy-t-butyl, 2,2,2-trikloroetyl, og acyloksy-metylestere; aralkylestere som f.eks. benzyl, p-tolylmetyl, p-nitrobenzyl, p-metoksybenzyl, ftalidyl, difenylmetyl, trityl og fenacylestere; metallestere som f.eks. trimetylsilyl, dimetyl-metoksysilyl, trimetylstannylestere og andre lett fjernbare alifatiske estere; og aromatiske estere som f.eks. fenyl, tolyl, 3,^-dimetylfenyl, og 5-indanylestere, og farmasoytisk tålbare salter (inklusive alkalimetallsalter som f.eks. natrium og kaliumsalter, jordalkalimetallsalter som f.eks. magnesium, kalsium og acyloksykalsiumsalter; og salter med organiske baser som f.eks. prokain, trietylamin og dicykloheksylamin). Hver karboksygruppe i molekylet kan være fri eller beskyttet ved like eller forskjellige grupper. t-butyl, mono-hydroxy-t-butyl, 2,2,2-trichloroethyl, and acyloxymethyl esters; aralkyl esters such as e.g. benzyl, p-tolylmethyl, p-nitrobenzyl, p-methoxybenzyl, phthalidyl, diphenylmethyl, trityl and phenacyl esters; metal esters such as e.g. trimethylsilyl, dimethylmethoxysilyl, trimethylstannyl esters and other readily removable aliphatic esters; and aromatic esters such as phenyl, tolyl, 3,^-dimethylphenyl, and 5-indanyl esters, and pharmaceutically acceptable salts (including alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium, calcium and acyloxycalcium salts; and salts with organic bases such as .eg procaine, triethylamine and dicyclohexylamine). Each carboxy group in the molecule can be free or protected by the same or different groups.
Foretrukket kan COB<1>, COB<2>og COB^ være fritt karboksy ellerPreferably, COB<1>, COB<2> and COB^ can be free carboxy or
dets farmasoytisk tålbare salter. Annen foretrukket COB •i-gruppe er 5-indanyloksykarbonyl, fenoksykarbonyl eller dimetylfenoksy-karbonyl. its pharmaceutically acceptable salts. Other preferred COB•i group is 5-indanyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.
Noen karboksybeskyttende grupper er imidlertid brukbare for å endre karakteren av produktene som legemidler. I slike tilfeller kan de være spesifikke, konvensjonelle, k£nte grupper for vanlige legemidler og disse grupper omfatter folgende farmasoytisk tålbare grupper: ftalidyl, acyloksymetyl, indanyl, fenyl, tolyl, dimetylfenyl og karbetoksymetylestere. However, some carboxy protecting groups are useful for changing the nature of the products as drugs. In such cases, they can be specific, conventional, known groups for common drugs and these groups include the following pharmaceutically tolerable groups: phthalidyl, acyloxymethyl, indanyl, phenyl, tolyl, dimethylphenyl and carbethoxymethyl esters.
Foretrukket er Y metoksy, selv om betydningen hydrogen for Y også er viktig. Preferred is Y methoxy, although the meaning of hydrogen for Y is also important.
Vanligvis tilfores forbindelsene (I) som salter innen human-ell.er veterinær-medisinen. De foretrukne salter er natrium-eller kalium-salter, eller salter med visse organiske baser. De velges fra synspunkter med hensyn til sikkerhet, opplbselighet, stabilitet, etc. Generally, the compounds (I) are administered as salts in human or veterinary medicine. The preferred salts are sodium or potassium salts, or salts with certain organic bases. They are chosen from the viewpoints of security, openability, stability, etc.
Spesifikke eksempler på forbindelser (I) omfatter de folgende: 7(3-/a- (2-tienyl)-a-karboksyacetamidc_7-3- (1-metyltetrazol-5-yD-tiometyl-1 -oksadetia-3-cef em-^f-karboksylsyre, Specific examples of compounds (I) include the following: 7(3-[α-(2-thienyl)-α-carboxyacetamidec_7-3-(1-methyltetrazol-5-yD-thiomethyl-1-oxadethia-3-cef em- ^f-carboxylic acid,
7(3-/a- (2- ti enyl )-a-karboksyåcetamid 07-3- (1-karboksymetyltetra-zol-5-yl) tiometyl-1 -oksadetia-3-cef em-^f-karboksyl syre , 7(3-[a-(2-thienyl)-a-carboxyacetamide 07-3-(1-carboxymethyltetra-zol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,
7(3-Za-(2-tienyl)-a-karboksyacetamidq7-3-(2-metyl-1 ,3, h-tiadiazol-5-yl)tiornetyl-1-oksad etia-3-cefem-V-karboksylsyre, 7(3-Za-(2-thienyl)-α-carboxyacetamide q7-3-(2-methyl-1,3,h-thiadiazol-5-yl)thio-methyl-1-oxad ethia-3-cephem-V-carboxylic acid,
7(3-/a- (3-tienyl)-a-karboksyacetamidq7-3_ (1-metyltetrazol-5-yD-tiomet<y>l- 1-oksadetia-3-cefem-^-karboksylsyre, 7(3-/α-(3-thienyl)-α-carboxyacetamide q7-3_ (1-methyltetrazol-5-yD-thiometh<y>1- 1-oxadethia-3-cephem-^-carboxylic acid,
7(3-^bc- (3- ti enyl) -a-karboksyacetamido7-3_ (1 -karboksymetyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7-(3-^bc-(3-thienyl)-α-carboxyacetamido7-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid,
7P-/JX- (3-tienyl)-a-karboksyacetamido7-3- (2-me ty 1-1 ,3 ,1+-tiadiazol-5-yl) tiometyl- 1 -oksadetia-3-cefem-^-karboksylsyre, 7P-(3-thienyl)-α-carboxyacetamido7-3-(2-methyl-1,3,1+-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid ,
7P-(a-fenyl-a-karboksyacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1 -oksad et ii a-3-cefem-^-karboksylsyre, 7P-(α-phenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad et ii α-3-cephem-^-carboxylic acid,
7(3- (a-f enyl-a-karboksyacetamido)-3- (1-karboksymetyltetrazol-5-yl) tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7-(3-(α-phenyl-α-carboxyacetamido)-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7(3- (a-f enyl-a-karboksyacetamido)-3- (2-metyl-1 ,3 ,^f-tiadiazol-5-yl)tiometyl-1-oksadetia-3~cefem-^—karboksylsyre, 7-(3-(α-phenyl-α-carboxyacetamido)-3-(2-methyl-1,3,β-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid,
7(3- (a-p-hydroksyf enyl-a-karboksyacetamido)-3- (1 -metyltetrazol-5-yl) tiometyl-1 -oksade tia-3-cef em->+-karboksylsyre, 7-(3-(α-β-Hydroxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxade thia-3-cef em->+-carboxylic acid,
7P-(a-p-hydroksyfenyl-a-karboksyacetamido)-3-(1-karboksymetyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-β-hydroxyphenyl-α-carboxyacetamido)-3-(1-carboxymethyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-(a-p-hydroksyfenyl-a-karboksyacetamido)-3-(2-metyl-1,3,<*>*-tiadiazol-5-yl)tiometyl-1-oksadetia-3-cef em- k-karboksylsyre, 7P-(α-β-hydroxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3,<*>*-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cef em-k-carboxylic acid,
7P-(<x-p-acetoksyfenyl-oc-karboksyacetamido)-3-(1-metyltetrazol-5-yl} tiometyl-1-oksadetia-3-cefem-lt-karboksylsyre, 7P-(<x-p-acetoxyphenyl-oc-carboxyacetamido)-3-(1-methyltetrazol-5-yl}thiomethyl-1-oxadethia-3-cephem-lt-carboxylic acid,
7P-(a-p-acetoksyfenyl-a-karboksyacetamido)-3-(.1-karboksymetyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-β-acetoxyphenyl-α-carboxyacetamido)-3-(.1-carboxymethyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-(a-p-acetoksyfenyl-a-karboksyacetamido)-3-(2-metyl-1,3 tiadiazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-β-acetoxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3 thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-(a-p-propionyloksyfenyl-a-karboksyacetamido)-3-(1-metyltetrazol-5-yDtiomet<y>l-1-oksadetia-3-cefem-lf-karboksylsyre, ,
7p-(a-p-pentanoyloksyfenyl-a-karboksyacetamido)-3-(2-metyl-1 ,3,W-tiadiazol-5-yl)tiometyl-1-oksadetia-3-cefem-lf-kar boksylsyre, 7p-(a-p-pentanoyloxyphenyl-a-carboxyacetamido)-3-(2-methyl-1,3,N-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylic acid,
7P-(a-karbamoyloksyfenyl-a-karboksyacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-carbamoyloxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-(oc-p-N-metylkarbamoyloksyfenyl-a-karboksyacetamido)-3- (1-metyltetrazol-5-yl) tiometyl- 1-oksadetia- 3- cef em- h-karboksylsyre, 7P-(oc-p-N-methylcarbamoyloxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl- 1-oxadethia- 3- cef em-h-carboxylic acid,
7P-(a-p-N-pentylkarbamoyloksyfenyl-a-karboksyacetamido)-3-(2-metyl-1 ,3, ^f-tiadiazol-5-yl) tiometyl- 1-oksadetia- 3-cefem-l+-karboksylsyre, 7P-(α-p-N-pentylcarbamoyloxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3,β-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid,
7P-(a-p-ureidokarbonyloksyfenyl-a-karboksyacetamido)-3-(1-metyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-p-ureidocarbonyloxyphenyl-α-carboxyacetamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-^a-(2-tienyl)-a-karboksyacetamido7-7a-metoksy-3-(1-metyltetra-zol-5-yl) tiometyl-1-oksadetia-3-cefem-^f-karboksylsyre, 7β-α-(2-thienyl)-α-carboxyacetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylic acid,
7P-Z«-(3-tienyl)-a-karboksyacetamido7-7a-metoksy-3-(1-metyl-tetrazol-5-yl) tiometyl-1-oksadetia-3-cef em-lf-karboksylsyre, 7P-Z«-(3-thienyl)-a-carboxyacetamido7-7a-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-1f-carboxylic acid,
7P-(a-fenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cef em-lf-karboksylsyre, 7P-(α-phenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,
7P- (*a-p-hydroksyf enyl-a-karboksyace tamido)-7a-metoksy-3- (1-metyltetrazol-5-yl) tiometyl-1-oksadetia-3-cef em-lf-karboksylsyre, 7P- (*α-β-hydroxyenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,
7P-(a-p-acetoksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-me tylte trazol-5-yl) tiometyl-1-oksadetia-3-cef em-lf-karboksylsyre, - -
7P-((3e-p^)ropionyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl) tiometyl-1-oksadetia-3-cef em-^f-kar boksylsyre, 7P-((3e-p^)ropionyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,
7P-(a-p-benzoyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-me tylte trazol-5-yl) tiometyl-1-oksadetia-3-cefem-l+-karboksylsyre, 7β-(α-β-benzoyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid,
7P-(a-p-karbamoyloksygenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl) tiometyl-1-oksadetia-3-cefem-^f-karboksylsyre, 7β-(α-β-carbamoyloxygenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-β-carboxylic acid,
7P-(a-p-N-metylkarbamoyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metylte trazol-5-yl) tiometyl-1-oksadetia-3-cef em-lf-karboksylsyre, 7P-(α-β-N-methylcarbamoyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,
7P-(a-p-N-propylkarbamoyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3- (1-me tyltetrazol-5-yl) tiometyl-1-oksadetia-3-cef em-^f-karboksylsyre, 7P-(a-p-N-propylcarbamoyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,
7P-(a-p-ureidokarbonyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre, 7P-(α-p-ureidocarbonyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,
7P-(a-p-Na<->metylureidokarbonyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl- 1-oksadetia-3-cef em- h-karboksylsyre, 7P-(a-p-Na<->methylureidocarbonyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl- 1-oxadethia-3-cef em-h-carboxylic acid,
og deres derivater beskyttet ved karboksygruppen med farmasoytisk tålbare grupper eller konvensjonelle beskyttende grupper i form salter (salter med uorganiske eller organiske baser som f.eks. natrium, kalsium, magnesium, kalium, og andre alkalimetall- eller jordalkalimetall-salter, trietylamin, dicykloheksylamin , morfolin eller N-metylmorfolinsalter) estere som f.eks. t-butyl, t-amyl, 2,2,2-trikloretyl, acyloksymetyl, ftalidyl, difenylmetyl, trityl, benzyl, p-nitrofenyl, p-metoksybenzyl, fenazyl, fenyl eller indanyl-estere og lignende grupper. and their derivatives protected at the carboxy group with pharmaceutically acceptable groups or conventional protecting groups in the form of salts (salts with inorganic or organic bases such as sodium, calcium, magnesium, potassium, and other alkali metal or alkaline earth metal salts, triethylamine, dicyclohexylamine, morpholine or N-methylmorpholine salts) esters such as e.g. t-butyl, t-amyl, 2,2,2-trichloroethyl, acyloxymethyl, phthalidyl, diphenylmethyl, trityl, benzyl, p-nitrophenyl, p-methoxybenzyl, phenazyl, phenyl or indanyl esters and similar groups.
Forbindelser (I) med 1 -metyltetrazol-5-yltiometyl i 3-stillingen er de sterkeste antibakterielle forbindelser overfor gram-negative bakterier forbundet med mindre tap av aktivitet ved hoyere inokulum-storrelse. Compounds (I) with 1-methyltetrazol-5-ylthiomethyl in the 3-position are the strongest antibacterial compounds against gram-negative bacteria associated with less loss of activity at higher inoculum size.
Forbindelser (I) med 1-karboksymetyltetrazol-5-yltiometyl ved 3-stillingen viser sterkere anti-infeksjonsvirkning in vivo enn ventet fra in vitro data, på grunn av deres evne til å oppnå et hoyt blodnivå. Compounds (I) with 1-carboxymethyltetrazol-5-ylthiomethyl at the 3-position show stronger anti-infective activity in vivo than expected from in vitro data, due to their ability to achieve a high blood level.
Forbindelser (I) med fenylmalonamido, (2-tienyl)malonamido, eller (3-tienyl)malonamido i 7-stillingen viser kraftig anti-bakteriell virkning spesielt mot gram-negative bakterier. Compounds (I) with phenylmalonamido, (2-thienyl)malonamido, or (3-thienyl)malonamido in the 7-position show strong anti-bacterial action especially against gram-negative bacteria.
Forbindelser (I) med p-hydroksyfenylmalonamido, p-acetoksyfenyl-malonamido, p-karbamoyloksyfenylmalonamido, p-N-metylkarbamoyl-oksyfenylmalonamido, eller p-ureidokarbonyloksyfenylmalonamido ved 7-stillingen er kraftige anti-bakterielle midler som blir mindre deaktivert på grunn av deres lavere proteinbinding og deres hoyere blodnivå enn for de tilsvarende usubstituerte arylmalonamido-forbindelser. De viser også sterkt intensivert virkning mot pseudomonas-stammer omfattende dem som er resistente overfor karbenicillin. Compounds (I) with p-hydroxyphenylmalonamido, p-acetoxyphenylmalonamido, p-carbamoyloxyphenylmalonamido, p-N-methylcarbamoyloxyphenylmalonamido, or p-ureidocarbonyloxyphenylmalonamido at the 7-position are potent antibacterial agents that are less deactivated due to their lower protein binding and their higher blood levels than for the corresponding unsubstituted arylmalonamido compounds. They also show greatly intensified activity against pseudomonas strains including those resistant to carbenicillin.
Forbindelsene (I) med metoksy for Y i 7a-stillingen er mer stabile mot B-laktamase, mer generelt effektive (f.eks. forbedret aktivitet mot pseudomonas-bakterier og andre gram-negative bakterier), og mer potent enn forbindelser med hydrogen for Y. The compounds (I) with methoxy for Y in the 7a position are more stable against B-lactamase, more generally effective (e.g., improved activity against pseudomonas bacteria and other gram-negative bacteria), and more potent than compounds with hydrogen for Y.
Alle forbindelser (I) er nye forbindelser som viser kraftig anti-bakteriell virkning mot gram-positive og gram-negative bakterier og er nyttige medisiner, veteinær-medisiner og desinfeksjonsmidler. F.eks. gis de konvensjonelt oralt eller pareriteralt til mennesker eller dyr i daglig dose på f.eks. 0,05 til 50 mg/kg kroppsvekt for behandling eller forhindring av bakterie-infeks joner. All compounds (I) are new compounds that show strong anti-bacterial activity against gram-positive and gram-negative bacteria and are useful medicines, veterinary medicines and disinfectants. E.g. are they conventionally given orally or parenterally to humans or animals in a daily dose of e.g. 0.05 to 50 mg/kg body weight for the treatment or prevention of bacterial infections.
Forbindelsene (I) tilfores vanligvis som kapsler som inneholder steriliserte mikrokrystaller eller frysetdrket produkt og tilfores som opplosninger fremstilt for tilfbrsel. Videre kan en effektiv mengde av forbindelsene konvensjonelt tilfores oralt eller parenteralt med farmasoytisk tålbare bæreradditiver, fortynningsmidler, eller stabiliseringsmidler, i form av preparater som f.eks. kapsler, injiserbare losninger, salver, opplosninger, tabletter, pulvere etc. De kan ha form av enhets-doser. Saltene omfattende alkalimetallsaltene anvendes hovedsakelig for parenteral tilfbrsel. Acyloksymetyl, indanyl, fenyl, ftalidyl o.l. estere er også egnet for oral tilfbrsel. Videre er forbindelsene (I) også ved omdannelse nyttige for fremstilling av andre forbindelser med formel (I). The compounds (I) are usually administered as capsules containing sterilized microcrystals or freeze-dried product and administered as solutions prepared for administration. Furthermore, an effective amount of the compounds can be conventionally administered orally or parenterally with pharmaceutically acceptable carrier additives, diluents or stabilizers, in the form of preparations such as e.g. capsules, injectable solutions, ointments, solutions, tablets, powders etc. They can take the form of unit doses. The salts including the alkali metal salts are mainly used for parenteral administration. Acyloxymethyl, indanyl, phenyl, phthalidyl, etc. esters are also suitable for oral administration. Furthermore, the compounds (I) are also useful for the preparation of other compounds of formula (I) by conversion.
Forbindelsene (I) fremstilles f.eks. ved å behandle et amin (II) med en arylmalonsyre (III) eller reaktive derivater derav, The compounds (I) are prepared, e.g. by treating an amine (II) with an arylmalonic acid (III) or reactive derivatives thereof,
med henhv. strukturformlerwith respective structural formulas
hvori- Ar, COB 1 , COB 2, Het og Y har den tidligere angitte betydning. in which Ar, COB 1 , COB 2, Het and Y have the previously indicated meaning.
Amino i 7-stillingen av aminet (II) kan aktiveres med silyl-eller stannyl-grupper, eller beskyttes eller aktiveres med 1-haloalkylidin, 1-alkoksyalkyliden, alkylen, karbonyl, lett fjernbart acyl o.l. grupper for acyleringen. Fjernelse av disse grupper gir de onskede forbindelser med formel (I). Amino in the 7-position of the amine (II) can be activated with silyl or stannyl groups, or protected or activated with 1-haloalkylidine, 1-alkoxyalkylidene, alkylene, carbonyl, easily removable acyl, etc. groups for the acylation. Removal of these groups gives the desired compounds of formula (I).
Når iarylmalonsyre (III) anvendes som fri syre gjennomføres acyleringen i et løsningsmiddel,(spesielt nitriler, etere, amider og halogenerte hydrokarboner som løsningsmiddel eller blandinger derav) i nærvær av et kondenserende middel som f.eks. N,N'-dialkylkarbodiimider som N,N'-dicykloheksylkarbodiimid, karbonylforbindelser som f.eks. karbonyldiimidazol, acylaminer som f.eks. 2-etoksy-1-etoksykarbonyl-1,2-dihydrokinolin, isoksazoliniumsalter som N-etyl-5-fenylisoksazolium-3-sulfonat, N-t-butyl-5-metylisoksazoliumperklorat, og andre kondensasjonsmidler ved temperatur mellom -10°C og 70°C. When arylmalonic acid (III) is used as free acid, the acylation is carried out in a solvent, (especially nitriles, ethers, amides and halogenated hydrocarbons as solvent or mixtures thereof) in the presence of a condensing agent such as e.g. N,N'-dialkylcarbodiimides such as N,N'-dicyclohexylcarbodiimide, carbonyl compounds such as e.g. carbonyldiimidazole, acylamines such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, isoxazolinium salts such as N-ethyl-5-phenylisoxazolium-3-sulfonate, N-t-butyl-5-methylisoxazolium perchlorate, and other condensing agents at temperatures between -10°C and 70°C .
Når arylmalonsyre (III) anvendes i form av reaktive derivater for acyleringen, kan dette være anhydrider som blandede anhydrider med alkylkarbonsyre, aralkylkarbonsyre, hydrohalogen-syrer, hydrogenazid, fosforsyre, fosforsyrling, svovelsyre, When arylmalonic acid (III) is used in the form of reactive derivatives for the acylation, these can be anhydrides such as mixed anhydrides with alkylcarboxylic acid, aralkylcarboxylic acid, hydrohalic acids, hydrogen azide, phosphoric acid, phosphoric acid, sulfuric acid,
svovelsyrling, hydrogencyanid, symmetriske intermolekylære anhydrider, blandede anhydrider med alifatiske eller aromatiske sulfon- eller karboksyl-syrer, spesielle intramolekylære anhydrider som keten, isocyanat o.l. reaktive anhydrider, reaktive estere som f.eks. enolester, arylestere som f.eks. pentaklorofenyl, p-nitrofenyl, 2 ,^-dinitrofenyl, benzotriazol-estere, diacyliminoestere, reaktive amider, f.eks. amider med imidazol eller triazol, reaktive amider som 2-etoksy-1,2-dihydrokinolin- 1 -amid , og f or/raiminoderivater som f.eks. N,N-dialkyliminometylestere, N,N-diacylaniliner. sulfuric acid, hydrogen cyanide, symmetrical intermolecular anhydrides, mixed anhydrides with aliphatic or aromatic sulphonic or carboxylic acids, special intramolecular anhydrides such as ketene, isocyanate etc. reactive anhydrides, reactive esters such as e.g. enol esters, aryl esters such as pentachlorophenyl, p-nitrophenyl, 2,^-dinitrophenyl, benzotriazole esters, diacyliminoesters, reactive amides, e.g. amides with imidazole or triazole, reactive amides such as 2-ethoxy-1,2-dihydroquinolin-1-amide, and f or/raimino derivatives such as e.g. N,N-dialkyliminomethyl esters, N,N-diacylanilines.
Om nodvendig kan disse acyleringsmidler anvendes i nærvær av en syreresgptor som f.eks. uorganiske baser som hydroksyder, karbonater eller bikarbonater av alkalimetaller eller jordalkali-metaller, organiske baser som f.eks. tertiære aminer, aromatiske baser, alkylenoksydet som f.eks. etylenoksyd, propylenoksyd, amider som f.eks. N,N-dimetylformamid, heksametylfosfortriaraid, og andre syrereseptorer, eller molekylsikter, foretrukket i et løsningsmiddel, spesielt keton, ester, eter, nitril, amid, halogenerte hydrokarbonlosningsmidler, eller blandinger derav. If necessary, these acylating agents can be used in the presence of an acid receptor such as e.g. inorganic bases such as hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, organic bases such as e.g. tertiary amines, aromatic bases, the alkylene oxide such as ethylene oxide, propylene oxide, amides such as N,N-dimethylformamide, hexamethylphosphorus triamide, and other acid receptors, or molecular sieves, preferably in a solvent, especially ketone, ester, ether, nitrile, amide, halogenated hydrocarbon solvents, or mixtures thereof.
Alternativt kan forbindelsene (I) fremstilles fra de tilsvarende azetidinoner med åpen ring ved ringslutning f.eks. ved hjelp av en Wittig-reaksjon. F.eks. oppvarmes azetidinonet (IV) i et inert lbsningsmiddel som eter, aromatisk hydrokarbon, halogenert hydrokarbon, amid, sulfoksyd og anhydrid-lbsningsmidler til å Alternatively, the compounds (I) can be prepared from the corresponding azetidinones with an open ring by ring closure, e.g. using a Wittig reaction. E.g. the azetidinone (IV) is heated in an inert solvent such as ether, aromatic hydrocarbon, halogenated hydrocarbon, amide, sulfoxide and anhydride solvents to
gi forbindelsen (I) med hoyt utbytte.give the compound (I) in high yield.
hvori Ar, COB 1 , COB 2, Het, og Y har den ovennevnte betydning, wherein Ar, COB 1 , COB 2 , Het, and Y have the above meaning,
og hver av de tre R er like eller forskjellige, med eventuelt substituert alkyl eller aryl. and each of the three R's are the same or different, with optionally substituted alkyl or aryl.
Når Ar er p-hydroksyfenyl kan forbindelsen (I) behandles med et uorganisk eller organisk acyleringsmiddel til å gi forbindelser (I) hvori Ar er acyloksyfenyl. Acyleringsmidlet og reaksjons-betingelsene er konvensjonelle. When Ar is p-hydroxyphenyl, the compound (I) can be treated with an inorganic or organic acylating agent to give compounds (I) in which Ar is acyloxyphenyl. The acylating agent and reaction conditions are conventional.
Når Ar er p-hydroksyfenyl kan forbindelsene forst beskyttes ved hydroksygruppen med en lett fjernbar beskyttende gruppe og deretter fjernes den beskyttende gruppe til å gi de bnskede hydroksyfenylforbindelser. Representative beskyttende grupper kan være grupper som danner estere, inklusive C-j-C^ a-halo-alkanoyl som trifluoroacetyl, trikloroacetyl, C-|-Cg alkanoyl som acetyl, formyl, C^-Cg 3-ketokarboksyl-acyl som acetoacetyl, C2~C12alkoicsykarbonyl som t-butoksykarbonyl, cyklopropylmetoksy-karbonyl, norbornyloksykarbonyl, 2,2,2-trikloroetoksykarbonyl, C8~C15aralkoksykarbonyl som benzyloksykarbonyl, p-metoksybenzyl-oksykarbonyl, p-nitro- eller p-metylbenzoyloksykarbonyl, difenylmetoksykarbonyl o.l. acylgrupper, og etere inklusive C^-Cg alkyl som metyl, t-butyl, cyklopropylmetyl, isobornyl, tetrahydropyranyl, metoksymetyl, C^-C^ aralkyl som benzyl, p-metoksy, p-metyl eller p-nitrobenzyl, difenylmetyl, trietyl, When Ar is p-hydroxyphenyl, the compounds can first be protected at the hydroxy group with an easily removable protecting group and then the protecting group is removed to give the desired hydroxyphenyl compounds. Representative protecting groups may be groups that form esters, including C-j-C^ a-halo-alkanoyl such as trifluoroacetyl, trichloroacetyl, C-|-Cg alkanoyl such as acetyl, formyl, C^-Cg 3-ketocarboxyl-acyl such as acetoacetyl, C2~C12alkoicsycarbonyl such as t-butoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, C8~C15aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro- or p-methylbenzoyloxycarbonyl, diphenylmethoxycarbonyl and the like. acyl groups, and ethers including C^-Cg alkyl such as methyl, t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl, C^-C^ aralkyl such as benzyl, p-methoxy, p-methyl or p-nitrobenzyl, diphenylmethyl, triethyl,
og ljgnende grupper. Den beskyttende gruppe kan foretrukket innfores ved trinnet for arylmalonsyre (III) eller reaktive derivater derav. Fjernelsen av den beskyttende gruppe gjennom-føres ved f.eks. 1) spalting av acylater eller etere med en syre f.eks. mineralsyre, Lewis-syre, sterk karboksylsyre, sulfonsyre, eller base. som natrium-kalium-karbonat, hydroksyd, organisk base ved romtemperatur eller forhbyet temperatur om dette er nbdvendig i nærvær av en kationfjerner, eller 2) hydrogenering av p-nitrobenzyloksykarbonyl eller benzyloksykarbonyl med hydrogen eller platina eller palladium på konvensjonell måte. Når karboksy i and lying groups. The protecting group can preferably be introduced at the step for arylmalonic acid (III) or reactive derivatives thereof. The removal of the protective group is carried out by e.g. 1) cleavage of acylates or ethers with an acid, e.g. mineral acid, Lewis acid, strong carboxylic acid, sulphonic acid, or base. such as sodium potassium carbonate, hydroxide, organic base at room temperature or elevated temperature if necessary in the presence of a cation scavenger, or 2) hydrogenation of p-nitrobenzyloxycarbonyl or benzyloxycarbonyl with hydrogen or platinum or palladium in a conventional manner. When carboxy i
Når karboksy i k- stillingen eller i sidekjeden i 7-stillingen eller Het beskyttes, kan den beskyttende gruppe fjernes til å gi de bnskede forbindelser (I) på konvensjonelle måter for fjernelse av de beskyttende grupper. F.eks. blir 1) sterkt reaktive estere, amider og anhydrider lett hydrolysert med en syre eller bas'e, eller 2) haloetyl, benzyl, metylbenzyl, nitrobenzyl og diarylmetyl-estere blir spaltet ved mild reduksjon med f.eks. tinn, zink, eller 2-verdige kromsalter i nærvær av syrer, natriumditionit, katalytisk hydrogenering med hydrogen over katalysatorer som platina, palladium, nikkel, eller 3) benzyl, metoksybenzyl, metylbenzyl, dimetoksybenzyl, t-alkyl, trityl, diarylmetyl og cyklopropylmetylestere blir spaltet ved innvirkning av syrer eller ved solvolyse som f.eks. med mineralsyrer som saltsyre, Lewis-syre som aluminiumklorid, sulfonsyre som f.eks. toluen-p-sulfonsyre, sterkt sure karboksylsyrer som f.eks. trifluoreddiksyre, maursyre, om nbdvendig i nærvær av en kation-akseptor som amizol, eller h) fenacyl, etynyl, p-hydroksy-3,5-di-t-butylbenzylestere blir spaltet ved innvirkning av base som alkalimetalltiofenoksyder, uorganiske baser, basiske salter o.l. metoder. When the carboxy in the k-position or in the side chain in the 7-position or Het is protected, the protecting group can be removed to give the desired compounds (I) by conventional means for removing the protecting groups. E.g. are 1) highly reactive esters, amides and anhydrides easily hydrolysed with an acid or base, or 2) haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters are cleaved by mild reduction with e.g. tin, zinc, or 2-valent chromium salts in the presence of acids, sodium dithionite, catalytic hydrogenation with hydrogen over catalysts such as platinum, palladium, nickel, or 3) benzyl, methoxybenzyl, methylbenzyl, dimethoxybenzyl, t-alkyl, trityl, diarylmethyl and cyclopropylmethyl esters are split by the action of acids or by solvolysis such as e.g. with mineral acids such as hydrochloric acid, Lewis acid such as aluminum chloride, sulphonic acid such as e.g. toluene-p-sulfonic acid, strongly acidic carboxylic acids such as e.g. trifluoroacetic acid, formic acid, if necessary in the presence of a cation acceptor such as amizol, or h) phenacyl, ethynyl, p-hydroxy-3,5-di-t-butylbenzyl esters are decomposed by the action of bases such as alkali metal thiophenoxides, inorganic bases, basic salts beer. methods.
Forbindelsen (I) med en eller flere fri karboksygrupper kan omdann.es til tilsvarende derivater ved karboksygruppen ved innfbring av beskyttende grupper^eller substituenter, ved konvensjonelle metoder (f.eks. -és^stere ved innvirkning av tilsvarende alkoholer med de nevnte kondensasjonsmidler, diazoforbindelser, halof ormiater , etc, og f^Fsalter ved 1 innvirkning av alkalimetallhydroksydet, karbonater, eller alkanoatsalter, eller innvirkning av organiske baser, ioneveksler-harpikser, etc. The compound (I) with one or more free carboxy groups can be converted into corresponding derivatives at the carboxy group by introducing protective groups or substituents, by conventional methods (e.g. -esters by reaction of corresponding alcohols with the aforementioned condensation agents, diazo compounds, halophormates, etc, and f^F salts by the action of the alkali metal hydroxide, carbonates, or alkanoate salts, or the action of organic bases, ion exchange resins, etc.
De fblgende eksempler gis for å illustrere oppfinnelsen. Elementæranalyse og fysikalske konstanter for produktene i hvert eksempel er i samsvar med den gitte struktur. I de fblgende eksempler inneholder produktene vanligvis en nesten lik mengde av isomerer ved det oc-assymetriske karbon i amid-sidekjeden. The following examples are given to illustrate the invention. Elemental analysis and physical constants of the products in each example are consistent with the given structure. In the following examples, the products usually contain an almost equal amount of isomers at the α-asymmetric carbon in the amide side chain.
Begge isomerer er inkludert innenfor oppfinnelsens ramme og kanBoth isomers are included within the scope of the invention and can
orn bnskes separeres med vanlig kjent kromatografisk teknikk eller andre konvensjonelle metoder. Nomenklaturen i beskrivelsen er i samsvar med den som er beskrevet i en japansk patentansbkning som er gjort alminnelige tilgjengelig, nemlig nr. l+9-1359l+ orn must be separated using commonly known chromatographic techniques or other conventional methods. The nomenclature in the description is in accordance with that described in a Japanese patent application which has been made generally available, namely No. 1+9-1359l+
ingitt av Merck Inc., USA.submitted by Merck Inc., USA.
Fremstilling 1: (Fremstilling av 7a-amino-forbindelser)Preparation 1: (Preparation of 7α-amino compounds)
(1) Til en lbsning av difenylmetyl 7P-fenylacetamido-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (1) To a solution of diphenylmethyl 7P-phenylacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate
(955 mg) i metylenklorid (21+ ml) tilsettes fosforpentaklorid (666 mg) og pyridin (0,258 ml) under nitrogengass ved -20°C. (955 mg) in methylene chloride (21+ ml) is added phosphorus pentachloride (666 mg) and pyridine (0.258 ml) under nitrogen gas at -20°C.
Etter omrbring ved -20°C i 30 min. og ved romtemperatur i 30 min. blandes blandingen med metanol (12 ml) ved -20°C og omrbres ved romtemperatur i 30 min. Reaksjonsblandingen fortynnes med vann After incubating at -20°C for 30 min. and at room temperature for 30 min. the mixture is mixed with methanol (12 ml) at -20°C and stirred at room temperature for 30 min. The reaction mixture is diluted with water
(6 ml) omrbres i 30 min. og konsentreres under redusert trykk. Resten opplbses i 3% vandig lbsning av natriumhydrogenkarbonat under isavkjbling og ekstraheres med etylacetat. Ekstrakten vaskes med vann, tbrkes over natriumsulfat og konsentreres under redusert trykk. De separerte krystaller samles ved filtrering og vaskes med eter til å gi difenylmetyl 7(3-amino-3- (1 -metyltetrazol- (6 ml) is stirred for 30 min. and concentrated under reduced pressure. The residue is dissolved in a 3% aqueous solution of sodium bicarbonate under ice cooling and extracted with ethyl acetate. The extract is washed with water, washed over sodium sulphate and concentrated under reduced pressure. The separated crystals are collected by filtration and washed with ether to give diphenylmethyl 7(3-amino-3-(1-methyltetrazol-
5-yl)tiometyl-1-oksadetia-3-cefem-lf-karboksylat (661 mg).5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (661 mg).
Smp. 151 - 156°C. Utbytte: 86,5$.Temp. 151 - 156°C. Dividend: 86.5$.
IR: v<CH>C133^<2>0, 33^5, 1790, 1718, 1630 cm"<1>, IR: v<CH>C133^<2>0, 33^5, 1790, 1718, 1630 cm"<1>,
maks.max.
NMR: CDC131.75<b>rs2H, 3.8ls3H, lf.28brs2H, h. 50d (U-Hz) 1H, NMR: CDC131.75<b>rs2H, 3.8ls3H, lf.28brs2H, h. 50d (U-Hz) 1H,
*+.6^brs2H, k. 98d (ifHz) 1H, 6.90s1H, 7.20 - 7.70m10H. *+.6^brs2H, k. 98d (ifHz) 1H, 6.90s1H, 7.20 - 7.70m10H.
(CHjoS000 <^nUV: >mak^2 286 nm (£=8695). /«^ _232>87'6(CHjoS000 <^nUV: >mak^2 286 nm (£=8695). /«^ _232>87'6
(c=0.360, (CH^)2S0)(c=0.360, (CH^)2S0)
(2) Ved en fremgangsmåte tilsvarende som ovenfor (1) behandles difenylmetyl 7(3-f enylacetamido-3- (2-metyl-1 ,3,If-diadiazol-5-yl)-tiometyl-1-oksadetia-3-cefem-l+-karboksylat (381 ,5 mg) i metylenklorid (8ml) med fosforpentaklorid (259 mg) og pyridin (0,1 ml) ved -20°C, med metanol (8 ml) og med vann ( h ml) til å gi difenylmetyl 7(3-amino-3- (2-metyl-1 ,3,i+-tiadiazoI-5~yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (273,3 mg). (2) In a method similar to above (1), diphenylmethyl 7(3-phenylacetamido-3-(2-methyl-1,3,If-diadiazol-5-yl)-thiomethyl-1-oxadethia-3-cephem is treated -l+-carboxylate (381.5 mg) in methylene chloride (8 ml) with phosphorus pentachloride (259 mg) and pyridine (0.1 ml) at -20°C, with methanol (8 ml) and with water (h ml) to give diphenylmethyl 7(3-amino-3-(2-methyl-1,3,1+-thiadiazoI-5-yl)-thiomethyl-1-oxadethia-3-cephem-3-carboxylate (273.3 mg).
Utbytte: 88,8$.Dividend: 88.8$.
IR: vCHC13 3^20, 3350, 179^,1723 cm-<1>, IR: vCHC13 3^20, 3350, 179^,1723 cm-<1>,
maks.max.
NMR- 6CDC13 1-88s2H' 2.67s3H, k. 2<j + If.55ABq(1^Hz)2H, NMR- 6CDCl3 1-88s2H' 2.67s3H, k. 2<j + If.55ABq(1^Hz)2H,
l+.52d(l+Hz)1H) ,<l>*.68s2E, 5.00d(tøz)1H, 7.07s1H.l+.52d(l+Hz)1H) ,<l>*.68s2E, 5.00d(töz)1H, 7.07s1H.
(3) Ved en fremgangsmåte tilsvarende metoden ovenfor under (1), behandles difenylmetyl 7(3-f enylacetamido-3- (1-t-butoksykarbonyl-metyltetrazol-5-yl)tiometyl-1-oksacetia-3-cefem-^-karboksylat (300 mg) i metylenklorid (10 ml) med fosforpentaklorid (180 mg) og pyridin (0,07 ml) ved -20°C, med metanol ( h ml), og med vann ( k ml) til å gi difenylmetyl 7(3-amino-3-(1 -t-butoksykarbonyl-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (189 mg). Utbytte: 76$. (3) In a method similar to the method above under (1), diphenylmethyl 7(3-phenylacetamido-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxacetia-3-cephem-^- carboxylate (300 mg) in methylene chloride (10 mL) with phosphorus pentachloride (180 mg) and pyridine (0.07 mL) at -20°C, with methanol ( h mL), and with water ( k mL) to give diphenylmethyl 7 (3-Amino-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (189 mg). Yield: 76$.
IR: y<CHC1>3 T753, 1795, 1722 cm<-1>, IR: y<CHC1>3 T753, 1795, 1722 cm<-1>,
maks.max.
NMR:SpDC<1>3 1A5s9H, 1.60 - 2.00m2H,<l>+.30s2H, lf.1+0-NMR: SpDC<1>3 1A5s9H, 1.60 - 2.00m2H,<l>+.30s2H, lf.1+0-
l+.60m1H,<l>+.65brs2H,<>>+.86s2H, 5.00d(l+Hz) 1H,l+.60m1H,<l>+.65brs2H,<>>+.86s2H, 5.00d(l+Hz) 1H,
6.95s1H. 6.95s1H.
Fremstilling 2 (Innforing av 7oc-metoksy)Preparation 2 (Introduction of 7oc-Methoxy)
(1) En lbsning av difenylmetyl 7(3-amino-3- (1 -metyltetrazol-5-yl)tiometyl-l-oksadetia-3-cefem-^-karboksylat (600 mg) og 3,5-di-t-butyl-^f-hydroksybenzaldehyd (353 mg) i en blanding av benzen 0 5 ml) og metylenklorid (5 ml) kokes under tilbakelbp i 1 time mens vann fjernes ved hjelp av en molekylsikt i en Dean Stark vann-separator. Den resulterende losning av difenylmetyl 7(3- (3,5-di-t-butyl-^-hydroksybenzal) amino-3- (1 -metyl-te trazol-5-yl)tiometyl-1-oksadetia-3-ceÉm-^-karboksylat avkjoles ved -10°C til -15°C, blandes med vannfritt magnesiumsulfat (1 g) og deretter med nikkelperoksyd (0,69 g) under omroring, og omrbres ved -10°C til -15°C i 30 min. og deretter .ved romtemperatur i 15 min. Reaksjonsblandingen filtreres og faststoffet vaskes med benzen. Til den resulterende lbsning av difenylmetyl 7- (3,5-di-t-butyl-l+-okso-2,5-cykloheksadienyliden-metyl)-imino-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3~cefem-^-karboksylat tilsettes metanol (10 ml), og lbsningen får stå ved romtemperatur i 1 time og konsentreres under tbrrhet under redusert trykk. Resten kromatograferes på silikagel (30 g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat (>+:1) til å gi difenylmetyl 7(3-(3,5-di-t-butyl-^--hydroksybenzal)amino-7a-metoksy-3-(1-metyltetrazol-5-yl)-tiometyl-l-oksadetia-3-cefem-^-karboksylat (906 mg) som et praktisk talt rent gult skum. Utbytte: 9937%. (2) Til en lbsning av de.t ovennevnte produkt i en blanding av metanol (10 ml) og tetrahydrofuran (5 ml) tilsettes Girard T-reagens (315 mg) og blandingen omrbres i 1 time ved romtemperatur, fortynnes med vann og ekstraheres med metylenklorid. Ekstrakten vaskes med vann, tbrkes over natriumsulfat og inndampes til tbrrhet under redusert trykk. Resten renses ved kromatografering på ksilikagel (30 g) inneholdende ^ 0% vann og elueres med en blanding av etylacetat:benzen:etylenklorid (1:1:1) til å gi difenylmetyl 7P-amino-7a-metoksy-3-(1-metyl-te trazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat C+69 mg). Et samlet utbytte i dette eksempel: 73?6%. (1) A solution of diphenylmethyl 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (600 mg) and 3,5-di-t- butyl-n-hydroxybenzaldehyde (353 mg) in a mixture of benzene (0.5 ml) and methylene chloride (5 ml) is refluxed for 1 hour while water is removed using a molecular sieve in a Dean Stark water separator. The resulting release of diphenylmethyl 7(3-(3,5-di-t-butyl-^-hydroxybenzal)amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-ceÉm- ^-carboxylate is cooled at -10°C to -15°C, mixed with anhydrous magnesium sulfate (1 g) and then with nickel peroxide (0.69 g) with stirring, and stirred at -10°C to -15°C for 30 min and then at room temperature for 15 min. The reaction mixture is filtered and the solid is washed with benzene. To the resulting solution of diphenylmethyl 7-(3,5-di-t-butyl-1+-oxo-2,5-cyclohexadienylidene-methyl) -imino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylate is added to methanol (10 ml), and the solution is allowed to stand at room temperature for 1 hour and concentrated to dryness under reduced pressure The residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (>+:1) to give diphenylmethyl 7(3-(3,5-di-t-butyl-^-- hydroxybenzal)amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxy lat (906 mg) as a practically pure yellow foam. Yield: 9937%. (2) To a solution of the above product in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml) is added Girard T reagent (315 mg) and the mixture is stirred for 1 hour at room temperature, diluted with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on xylica gel (30 g) containing ^0% water and eluted with a mixture of ethyl acetate:benzene:ethylene chloride (1:1:1) to give diphenylmethyl 7P-amino-7a-methoxy-3-(1- methyl terazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate C+69 mg). A total dividend in this example: 73.6%.
Smp. 160 - 162°C (spalting).Temp. 160 - 162°C (decomposition).
IR:vCHC13 3if25, 3350, 1792, 1?2hcm"<1>, IR: vCHC13 3if25, 3350, 1792, 1?2hcm"<1>,
maks.max.
NMR:SCDC132.00brs2H, 3.38S3H, 3.87S3H, 1+.32s2H, *+.73s2H, NMR: SCDC132.00brs2H, 3.38S3H, 3.87S3H, 1+.32s2H, *+.73s2H,
^.92s1H, 7-OOslH.^.92s1H, 7-OOslH.
Som det fremgår av den ovennevnte fremstilling er nikkeloksyd funnet å være et av de beste oksydasjonsmidler for det fenoliske mellomprodukt for innfbring av metoksy i 7a-stillingen av 1-oksa- og også 1-tia cefern-ringer. As can be seen from the above-mentioned preparation, nickel oxide has been found to be one of the best oxidizing agents for the phenolic intermediate for the introduction of methoxy in the 7a position of 1-oxa and also 1-thia ceferne rings.
I. Ringdannelse.I. Ring formation.
Eksempel 1- 1Example 1- 1
En opplbsning av difenylmetyl a-AP-(1-metyltetrazol-5-yl)-tioacetonyloksy-3P-(a-fenyl-a-difenylmetoksykarbonylacetamido)-2-oksoacetidin-1-yl7-a-trifenylfosforanylidenacetat (650 mg) i dioksan (5 ml) kokes under tilbakelbp under nitrogenatmosfære i 16 timer. Reaksjonsblandingen konsentreres under redusert trykk. Resten renses ved kromatografering på silikagel (20- g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat C+:1) til å gi difenylmetyl 7(3- (a-fenyl-a-difenyl-me toksykarbonylacetamido)-3-(1-metyl-tetrazol-5-yl)tiometyl-1-oksad e ti a-3-cef em-^--karboksy lat. A solution of diphenylmethyl α-AP-(1-methyltetrazol-5-yl)-thioacetonyloxy-3β-(α-phenyl-α-diphenylmethoxycarbonylacetamido)-2-oxoacetidin-1-yl7-α-triphenylphosphoranylidene acetate (650 mg) in dioxane ( 5 ml) is refluxed under a nitrogen atmosphere for 16 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (20-g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (C+:1) to give diphenylmethyl 7(3-(α-phenyl-α-diphenyl-methoxycarbonylacetamido)-3 -(1-methyl-tetrazol-5-yl)thiomethyl-1-oxad e ti a-3-cef em-^--carboxy lat.
(1+32 mg). Smp. 107 - 109°C Utbytte: 80%.(1+32 mg). Temp. 107 - 109°C Yield: 80%.
IR: Vmaks. 3<l>f10'1793'1719'l69<l>f'1630'1600 cm_1- IR: Vmax. 3<l>f10'1793'1719'l69<l>f'1630'1600 cm_1-
Eks empel 1- 2Example 1-2
Ved en fremgangsmåte tilsvarende den som er beskrevet iBy a method similar to that described in
eksempel 1-1, kokes difenylmetyl a-/!+P-(1-metyltetrazol-5-yl)-tioacetonyloksy-3P~(a-fenyl-a-difenylmetoksykarbonylacetamido)-3a-metoksy-2-okso-azetidin-1-yl/-a-trifenylfosforanylidenacetat (5^3 m§) under tilbakelbp i dioksan (5 ml) i 15 timer under nitrogengass, og renses ved kromatografering på silikagel (15 g) til å gi difenylmetyl 76-(a-difenylmetoksykarbonyl-a-fenyl-acetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1 -oksa-detia-3-cefem-<1>+-karboksylat (5^-0 mg). Utbytte: 67%. example 1-1, diphenylmethyl a-/!+P-(1-methyltetrazol-5-yl)-thioacetonyloxy-3P~(a-phenyl-a-diphenylmethoxycarbonylacetamido)-3a-methoxy-2-oxo-azetidine-1- is boiled yl/-α-triphenylphosphoranylidene acetate (5^3 m§) under reflux in dioxane (5 ml) for 15 h under nitrogen gas, and purified by chromatography on silica gel (15 g) to give diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α- phenylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem-<1>+-carboxylate (5^-0 mg). Yield: 67%.
Eksempel 1-^ Example 1-^
Ved en metode tilsvarende den i eksempel 1-2 kokes difenylmetyl a-/3P-(a-p-benzyloksyfenyl-a-difenylmetoksykarbonylacetamido)-3a-metoksy-l+6-■[ 3-(1 -metyltetrazol-5-yl) tiometyl-2-oksopropoksyj - 2- oksoazetidin-1-yl7-a-trifenylfosforanilidenacetat under tilbakelop i dioksan i 10 timer under nitrogen og renses ved kromatografering på silikagel til å gi difenylmetyl 78-(a-difenylmetoksykarbonyl-a-p-benzyloksyfenylacetamido)-7a-metoksy-3- (1 -me tylte tr azol-5-yl) tiometyl-1 -oksade tia-3-cef em-^--karboksylat. In a method similar to that in example 1-2, diphenylmethyl a-/3P-(a-p-benzyloxyphenyl-a-diphenylmethoxycarbonylacetamido)-3a-methoxy-1+6-■[ 3-(1-methyltetrazol-5-yl)thiomethyl- 2-oxopropoxyj - 2- oxoazetidin-1-yl7-a-triphenylphosphoranylidene acetate under reflux in dioxane for 10 hours under nitrogen and purified by chromatography on silica gel to give diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-benzyloxyphenylacetamido)-7a-methoxy- 3-(1-Metylte trazol-5-yl)thiomethyl-1-oxade thia-3-cef em-^-carboxylate.
Utgangsmaterialet for dette fremstilles fra difenylmetyl a-(3B-benzamido-1+8-allyloksy-2-oksoazetidin-1 - yl) -a-isopropyliden-acetat ved anvendelse av reaksjoner omfattende 1) persyre, 2) t-butyl-hypoklorit, 3) litium-metoksyd, •+) litium-1-metyl-tetrazol-5-ylmerkaptid og 5) krom-trioksyd til å gi difenylmetyl a-/38-benzamido-3a-metoksy-l+P-7'3- (1 -me ty 1te tr azol-5-yl)-ti orne tyl-2-oksopropoksy/1- 2-oksoaze tidin-1 -y]_7- a-isopropyliden-acetat som behandles med 6) fosfor-pentaklorid, 7) metanol, og 8) trietylamin til å gi difenylmetyl a-/"38-amino-3a-metoksy-^P-{ 3"(1-metyltetrazol-5-yl)tiometyl-2-oksopropoksy^ -2okso-azetidin-1-yl7-a-isopropylidenacetat, som behandles med 9) a-p-benzyloksyfenyl-a-benzyloksykarbonylacetylklorid og trietylamin, 10) ozon, 11) zink og eddiksyre, 12) tionylklorid og pyridin, og 13) trifenylfosfin. The starting material for this is prepared from diphenylmethyl α-(3B-benzamido-1+8-allyloxy-2-oxoazetidin-1-yl)-α-isopropylidene acetate using reactions comprising 1) peracid, 2) t-butyl hypochlorite, 3) lithium methoxide, •+) lithium 1-methyl-tetrazol-5-yl mercaptide and 5) chromium trioxide to give diphenylmethyl α-β-benzamido-3α-methoxy-1+β-7'3- ( 1-methyltriazol-5-yl)-thioronetyl-2-oxopropoxy/1-2-oxoazetidin-1-y]_7-a-isopropylidene acetate which is treated with 6) phosphorus pentachloride, 7) methanol, and 8) triethylamine to give diphenylmethyl α-/"38-amino-3α-methoxy-^P-{ 3"(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy^-2oxo-azetidine-1- yl7-α-isopropylidene acetate, which is treated with 9) α-β-benzyloxyphenyl-α-benzyloxycarbonylacetyl chloride and triethylamine, 10) ozone, 11) zinc and acetic acid, 12) thionyl chloride and pyridine, and 13) triphenylphosphine.
II. Amid-dannelse.II. Amide formation.
Eksempel II- 1Example II- 1
Til en omrort opplosning av difenylmetyl 7B-amino-3-(1-metyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat To a stirred solution of diphenylmethyl 7B-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate
(192 mg) i tetrahydrofuran (2 ml) og aceton (1 ml) tilsettes mono-difenylmetyl-fenylmalonat (208 mg) og N-etoksykarbonyl-2-etoksy-1,2-dihydrokinolin (1^8 mg) ved 0°C og blandingen får deretter stå over natten ved romtemperatur. Reaksjonsblandingen fortynnes med etylacetat, vaskes med 2N-saltsyre, vann, 5% vandig losning av natriumhydrogenkarbonat og deretter vann, torkes over natriumsalt og inndampes til tbrrhet. Resten renses ved kromatografering på silikagel (20 g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat (l+:1). De krystaller som oppnås fra fraksjonen vaskes med en blanding av eter og n-pentan og gir difenylmetyl 7B- (a-fenyl-oc-difenylmetoksy-karbonylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cef em-^-karboksylat, smp. 100 - 105°C. Utbytte: k- 0%. (192 mg) in tetrahydrofuran (2 ml) and acetone (1 ml) are added mono-diphenylmethyl-phenylmalonate (208 mg) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1^8 mg) at 0°C and the mixture is then allowed to stand overnight at room temperature. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and then water, dried over sodium salt and evaporated to dryness. The residue is purified by chromatography on silica gel (20 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (1+:1). The crystals obtained from the fraction are washed with a mixture of ether and n-pentane to give diphenylmethyl 7B-(α-phenyl-oc-diphenylmethoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia- 3-cef em-^-carboxylate, m.p. 100 - 105°C. Yield: k- 0%.
IR: y CHC131800, 1720, 1680 cm"<1>, IR: y CHC131800, 1720, 1680 cm"<1>,
maks.max.
NMR:&CDC137-OOslH, 6.95s1H, 5 . 80dd (^;9Hz) 1H, 5-06d (>+Hz) 1H, NMR: & CDCl 37 -OOslH, 6.95s 1H, 5 . 80dd (^;9Hz) 1H, 5-06d (>+Hz) 1H,
i+.75s1H, ^f.65brs2H, ^.33s2H, 3.86s3H. i+.75s1H, ^f.65brs2H, ^.33s2H, 3.86s3H.
Ved å anvende a-(difenylmetoksykarbonyl-a-fenyl)acetylklorid, trietylamin-hydroklorid og pyridin i stedet for mono-difenylmetyl-fenylmalonat og N-etoksykarbonyl-2-etoksy-1,2-dihydrokinolin, gjennomfores reaksjonen på analog måte i 25 min. til å gi det samme produkt som nevnt ovenfor med 99% utbytte. Smp. 107-109°C By using α-(diphenylmethoxycarbonyl-α-phenyl)acetyl chloride, triethylamine hydrochloride and pyridine instead of mono-diphenylmethyl-phenylmalonate and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, the reaction is carried out in an analogous manner for 25 min . to give the same product as mentioned above with 99% yield. Temp. 107-109°C
IR: V3^10,<1>793, 1719, 169A, 1630, 1600 cm<1>. IR: V3^10,<1>793, 1719, 169A, 1630, 1600 cm<1>.
UV: (CH3)2<S0>281^ ( £_ 10136)_ UV: (CH3)2<S0>281^ ( £_ 10136)_
maks.max.
NMR:£(<CD>3)2<S0>3.8^s3H, >f.30brs2H,<l>+.58brs2H, lf.69s1H/2, NMR: £(<CD>3)2<SO>3.8^s3H, >f.30brs2H,<l>+.58brs2H, lf.69s1H/2,
<i>+.71s1H/2, 5.02d(<>>+Hz)1H, 5-76dd ( h ;9Hz) 1H, 8.86brs1H, 6.90brs1H, 7.0-7.5m20H, 7.76d(9Hz)1H, <i>+.71s1H/2, 5.02d(<>>+Hz)1H, 5-76dd ( h ;9Hz) 1H, 8.86brs1H, 6.90brs1H, 7.0-7.5m20H, 7.76d(9Hz)1H,
/o7p<3>- 1Mk2<±>8.1° (c = 0.226, (CH^SO) /o7p<3>- 1Mk2<±>8.1° (c = 0.226, (CH^SO)
Eksempel II- 2Example II-2
Til en omrort losning av difenylmetyl 7B-amino-3-(1-metyltetra-zol-5-yl)tiometyl-1-oksadetia-3-cefem-'+-karboksylat (500 mg) i metylenklorid (20 ml) tilsettes pyridin (0,1 ml) og en losning av a-(p-nitrobenzyloksykarbonyl)-a-fenylacetylklorid (510 mg) Pyridine ( 0.1 ml) and a solution of α-(p-nitrobenzyloxycarbonyl)-α-phenylacetyl chloride (510 mg)
i metylenklorid (2 ml) under isavkjbling under nitrogenatmosfære, og blandingen omrbres i 25 min. Reaksjonsblandingen helles ut i vann og ekstraheres med metylenklorid. Ekstrakten torkes over natriumsulfat og inndampes til torrhet til å gi en rest (1 ,0*+ g) som kromatograferes på silikagel ( ho g) inneholdende 10% vann, elueres med en blanding av benzen og etylacetat (^:1), og krystalliseres fra en blanding av etylacetat og eter til å gi difenylmetyl 7B- (oc-p-nitrobenzyloksykarbonyl-cc-f enylacetamido)-3- (1 -me tyl-te tr azol-5-yl) tiometyl-1 -oksad eti a- 3_ cef em-!+-karboksylat (67O mg), smp. 122 - 125°C. Utbytte: 83%. in methylene chloride (2 ml) under ice-cooling under a nitrogen atmosphere, and the mixture is stirred for 25 min. The reaction mixture is poured into water and extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated to dryness to give a residue (1.0*+ g) which is chromatographed on silica gel (ho g) containing 10% water, eluted with a mixture of benzene and ethyl acetate (^:1), and crystallized from a mixture of ethyl acetate and ether to give diphenylmethyl 7B-(oc-p-nitrobenzyloxycarbonyl-cc-phenylacetamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethyl a- 3_ cef em-!+-carboxylate (67O mg), m.p. 122 - 125°C. Yield: 83%.
UV: >((cH3)2S0 2?8 ^ ( i= ^ 8k90). UV: >((cH3)2S0 2?8 ^ ( i= ^ 8k90).
maks.max.
IR:YSs. 3Lf00' 33<lf0>'1792'1?Lf2' 1718'1680'1631 ' l60<l>f'IR:YSs. 3Lf00' 33<lf0>'1792'1?Lf2' 1718'1680'1631 ' l60<l>f'
1520, 131+5 cm<1>. 1520, 131+5 cm<1>.
NMR: _g(<CD>3)2<S0>3.88s3H/2, 3.89s3H/2, l+.2l+brs2H, »+. 65 brs2H, NMR: _g(<CD>3)2<SO>3.88s3H/2, 3.89s3H/2, 1+.21+brs2H, »+. 65 brs2H,
5.05s1H, 5.20dC+Hz)1H, 5.32brs2H, 5.75m1H, 6.86s1H, 7.20 - 7.70mUH, 7-50 - 8.0A2X2tø. 5.05s1H, 5.20dC+Hz)1H, 5.32brs2H, 5.75m1H, 6.86s1H, 7.20 - 7.70mUH, 7-50 - 8.0A2X2tø.
/o722-^ — 150.6 - 5A° (c = 0.350, (ch3)2so). /o722-^ — 150.6 - 5A° (c = 0.350, (ch3)250).
Eksempel II-^Example II-^
Til en omrort opplosning av difenylmetyl 7(3-amino-3- (1-metyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat To a stirred solution of diphenylmethyl 7(3-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate
(100 mg) i metylenklorid i (11 ml) tilsettes pyridin (21 mg) og en opplosning av a-(indan-5-yl)oksykarbonyl-a-fenylacetylklorid (fremstilt fra den tilsvarende syre (77 mg)) i metylenklorid (100 mg) in methylene chloride in (11 ml) add pyridine (21 mg) and a solution of α-(indan-5-yl)oxycarbonyl-α-phenylacetyl chloride (prepared from the corresponding acid (77 mg)) in methylene chloride
( 2 ml) under isavkjbling, og blandingen omrbres i 30 min. Reaksjonsblandingen helles inn i en blanding av etylacetat og vann og det organiske skikt isoleres. Dette vaskes med (2 ml) under ice cooling, and the mixture is stirred for 30 min. The reaction mixture is poured into a mixture of ethyl acetate and water and the organic layer is isolated. This is washed with
fortynnet saltsyre, en vandig lbsning av natriumhydrogenkarbonat, . vann, og en vandig lbsning av natriumklorid, tbrkes over magnesiumsulfat og inndampes til tbrrhet. Resten renses ved kromatografering på silikagel (5,5 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat C+:1) til å gi difenylmetyl 7P~Za- (5-indanyl) oksykarbonyl-a-fenylacetamido.7-3- (1 -me tylte tr azol- 5-yD ti orne ty 1- 1-oksadetia-3- cef em- k- kar boksy-lat OM+ mg) som et blekgult skum. Utbytte: 95,^%. dilute hydrochloric acid, an aqueous solution of sodium bicarbonate, . water, and an aqueous solution of sodium chloride, is washed over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel (5.5 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (C+:1) to give diphenylmethyl 7P~Za-(5-indanyl)oxycarbonyl-a-phenylacetamido.7 -3- (1-me tylte tr azol- 5-yD ti orne ty 1- 1-oxadethia-3- cef em- k- kar boxy-lat OM+ mg) as a pale yellow foam. Yield: 95.^%.
IR:V<CH>C131800, 1735, 1685 cm"<1>, IR:V<CH>C131800, 1735, 1685 cm"<1>,
maks.max.
Eksempel II-^-Example II-^-
Til en lbsning av difenylmetyl 7B-amino-3-(1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-'+-karboksylat (1M+ mg) i metylenklorid ( h- ml) tilsettes pyridin (0,0^8 ml) og en lbsning av fenylmalonyl-hemiklorid i metylenklorid (2 ml) (fremstilt ved omsetning mellom fenylmalonsyre (108 mg) og tionylklorid (0,0^8 ml) i en blanding av eter (1 ml) og dimetylformamid (2 dråper) ved romtemperatur i 20 timer) og blandingen holdes ved 0°C i 20 min. Rreaksjonsblandingen fortynnes med etylacetat, vaskes med fortynnet saltsyre og vann, tbrkes over natriumsulfat og inndampes. Resten renses ved kromatografering på silikagel inneholdende 10% vann og elueres med en blanding av etylacetat og benzen (1:1 til 1:0) til å gi difenylmetyl 7(3- (a-karboksy-a-fenylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3~cefem-^-karboksylat (107 mg). Utbytte: 61%. Pyridine (0 .0^8 ml) and a solution of phenylmalonyl hemichloride in methylene chloride (2 ml) (prepared by reaction between phenylmalonic acid (108 mg) and thionyl chloride (0.0^8 ml) in a mixture of ether (1 ml) and dimethylformamide (2 drops) at room temperature for 20 hours) and the mixture is kept at 0°C for 20 min. The reaction mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid and water, washed over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel containing 10% water and eluted with a mixture of ethyl acetate and benzene (1:1 to 1:0) to give diphenylmethyl 7(3-(α-carboxy-α-phenylacetamido)-3-(1 -methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylate (107 mg) Yield: 61%.
Eksempel II- 5Example II-5
Til en lbsning av 7(3-amino-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre (78 mg) og trietylamin (0,036 ml) i metylenklorid (1 ml) tilsettes en lbsning av fenylmalonyl-monoklorid monobenzhydrylester i metylenklorid (2 ml) To a solution of 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (78 mg) and triethylamine (0.036 ml) in methylene chloride (1 ml) a solution of phenylmalonyl monochloride monobenzhydryl ester in methylene chloride (2 ml) is added
(fremstilt ved å omsettemonobenzhydrylfenylmalonat (60 ml) med tionylklorid (0,0^ ml) i en blanding av eter (1 ml) og dimetylformamid (1 dråpe) ved romtemperatur i 10 timer), og blandingen holdes ved 0°C i 1 time. Reaksjonsblandingen fortynnes med en blanding av etylacetat og eddiksyre (9:1) til å gi 7(3- (a-difenylmetoksykarbonyl-a-fenylacetamido)-3- (1-metyl-te tr azol-5-yl) tiometyl-1- oksad e tia- 3- cef em- ^--karboksylsyre (60 mg). (prepared by reacting monobenzhydrylphenylmalonate (60 ml) with thionyl chloride (0.0^ ml) in a mixture of ether (1 ml) and dimethylformamide (1 drop) at room temperature for 10 hours), and the mixture is kept at 0°C for 1 hour . The reaction mixture is diluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7(3-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1-methyl-tetra azol-5-yl)thiomethyl-1- oxad e tia- 3- cef em- ^--carboxylic acid (60 mg).
Eksempel II- 6Example II- 6
Til en lbsning av 7(3-amino-3- (1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-V-karboksylsyre (78mg) og trietylamin (0,036 ml) i metylenklorid (1 ral) tilsettes en lbsning av fenylkloroformylketen ( K5 mg) i metylenklorid (0,5 ml) og blandingen holdes ved 0°C i 2 timer. Reaksjonsblandingen vaskes med vann, tbrkes og inndampes. Resten opplbses i etylacetat, renses ved kromatografering på silikagel (10 g) inneholdende 10% vann, og elueres med en blanding av etylacetat og eddiksyre (9:1) til å gi 7(3- (oc-fenyl-a-karboksyacetamido)-3- (1-metyl-te tr azol- 5-yl) tiometyl-1 - oksad et ia-3-cef em-!+-kar boksylsyre (88 mg). Utbytte: 7k%. To a solution of 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (78 mg) and triethylamine (0.036 ml) in methylene chloride (1 ral) is added a solution of phenylchloroformyl ketene (K5 mg) in methylene chloride (0.5 ml) and the mixture is kept at 0°C for 2 hours. The reaction mixture is washed with water, dried and evaporated. The residue is dissolved in ethyl acetate, purified by chromatography on silica gel (10 g) containing 10% water, and eluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7(3-(oc-phenyl-α-carboxyacetamido)-3-(1-methyl-tetrazol-5-yl ) thiomethyl-1-oxad et ia-3-cef em-!+-carboxylic acid (88 mg).Yield: 7k%.
Eksempel II- 7Example II-7
En lbsning av difenylmetyl 7(3-amino-3- (1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (96 mg) i metylenklorid (3 ml) tilsettes til en lbsning av et blandet anhydrid (fremstilt ved å omsette mono-t-butyl-p-hydroksyfenylmalonat (76 mg) med i-butylkloroformat (0,037 ml) i nærær av trietylamin (0,0^16 ml) i metylenklorid ( h ml) ved -30°C i 30 min. og ved 0°C i 10 min.), og blandingen omrores ved -30°C i 30 min., ved 0°C i 2 timer, og ved romtemperatur i 30 min. Reaksjonsblandingen konsentreres under redusert trykk. Resten opplbses i en blanding (2 ml) av pyridin og vann (7:3) og omrbres ved romtemperatur i 1 time. Reaksjonsblandingen helles ut i isblandet vann og ekstraheres med etylacetat. Ekstrakten vaskes med vann, 2N-saltsyre, vann, 5% vandig lbsning av natriumhydr ogen-karbonat, og vann, tbrkes over natriumsulfat, og inndampes under redusert trykk. Resten (1^+8 mg) renses ved kromatograf ering på silikagel 0 5 g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat C+:1). Eluatet behandles med en blanding av eter og pentan til å gi difenylmetyl 7B-(a-p-hydroksyfenyl-a-t-butoksykarbonylacetamido)-3-(1-metyltetrazol-5-yDtiometyl-1-oksadetia-3-cefem-^-karboksylat (66 mg). A solution of diphenylmethyl 7(3-amino-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (96 mg) in methylene chloride (3 ml) is added to a solution of a mixed anhydride (prepared by reacting mono-t-butyl-p-hydroxyphenylmalonate (76 mg) with i-butyl chloroformate (0.037 ml) in the presence of triethylamine (0.0^16 ml) in methylene chloride (h ml) at -30 °C for 30 min. and at 0 °C for 10 min.), and the mixture is stirred at -30 °C for 30 min., at 0 °C for 2 h, and at room temperature for 30 min. The reaction mixture is concentrated under reduced pressure The residue is dissolved in a mixture (2 ml) of pyridine and water (7:3) and stirred at room temperature for 1 hour. The reaction mixture is poured into ice-cold water and extracted with ethyl acetate. The extract is washed with water, 2N hydrochloric acid, water, 5 % aqueous solution of sodium hydrogen carbonate, and water, is washed over sodium sulfate, and evaporated under reduced pressure. The residue (1^+8 mg) is purified by chromatography on silica gel (0 5 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate C+:1). The eluate is treated with a mixture of ether and pentane to give diphenylmethyl 7B-(α-p-hydroxyphenyl-α-t-butoxycarbonylacetamido)-3-(1-methyltetrazol-5-yDthiomethyl-1-oxadethia-3-cephem-^-carboxylate (66 mg ).
Smp. 12<1>+ - 126°C. Utbytte: k6%.Temp. 12<1>+ - 126°C. Yield: k6%.
IR: y CHC133<1>+10, 3320, 1800, 1717, 1679, 1510 cm-<1>, IR: y CHC133<1>+10, 3320, 1800, 1717, 1679, 1510 cm-<1>,
maks.max.
NMR-&CDC131A0s9H, 3.80s3H, ^+.27brs2H, l+.38s1H/2, NMR-&CDC131A0s9H, 3.80s3H, ^+.27brs2H, 1+.38s1H/2,
1+.1+2S1H/2, ^+.62brs2H, 5 . 0*+d (*+Hz) 1H, 5.70dd(^+; 1+.1+2S1H/2, ^+.62brs2H, 5 . 0*+d (*+Hz) 1H, 5.70dd(^+;
10Hz)1H, 6A6 - 8.31ml7H. 10Hz)1H, 6A6 - 8.31ml7H.
Eksempel II- 8 •■ ' Example II- 8 •■ '
Til en suspensjon av a-p-hydroksyf enylmalonsyre-monobenzhydrylester (507 mg) i metylenklorid (3 ml) tilsettes trietylamin To a suspension of α-β-hydroxyenylmalonic acid monobenzhydryl ester (507 mg) in methylene chloride (3 ml) is added triethylamine
(139Pl) og oksalylklorid (85 M-l) ved 0°C. Etter omrbring i(139Pl) and oxalyl chloride (85 M-l) at 0°C. After conversion in
<!>+5 min. ved 0°C tilsettes blandingen til en lbsning av difenylmetyl 7P~amino-3-(1-me tyltetrazol-5-yl)-tiometyl-1 - oksadetia-3-cefem-^-karboksylat (191 mg) i metylenklorid (3 ml) og pyridin (80 )il) ved 0°C. Etter omrbring i 30 min. ved 0°C fortynnes reaksjonsblandingen med etylacetat, vaskes med 2N saltsyre, vann, vandig 5% natriumhydrogenkarbonatlbsning, <!>+5 min. at 0°C, the mixture is added to a solution of diphenylmethyl 7β-amino-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (191 mg) in methylene chloride (3 ml ) and pyridine (80 µl) at 0°C. After stirring for 30 min. at 0°C the reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution,
og med vann, tbrkes over natriumsulfat, og inndampes under redusert trykk. Resten kromatograferes på silikagel (15 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (9:1) til å gi difenylmetyl 7S-/q<->p-hydroksyfenyl-oc-dif enylme toksykarbonylace tamido_7-3- (1 -me tylte tr azol- 5~yl)-tiometyl-1-oksadetia-3_cefem-l+-karboksylat som et farvelbst skum (137 mg). Utby-tte: *f1 ,6%. and with water, washed over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (15 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (9:1) to give diphenylmethyl 7S-/q<->p-hydroxyphenyl-oc-dif enylme toxycarbonylace tamido_7-3 - (1-methyltriazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate as a pale foam (137 mg). Yield: *f1 .6%.
IR: yCHC133325,<1>798, 1722, 1679 cm"<1>, IR: yCHC133325,<1>798, 1722, 1679 cm"<1>,
maks.max.
NMT,. iCDCl, 3.73s3H, ^.20brs2H, l+.53brs2H, (*+.60s +NMT,. iCDCl, 3.73s3H, ^.20brs2H, l+.53brs2H, (*+.60s +
in rui.0j l+.63s)1H, l+.93brd(l+Hz)1H, 5.1+7 - 5.77m1H.in rui.0j l+.63s)1H, l+.93brd(l+Hz)1H, 5.1+7 - 5.77m1H.
Eksempel II- 9Example II-9
Til; en losning av difenylmetyl 7B-amino-3-(1-metyltetrazol-5-yDtiometyl-l-oksadetia-3-cefem-^-karboksylat (96 mg) i en blanding av tetrahydrofuran (1 ml) og aceton (0,5 ml) tilsettes mono-t-butyl a-(2-tienyl)malonat (129 mg) og 1-etoksykarbonyl-2-etoksy-1,2-dihydrokinolin (132 mg) i fire like deler med 1 times mellomrom under omrbring ved romtemperatur i nitrogengass, og blandingen omrbres i 1 time. Reaksjonsblandingen fortynnes med etylacetat, vaskes med 2N saltsyre, vann, 5% vandig natriumhydrogenkarbonat, og med vann, tbrkes over natriumsulf at, og inndampes under redusert trykk. Resten (251 mg) renses ved kromatografering på silikagel (10 g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat C+:1). Eluatet behandles med en blanding av eter og pentan til å gi difenylmetyl 7a-/a-(2-tienyl)-a-t-butoksykarbonylacetamido/-3-(1-metyltetrazol-5~yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat som et amorft pulver (1+9 mg). Smp. 97 - 99°C. Utbytte: 3h. 8%. To; a solution of diphenylmethyl 7B-amino-3-(1-methyltetrazol-5-ylDthiomethyl-1-oxadethia-3-cephem-^-carboxylate (96 mg) in a mixture of tetrahydrofuran (1 ml) and acetone (0.5 ml ) mono-t-butyl α-(2-thienyl)malonate (129 mg) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (132 mg) are added in four equal portions at 1 hour intervals with stirring at room temperature in nitrogen gas, and the mixture is stirred for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate, and with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue (251 mg) is purified by chromatography on silica gel (10 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate C+:1). The eluate is treated with a mixture of ether and pentane to give diphenylmethyl 7α-/α-(2-thienyl)-α-t-butoxycarbonylacetamido/-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylate as an amorphous powder (1+9 mg). Temp. 97 - 99°C. Yield: 3h. 8%.
IR: V<CH>C133^-00, 1800, 1720, 1690, 1511cm"<1>, IR: V<CH>C133^-00, 1800, 1720, 1690, 1511cm"<1>,
maks.max.
NMR:åCDC131A7s9H, 3-93s3H, l+.32s2H,<l>+.69brs2H,NMR: aCDC131A7s9H, 3-93s3H, 1+.32s2H, <1>+.69brs2H,
i+.SObrslH, 5.09d(<l>+Hz)1H, 5.75dd(10;<!>+Kz)1H,i+.SObrslH, 5.09d(<l>+Hz)1H, 5.75dd(10;<!>+Kz)1H,
6.90 - 7.73ml5H. 6.90 - 7.73ml5H.
Eksempel 11- 10Example 11-10
Til en losning av difenylmetyl 7B-amino-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-l+-karboksylat (96 mg) i en blanding av tetrahydrofuran (1 ml) og aceton (0,5 ml) tilsettes mono-t-butyl a-(3-tienyl)malonat (132 mg) og 1-etoksykarbonyl-2-etoksy-1,2-dihydrokinolin (132 mg) under isavkjoling, og blandingen omrores ved romtemperatur i h timer. Reaksjonsblandingen fortynnes med etylacetat, vaskes med vann, 1N saltsyre, vann, vandig 5% losning av natriumhydrogenkarbonat, og mettet losning av natriumklorid, torkes over magnesiumsulfat og inndampes. Resten (198 mg) renses ved kromatografering på silikagel (10 g) innholdende 10% vann, og elueres med en blanding av benzen og etylacetat (1:1) til å gi difenylmetyl-76-/bc- (3-tienyl)-a-t-butoksykarbonylacetamidCi7-3- (1-me tylte trazol-5-yl)tiometyl-1-oksadetia-3-cefem-<l>+-karboksylat (56 mg) som et farvelost pulver. Smp. 85 - 90°C Utbytte: 39,7%. To a solution of diphenylmethyl 7B-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (96 mg) in a mixture of tetrahydrofuran (1 ml) and acetone (0 .5 ml) mono-t-butyl α-(3-thienyl)malonate (132 mg) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (132 mg) are added under ice-cooling, and the mixture is stirred at room temperature for h hours . The reaction mixture is diluted with ethyl acetate, washed with water, 1N hydrochloric acid, water, aqueous 5% solution of sodium bicarbonate, and saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue (198 mg) is purified by chromatography on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl-76-/bc-(3-thienyl)-a-t -butoxycarbonylacetamide C17-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<1>+-carboxylate (56 mg) as a colorless powder. Temp. 85 - 90°C Yield: 39.7%.
IR: V<CHC1>3 1798, 1720, 1685, 1630 cm-<1>, IR: V<CHC1>3 1798, 1720, 1685, 1630 cm-<1>,
maks.max.
jrørø.<5CDC131A5S9H, 3.85s3H, ^f.32s2H, lf.67m3H,jrørø.<5CDC131A5S9H, 3.85s3H, ^f.32s2H, lf.67m3H,
5.06d(l+Hz)1H, 5-86dd(10-, ^-Hz)1H, 7.00s1H, 5.06d(l+Hz)1H, 5-86dd(10-, ^-Hz)1H, 7.00s1H,
7.1 - 7-65ml<l>+H. 7.1 - 7-65ml<l>+H.
Eksempel 11- 11Example 11- 11
Til en losning av difenylmetyl 7(3-amino-3- (1 -t-butoksy-karboksyImetyltetrazol-5-yl)ti ornety1-1-oksadetia-3-cefem- h-karboksylat (102 mg) i en blanding av tetrahydrofuran (2 ml) To a solution of diphenylmethyl 7-(3-amino-3-(1-t-butoxy-carboxylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-h-carboxylate (102 mg) in a mixture of tetrahydrofuran ( 2 ml)
og aceton (1 ml) tilsettes monobenzhydryl a-fenylmalonatand acetone (1 ml) is added monobenzhydryl α-phenylmalonate
(186 mg) og N-etoksykarbonyl-2-etoksy-1 ,2-dihydrokinolin (88 mg)(186 mg) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (88 mg)
i to deler, og blandingen omrores ved romtemperatur i 3,5 timer. Reaksjonsblandingen blandes med etylacetat, vaskes med 2N saltsyre, vann, vandig 5% natriumhydrogenkarbonatlosning og vann, torkes over natriumsulfat, og inndampes under redusert trykk. Resten kromatograferes på silikagel (10 g) inneholdende 10% vann, elueres med en blanding av benzen og etylacetat in two parts, and the mixture is stirred at room temperature for 3.5 hours. The reaction mixture is mixed with ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution and water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (10 g) containing 10% water, eluted with a mixture of benzene and ethyl acetate
(9:1) og inndampes til å gi difenylmetyl 7(3-(a-dif enylmetoksy-karbonyl-a-fenylacetamido)-3-(1 -t-butoksykarbonylmetyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-'+-karboksylat (63 mg) som et farvelost skum. Utbytte: 39%. (9:1) and evaporated to give diphenylmethyl 7(3-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1 -t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -'+-carboxylate (63 mg) as a colorless foam.Yield: 39%.
IR:YCHC131800, 1750, 1725, 1680cm"<1>, IR:YCHC131800, 1750, 1725, 1680cm"<1>,
maks.max.
NMR: S<CD>C136.96s1H, 6.93s1H, 5.75ddC+; 9Hz)1H, 5.03d(t+Hz) 1H, NMR: S<CD>C 136.96s1H, 6.93s1H, 5.75ddC+; 9Hz)1H, 5.03d(t+Hz) 1H,
l+.90s2H,<l>f.73s1H/2, U.71s1H/2,<>>+.60brs2H,l+.90s2H,<l>f.73s1H/2, U.71s1H/2,<>>+.60brs2H,
l+.30s2H, 1.I+0S9H.l+.30s2H, 1.I+0S9H.
Eksempel 11- 12Example 11-12
Til en losning av difenylmetyl 7B-amino-3-(1-t-butoksykarbonyl-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (87 mg) i acetonitril (2 ml) tilsettes N-/a-t-butoksykarbonyl-a-(2-tienyl)acetoksyj7succinimid (76 mg) og N-metylmorf olin (0,016 ml) under nitrogenatmosfære, og blandingen omrbres i 90 min. Reaksjonsblandingen blandes med etylacetat, vaskes med fortynnet saltsyre, vann, vandig 5% natriumhydrogenkarbonatlbsning og vann, tbrkes over natriumsulfat, og inndampes. Resten kromatograferes på silikagel (10 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (9:1) til å gi difenylmetyl 7(B-/a-t-butoksykarbonyl-a- (2-tienyl)-acetamido7-3-(1 - t-butoksykarbonyImetyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-<>>+-karboksylat (96 mg) som et farvelost skum. Utbytte:80%. To a solution of diphenylmethyl 7B-amino-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (87 mg) in acetonitrile (2 ml) is added /α-t-butoxycarbonyl-α-(2-thienyl)acetoxyj7succinimide (76 mg) and N-methylmorpholine (0.016 ml) under a nitrogen atmosphere, and the mixture is stirred for 90 min. The reaction mixture is mixed with ethyl acetate, washed with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate solution and water, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (9:1) to give diphenylmethyl 7(B-/a-t-butoxycarbonyl-a-(2-thienyl)-acetamido7- 3-(1-t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<>>+ -carboxylate (96 mg) as a colorless foam.Yield: 80%.
IR: v<CHC1>3 1802, 1750, 1722, 1690 cm"<1>, IR: v<CHC1>3 1802, 1750, 1722, 1690 cm"<1>,
maks.max.
NMR: £<CD>C136.93<s>1H, 5.72dd(<l>+; 9Hz)1H, 5.06d(<l>+Hz)lH,NMR: δ<CD>C 136.93<s>1H, 5.72dd(<l>+; 9Hz)1H, 5.06d(<l>+Hz)1H,
^.83s2H,<l>+.75brs1K, *+.60brs2H, l+.30s2H,^.83s2H,<l>+.75brs1K, *+.60brs2H, l+.30s2H,
1 .l+5sl8H.1 .l+5sl8H.
Eksempel 11- 13Example 11-13
Til en lbsning av difenylmetyl 73-amino~3-(2-metyl-1 ,3 ,^f-ti^dlazol-5-yl) tiometyl-1 - oksad e tia-3-cef em-lf-karboksylat (215 mg)" i en blanding av tetrahydrofuran ( k ml) og aceton (2 ml) tilsettes'tre porsjoner hemidifenylmetyl a-fenylmalonat (131 mg x 3) og 1-etoksykarbonyl-2-etoksy-1,2-dihydrokinolin (107 mg x 3) ved romtemperatur med 1,5 timers mellomrom. Etter 2 timer fortynnes reaksjonsblandingen med etylacetat, vaskes med vann, fortynnet saltsyre, vann, vandig natrlumhydrogenkarbonat, og vann, tbrkes over natriumsulfat og inndampes. Resten renses ved kromatografering på silikagel (30 g) inneholdende 10% vann, elueres med en blanding av benzen og etylacetat (^:1) og eluatet behandles med en blanding av eter og n-pentan til å gi difenylmetyl 7(3- ( a- f enyl-oc-dif enylme toksykarbonylace tamido) -3-(2-metyl-1, 3., ^-- tiadia^oT^-yl) tiometyl-1-oksadetia-3-cef em-^-karboksylat (170 mg) som et farvelost skum. Utbytte: *+7,5% To a solution of diphenylmethyl 73-amino~3-(2-methyl-1 ,3 ,^f-thi^dlazol-5-yl) thiomethyl-1 - oxad e thia-3-cephem-1f-carboxylate (215 mg )" in a mixture of tetrahydrofuran (k ml) and acetone (2 ml) are added three portions of hemidiphenylmethyl α-phenylmalonate (131 mg x 3) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (107 mg x 3 ) at room temperature at 1.5 hour intervals. After 2 hours, the reaction mixture is diluted with ethyl acetate, washed with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water, washed over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (30 g) containing 10% water, eluted with a mixture of benzene and ethyl acetate (^:1) and the eluate treated with a mixture of ether and n-pentane to give diphenylmethyl 7(3-( a- ph enyl-oc-di enylme toxycarbonylace tamido) -3-(2-methyl-1, 3, ^-- thiadia^oT^-yl) thiomethyl-1-oxadethia-3-cef em-^-carboxylate (170 mg) as a colorless foam.Yield: *+ 7.5%
IR: VCHC13 3350,1799, 1715, l690sh cm"<1>, IR: VCHC13 3350,1799, 1715, l690sh cm"<1>,
maks.max.
NMR:$CD<C1>3 2.67s3<H,>k. 22 + k. 53ABq(ll+Hz)2H,<!>+.57s2H, NMR: $CD<C1>3 2.67s3<H,>k. 22 + k. 53ABq(ll+Hz)2H,<!>+.57s2H,
<l>f.75s1H, 5.00d(<t>+Hz)1H, 5.73dd( k;9.5Hz) 1H, 6.92s1H, 6.97s1H. <l>f.75s1H, 5.00d(<t>+Hz)1H, 5.73dd( k;9.5Hz) 1H, 6.92s1H, 6.97s1H.
Eksempel II- AExample II-A
Til en losning av a-difenylmetoksykarbonyl-a-fenyl-eddiksyre (103,9 mg) i metylenklorid (2 ml) avkjolt til 0°C tilsettes trietylamin (0,0^2 ml) og oksalylklorid (0,0256 ml). Etter omrbring ved 0°C i 10 min. helles blandingen ut i ': en lbsning av difenylmetyl 7(3-amino-7a-metoksy-3- (1 -me tyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-1+-karboksylat (101,7 mg) og pyridin (0,059^ ml)i metylenklorid (5 ml) ved 0°C, omrbres i 1 time ved 0°C, fortynnes med etylacetat, vaskes med fortynnet saltsyre, vann, vandig natriumhydrogenkarbonat, og vann, tbrkes over natriumsulf at og konsentreres -onder redusert trykk. Den oppnådde rest kromatograferes på silikagel (20 g) inneholdende 1.0% vann og elueres med en blanding av benzen og etylacetat (1+:1) til å gi difenylmetyl 7(3- (a-difenylmetoksykarbonyl-a-fjmy_laLcetamido)-7a-metoksy-3- (1 - me ty 1te tr azol-5-yl) tiometyl-1 - oksadetia-3-cefem-^-karboksylat (121,2 mg) som et farvelost skum. Utbytte: 72, k%. Triethylamine (0.0^2 ml) and oxalyl chloride (0.0256 ml) are added to a solution of α-diphenylmethoxycarbonyl-α-phenylacetic acid (103.9 mg) in methylene chloride (2 ml) cooled to 0°C. After stirring at 0°C for 10 min. the mixture is poured into ': a solution of diphenylmethyl 7(3-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (101, 7 mg) and pyridine (0.059 ml) in methylene chloride (5 ml) at 0°C, stirred for 1 hour at 0°C, diluted with ethyl acetate, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water, washed over sodium sulfate that and concentrated -under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 1.0% water and eluted with a mixture of benzene and ethyl acetate (1+:1) to give diphenylmethyl 7(3-(α-diphenylmethoxycarbonyl- α-fjmy_laLcetamido)-7α-methoxy-3-(1 - methyl 1te trazol-5-yl) thiomethyl-1 - oxadethia-3-cephem-^-carboxylate (121.2 mg) as a colorless foam. Yield: 72, k%.
IR:vCHCl33320, 1792, 1725, 1700cm"<1>, IR:vCHCl33320, 1792, 1725, 1700cm"<1>,
maks.max.
NMR:<S"CDC13(3.1+Os<+>3<A>2s)3H, 3-69s3H,<l>f.22s2H,<l>+A5s2H, NMR:<S"CDC13(3.1+Os<+>3<A>2s)3H, 3-69s3H,<l>f.22s2H,<l>+A5s2H,
>+.75s1H, 5.00s1H, 6.92s2H, 7.85s1H. >+.75s1H, 5.00s1H, 6.92s2H, 7.85s1H.
Eksempel II- 1^Example II- 1^
En blanding av a-^indan-5-yl)oksykarbonyl-a-fenyleddiksyreA mixture of α-[indan-5-yl)oxycarbonyl-α-phenylacetic acid
( ikQ mg) og tienylklorid (0,25 ml) oppvarmes ved 70°C i 1 time og inndampes under redusert trykk. Resten opplbses i benzen (2 ml) og inndampes på nytt til tbrrhet. Resten opplbses i metylenklorid (2 ml) og helles ut i en lbsning av difenylmetyl-78-amino-7oc-metoksy-3- (1 -me tylte tr azol- 5-yl)tiometyl-1-oksa-detia-3-cefem-^f-karboksylat (101,7 mg) og pyridin (0,016 ml) i metylenklorid (•+ ml) ved 0°C Etter omrbring i 30 min. ved 0°C fortynnes blandingen med etylacetat, vaskes med vandig natriumhydrogenkarbonat, vann, fortynnet saltsyre, og vann, tbrkes over natriumsulfat, og inndampes under redusert trykk. Resten kromatograferes på silikagel (20 g) inneholdende 10% vann til å gi difenylmetyl 7B-/q-(indan-5-yl)oksykarbonyl- a- fenylacetamido7- mJ) 7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (116,1 mg) som et farvelost skum. Utbytte: 73,8%. ( ikQ mg) and thienyl chloride (0.25 ml) are heated at 70°C for 1 hour and evaporated under reduced pressure. The residue is dissolved in benzene (2 ml) and re-evaporated to dryness. The residue is dissolved in methylene chloride (2 ml) and poured into a solution of diphenylmethyl-78-amino-7oc-methoxy-3-(1-methyltriazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem -^f-carboxylate (101.7 mg) and pyridine (0.016 ml) in methylene chloride (•+ ml) at 0°C After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate, water, dilute hydrochloric acid, and water, washed over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (20 g) containing 10% water to give diphenylmethyl 7B-[q-(indan-5-yl)oxycarbonyl-a-phenylacetamido7-mJ) 7a-methoxy-3-(1-methyltetrazol-5-yl )thiomethyl-1-oxadethia-3-cephem-^-carboxylate (116.1 mg) as a colorless foam. Yield: 73.8%.
IR: Y<CHC1>3 3390, 3320, 1730, 1727, 1700 cm"<1>, IR: Y<CHC1>3 3390, 3320, 1730, 1727, 1700 cm"<1>,
maks.max.
i... NMR:<£CDC132.05<qu>intet(7Hz)2H, 2.87t(7Hz)<*>fH, 3A8S3H,i... NMR:<£CDC132.05<qu>none(7Hz)2H, 2.87t(7Hz)<*>fH, 3A8S3H,
3.77s3H, lf.23s2H,<l>f.53s2H, lf.87s1H, 5-02s1H. 3.77s3H, lf.23s2H,<l>f.53s2H, lf.87s1H, 5-02s1H.
Eksempel II- 16Example II- 16
Til en lbsning av a-difenylmetoksykarbonyl-a-p-acetoksyfenyl-eddiksyre (1<*>+2 mg) i metylenklorid (2 ml) avkjblt til 0°C To a solution of α-diphenylmethoxycarbonyl-α-β-acetoxyphenyl-acetic acid (1<*>+2 mg) in methylene chloride (2 ml) cooled to 0°C
tilsettes trietylamin ( 0, 0^ 6 ml) og oksalylklorid (0,0256 ml). Etter omrbring i 15 min. ved 0°C blandes blandingen gradvis med triethylamine (0.0^6 ml) and oxalyl chloride (0.0256 ml) are added. After stirring for 15 min. at 0°C the mixture is gradually mixed with
en lbsning av difenylmetyl 7P-amino-7a-metoksy-3-(1-metyl-te tr azol-5-yl) tiometyl-1-oksadetia-3-cefem-^-karboksylat (101,7 mg) og pyridin (0,02"+ ml) i metylenklorid ( h ml) ved 0°C, omrbres i 15 min., fortynnes med etylacetat, vaskes med vandig natriumhydrogenkarbonat, vann, fortynnet saltsyre, og vann, A solution of diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylate (101.7 mg) and pyridine (0 .02"+ ml) in methylene chloride (h ml) at 0°C, stirred for 15 min., diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, dilute hydrochloric acid, and water,
tbrkes over natriumsulfat, og inndampes under redusert trykk. Den oppnådde rest kromatograferes på silikagel (20 g) inneholdende 10% vann til å gi difenylmetyl 76-(a-difenylmetoksykarbonyl-a-p- trub over sodium sulfate, and evaporate under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 10% water to give diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α-p-
acetoksyf enylacetamido)-7a-metoksy-3- (1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-<>>+-karboksylat 0 33,^ mg) som et farvelost skum fra fraksjoner eluert med en blanding av benzen og etylacetat (2:1). Utbytte: 7^,5%. acetoxy enylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-<>>+-carboxylate 0 33.^ mg) as a colorless foam from fractions eluted with a mixture of benzene and ethyl acetate (2:1). Dividend: 7^.5%.
IR: v<CHC1>3 3325, 1792, 1730, 1700sh cm"1, IR: v<CHC1>3 3325, 1792, 1730, 1700sh cm"1,
maks.max.
44
NMR: £<C>DC13 2.<1>+OS3H, 3AOS3H, 3.67S3H,<>>+._17s2H, l+A2s2H, NMR: £<C>DC13 2.<1>+OS3H, 3AOS3H, 3.67S3H,<>>+._17s2H, 1+A2s2H,
^.73s1H, lf.98s1H.^.73s1H, lf.98s1H.
Eksempel 11- 17Example 11-17
Til en lbsning av a-difenylmetoksykarbonyl-a-p-hydroksyfenyl-eddiksyre (25<*>+ mg) i metylenklorid (3 ml) tilsettes trietylamin (0,083 ml) og oksalylklorid (0,051 ml) ved 0°C. Etter omrbring i 15 min. tilsettes blandingen til en lbsning av difenylmetyl-7B-amino7a-metoksy-3-(1-mety1tetrazol-5-yl)ti orne ty1-1-oksadetia-3-cef emA-karboksylat (101 ,7 mg) og pyridin (0,0^8 ml) i metylenklorid ( h ml) ved 0°C. Etter omrbring i 30 min. ved 0°C fortynnes blandingen med etylacetat, vaskes med vandig natriumhydrogenkarbonat, vann, saltsyre, og vann, tbrkes over natriumsulfat, og inndampes under redusert trykk. Den oppnådde rest kromatograferes på silikagel (20 g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat (2:1) til å gi difenylmetyl 7P-(a-difenylmetoksykarbonyl-a-p-hydroksyfenyl-acetamido)-7a-metoksy-3-(1-mety1tetrazol-5-yl)tiometyl-1 - oksadetia-3-cefemA-karboksylat (86, k mg) som et farvelost skum. Utbytte: ^9,6%. To a solution of α-diphenylmethoxycarbonyl-α-β-hydroxyphenyl-acetic acid (25<*>+ mg) in methylene chloride (3 ml) is added triethylamine (0.083 ml) and oxalyl chloride (0.051 ml) at 0°C. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl-7B-amino7a-methoxy-3-(1-methyltetrazol-5-yl)thiol-1-oxadethia-3-cef emA-carboxylate (101.7 mg) and pyridine (0. 0^8 ml) in methylene chloride (h ml) at 0°C. After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, hydrochloric acid and water, washed over sodium sulfate, and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (2:1) to give diphenylmethyl 7P-(α-diphenylmethoxycarbonyl-α-β-hydroxyphenyl-acetamido)-7α-methoxy- 3-(1-Methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem A-carboxylate (86.k mg) as a colorless foam. Yield: ^9.6%.
IR:Y<CE>C133585, 3315, 1790, 1722, 1700sh cm"<1>, IR:Y<CE>C133585, 3315, 1790, 1722, 1700sh cm"<1>,
maks.max.
NMR: S<CD>C13(3A5s<+>3A8s)3H, (3-72s<+>3-75s)3H, »+.18s2H, NMR: S<CD>C13(3A5s<+>3A8s)3H, (3-72s<+>3-75s)3H, »+.18s2H,
l+A5s2H, ( k. 67s +<l>+.70s)1H, 5.02s1H. l+A5s2H, ( k. 67s +<l>+.70s)1H, 5.02s1H.
Eksempel II-18 \ V' Example II-18 \V'
J V ' i,.''/ ' i J V ' i,.''/ ' i
Til en suspensjon av a-(5-indanyl)oksykarbonyl-a-p-hydroksy-fenyleddiksyre (370 mg) i metylenklorid ( h ml) tilsettes trietylamin (139 pl) og oksalylklorid (85 pl) ved 0°C under nitrogen til å gi en klar losning. Etter omrbring i 20 min. To a suspension of α-(5-indanyl)oxycarbonyl-α-β-hydroxy-phenylacetic acid (370 mg) in methylene chloride (h ml) is added triethylamine (139 µl) and oxalyl chloride (85 µl) at 0°C under nitrogen to give a clear solution. After stirring for 20 min.
ved 0°C tilsettes blandingen til en lbsning av difenylmetyl-7S-aminoJ?a-metoksy-3- (1-me tylte tr azol-5-yl) tiometyl-1-oksad etia-3-cefem-^-karboksylat (203 mg) i metylenklorid (5 ml) og pyridin (80 p. 1) og blandingen omrbres i 10 min. Reaksjonsblandingen fortynnes med etylacetat, vaskes med 2N saltsyre, at 0°C, the mixture is added to a solution of diphenylmethyl-7S-aminoJ?a-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (203 mg) in methylene chloride (5 ml) and pyridine (80 p. 1) and the mixture is stirred for 10 min. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid,
vann, vandig 5% natriumhydrogenkarbonatlbsning, og vann, tbrkes over natriumsulfat, og det inndampes under redusert trykk til å water, aqueous 5% sodium hydrogencarbonate solution, and water, washed over sodium sulfate, and evaporated under reduced pressure to
gi et blekgult skum, som kromatograferes på silikagel (50 g) inneholdende 10% vann, og elueres med en blanding av benzen og eddiksyre (1:1) til å gi difenylmetyl 7P-/a-p-hydroksyfenyl-a-(5-indanyl)-oksykarbonylacetamidoJ7-7a-metoksy-3- (1 -metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-lf-karboksylat som en krystallinsk rest (230 mg; Utbytte•71,6% ) som omkrystalliseres fra en blanding av kloroform og eter til å gi rene krystaller som smelter ved 11<*>+ - 116°C. give a pale yellow foam, which is chromatographed on silica gel (50 g) containing 10% water, eluting with a mixture of benzene and acetic acid (1:1) to give diphenylmethyl 7P-/α-p-hydroxyphenyl-α-(5-indanyl) -oxycarbonylacetamidoJ7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate as a crystalline residue (230 mg; Yield•71.6%) which is recrystallized from a mixture of chloroform and ether to give pure crystals melting at 11<*>+ - 116°C.
UV: yCH30H .272 ( <f= 9500), 2&A ( £= 9260) nm. UV: yCH 3 0 H .272 ( <f= 9500), 2&A ( £= 9260) nm.
maks.max.
NMR:£CD3<C>OCD32.1m2H, 2.87t(7Hz)lfH, 3A3S3H, 3-91 s3H,NMR: £CD3<C>OCD32.1m2H, 2.87t(7Hz)1fH, 3A3S3H, 3-91 s3H,
!+.31s2H, ^.65s2H, 5.07s1H, 5 .1 3s1H, !+.31s2H, ^.65s2H, 5.07s1H, 5 .1 3s1H,
6.92brs3H.6.92brs3H.
IR: y-CHC133590, 3335, 1789, 1736, 1722, 1700, 1601 cm"<1>, IR: γ-CHC133590, 3335, 1789, 1736, 1722, 1700, 1601 cm"<1>,
maks.max.
Eksempel 11- 19Example 11-19
Til en lbsning av a-t-butoksykarbonyl-a-(3-tienyl)eddiksyreTo a solution of α-t-butoxycarbonyl-α-(3-thienyl)acetic acid
(97 mg) i metylenklorid (1 ml) tilsettes trietylamin (0,0^2 ml)(97 mg) in methylene chloride (1 ml) is added triethylamine (0.0^2 ml)
og oksalylklorid (0,026 ml) ved 0°C under nitrogenatmosfære.and oxalyl chloride (0.026 mL) at 0°C under a nitrogen atmosphere.
Etter omrbring i 30 min. ved 0°C helles blandingen ut i enAfter stirring for 30 min. at 0°C, the mixture is poured into a
lbsning av difenylmetyl 7P-amino-7cc-metoksy-3- (1 -metyltetrazol- solution of diphenylmethyl 7P-amino-7cc-methoxy-3-(1-methyltetrazol-
5-yl)tiometyl-1-oksadetia-3-cef em-<>>+-karboksylat (101 mg) og pyridin (0,02<*>+ ml) i metylenklorid (3 ml) ved 0°C under nitrogenatmosfære. Etter omrbring ved 0°C i 90 min. fortynnes blandingen med metylenklorid, vaskes med 5% natriumhydrogenkarbonat i vann, vann, 2N-saltsyre, og vann, tbrkes over natriumsulfat, inndampes under redusert trykk, kromatograferes på silikagel (5 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (2:1) til å gi difenylmetyl 7(3-/a-1-butoksykarbonyl-a-(3-tienyl)acetamido7-7a-metoksy-3-(1-metyl-te tr azol- 5-yl) tiometyl-1-oksad eti a-3-cef em-^f-karboksylat (1M+ mg) som et farvelost skum. Utbytte: kvantitativt. 5-yl)thiomethyl-1-oxadethia-3-cef em-<>>+ -carboxylate (101 mg) and pyridine (0.02<*>+ ml) in methylene chloride (3 ml) at 0°C under nitrogen atmosphere. After stirring at 0°C for 90 min. the mixture is diluted with methylene chloride, washed with 5% sodium bicarbonate in water, water, 2N hydrochloric acid, and water, washed over sodium sulfate, evaporated under reduced pressure, chromatographed on silica gel (5 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (2:1) to give diphenylmethyl 7(3-[α-1-butoxycarbonyl-α-(3-thienyl)acetamido7-7α-methoxy-3-(1-methyl-tetrazol-5-yl) thiomethyl-1-oxad ethyl α-3-cef em-^f-carboxylate (1M+ mg) as a colorless foam Yield: quantitative.
IR: vCHC13 1795, 1720, ca. 1700 cm-1, IR: vCHC13 1795, 1720, ca. 1700 cm-1,
maks.max.
NMR:£CDC136.96s1H, (5-07s + 5.05s)1H, ^.60brs3H, >+.30brs2H, NMR: δCDC136.96s1H, (5-07s + 5.05s)1H, ^.60brs3H, >+.30brs2H,
3-83s3H, (3-53S<+>3-50s)3H, lAls9H. 3-83s3H, (3-53S<+>3-50s)3H, 1Als9H.
Eksempel 11- 20 Example 11-20
Til en lbsning av 3-tienylmalonsyre-indanylester (120 mg) i metylenklorid (1,5 ml) tilsettes trietylamin (<1>+2 pl) og oksalylklorid (26 ul) under isavkjbling. Etter omrbring i 15 min. tilsettes blandingen til en lbsning av difenylmetyl 7(3-amino-7ct-metoksy-3- (1 -me tyl te tr azol-5-yl)-tiometyl-1 -oksadetia-3-cefem-*+-karboksylat (116 mg) i metylenklorid (3 ml) og pyridin (2<*>+ pl) og blandingen omrbres ved 0°C i 1 time. Reaks jonsblandingen helles ut i etylacetat, og vaskes med 2N saltsyre, vann, 5% vandig natriumhydrogenkarbonatlbsning, og vann, tbrkes over magnesiumsulfat, og inndampes. Resten kromatografer es på silikagel (10 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (10:1) til å gi difenylmetyl-7(3-/a- (3-tienyl)-a- (indan-5-yl) oksykarbonylacetamido7-7<x-metoksy-3- (1 -metylt etr azol-5-yl) tiometyl-1 - oksad et ia-3-cef em-l+-karboksylat (l^+Omg). Utbytte: 78%. To a solution of 3-thienylmalonic acid indanyl ester (120 mg) in methylene chloride (1.5 ml) is added triethylamine (<1>+2 µl) and oxalyl chloride (26 µl) under ice cooling. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl 7(3-amino-7ct-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-*+-carboxylate (116 mg ) in methylene chloride (3 ml) and pyridine (2<*>+ pl) and the mixture is stirred at 0° C. for 1 hour. The reaction mixture is poured into ethyl acetate, and washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water , washed over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl-7(3-/a- (3 -thienyl)-α-(indan-5-yl)oxycarbonylacetamido7-7<x-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad et ia-3-cephem-1+-carboxylate (l^+Omg).Yield: 78%.
IR:<yCHCl>3 3h0Q^ 332?^ 17g9j 1736^ 1?12 cm<-1>_ IR:<yCHCl>3 3h0Q^ 332?^ 17g9j 1736^ 1?12 cm<-1>_
maks.max.
NMR:£CDC132.07m2H, 2.87br-t(7Hz)<i>+H, 3-50s3H, 3.77s3H,NMR: δCDC132.07m2H, 2.87br-t(7Hz)<i>+H, 3-50s3H, 3.77s3H,
k. 2hs2R,<l>f.56s2H,<»>f.97s1H, (5-02s + 5-O<l>+s)1H, 6.88brs3H. k. 2hs2R,<l>f.56s2H,<»>f.97s1H, (5-02s + 5-O<l>+s)1H, 6.88brs3H.
/a7p2'5 - 68.2 - 1.1° (c 1.023, CHC13). /a7p2'5 - 68.2 - 1.1° (c 1.023, CHCl3).
4 4
Eksempel 11- 21 wV.Example 11- 21 wV.
/v ' lb. I. Tl Til en lbsning av 3-tienylmalonsyre-monobenzhydrylester (710 mg) /v ' lb. I. Tl To a solution of 3-thienylmalonic acid monobenzhydryl ester (710 mg)
i metylenklorid (5 ml) tilsettes trietylamin (210 pl) og oksalylklorid (130 pl) under isavkjbling. Etter omrbring i 15 min. ved den samme temperatur tilsettes blandingen til en lbsning av difenylmetyl 7P-amino-7a-metoksy-3-(1 -metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-<l>+-karboksylat (510 mg) i metylenklorid (15 ml) og pyridin (120 jil) under isavkjbling. triethylamine (210 µl) and oxalyl chloride (130 µl) are added to methylene chloride (5 ml) under ice cooling. After stirring for 15 min. at the same temperature, the mixture is added to a solution of diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylate (510 mg) in methylene chloride (15 ml) and pyridine (120 µl) under ice-cooling.
Etter omrbring i 30 min. helles blandingen ut i etylacetat,After stirring for 30 min. the mixture is poured into ethyl acetate,
vaskes med 2N saltsyre, vann, 5% natriumhydrogenkarbonat og med vann, tbrkes over magnesiumsulf at, og inndampes. Resten kromatograf eres på silikagel (100 g) inneholdende 10% vann, og -j elueres med en blanding av benzen og etylacetat (10:1 - ^:1) washed with 2N hydrochloric acid, water, 5% sodium bicarbonate and with water, washed over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel (100 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1 - ^:1)
til å gi difenylmetyl 7P-/a-(3-tienyl)-a-difenylmetoksykarbonyl-acetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1 - oksadetia-3-cefem-^-karboksylat som et farvelost skum (83<*>+ mg). to give diphenylmethyl 7β-[α-(3-thienyl)-α-diphenylmethoxycarbonyl-acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate as a colorless foam (83<*>+ mg).
IR: y<CH>C13179<0,>1728, 1710sh cm"<1>, IR: y<CH>C13179<0,>1728, 1710sh cm"<1>,
maks.max.
NMR:é°<DC1>3 3-30<S>3H, 3.60s3H, t+.09s2H,<l>+.37s2H, ^.79s1H, NMR: é°<DC1>3 3-30<S>3H, 3.60s3H, t+.09s2H,<l>+.37s2H, ^.79s1H,
*f.90s1H, 6.87s2H. *f.90s1H, 6.87s2H.
Eksempel 11- 22 (fenylester) Example 11-22 (phenyl ester)
Til en suspensjon av 3-tienylmalonsyre-monofenylester (105 mg)For a suspension of 3-thienylmalonic acid monophenyl ester (105 mg)
i metylenklorid (1,5 ml) tilsettes trietylamin ( k2 pl) og oksalylklorid (26 yl) under isavkjbling. in methylene chloride (1.5 ml) add triethylamine (k2 pl) and oxalyl chloride (26 ml) under ice cooling.
Etter omrbring i 15 min. tilsettes blandingen til en lbsning av difenylmetyl 7B-amino-7a-metoksy-3-(1-mety1tetrazol-5-yl)-tiometyl-l-oksadetia-S-cefem-^-karboksylat (116 mg) i metylenklorid (3 ml) og pyridin ( 2h yl) ved 0°C og blandingen omrores ved 0°C i 1 time. Reaksjonsblandingen helles ut i etylacetat, vaskes med 2N saltsyre, vann, vandig 5% natriumhydrogenkarbonatlosning, og vann, torkes over magnesiumsulfat og inndampes. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-S-cephem-^-carboxylate (116 mg) in methylene chloride (3 ml) and pyridine (2h yl) at 0°C and the mixture is stirred at 0°C for 1 hour. The reaction mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and water, dried over magnesium sulfate and evaporated.
Resten kromatograferes på silikagel (10 g) inneholdende 10% vannThe residue is chromatographed on silica gel (10 g) containing 10% water
og elueres med en blanding av benzen og etylacetat (8:1) til åand eluted with a mixture of benzene and ethyl acetate (8:1) to
gi difenylmetyl 7B-/a-(3-tienyl)-a-fenoksykarbonylacetamidQ7-7a-metoksy-3-(1-mety1tetrazol-5-yl)tiornetyl-1-oksadetia-3-cefem-lf-karboksylat som et farvelost skum (125 mg).j/ Utbytte: 76%. give diphenylmethyl 7B-/a-(3-thienyl)-a-phenoxycarbonylacetamide Q7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate as a colorless foam ( 125 mg).j/ Yield: 76%.
IR:<VCHC1>3 3^06, 33»+1 , 1789, 17^0, 1711 cm"<1>, IR:<VCHC1>3 3^06, 33"+1 , 1789, 17^0, 1711 cm"<1>,
maks.max.
NMR:£CD<C1>3 3.<l>+9s3H, 3.78S3H, U.2>+s2H,<l>+.55's2H,<!>+.97s1H, NMR: £CD<C1>3 3.<l>+9s3H, 3.78S3H, U.2>+s2H,<l>+.55's2H,<!>+.97s1H,
5.03s1H, 6.88s1H. 5.03s1H, 6.88s1H.
/"aj<22>,<5>-7^.8 - 1.1° (c = 1.005 CHC13). /"aj<22>,<5>-7^.8 - 1.1° (c = 1.005 CHCl 3 ).
Eksempel 11- 23 »v,"Example 11- 23 »v,"
/ v V, r'7 Til en losning av 3-tienyleddiksyre-mono~3,^-dimetylfenylester / v V, r'7 To a solution of 3-thienylacetic acid mono~3,^-dimethylphenyl ester
(120 mg) i metylenklorid (1,5 ml) tilsettes trietylamin ( h2 ul)(120 mg) in methylene chloride (1.5 ml) add triethylamine ( h2 ul)
og oksalylklorid (26 ul) under/Lsavkjbling. Etter omrbring i 15 min. tilsettes blandingen til en lbsning av difenylmetyl-7B-amino-7a-metoksy-3~(1-me tyltetrazol-5-yl)tiometyl-1-oksa-detia-3-cefem-^-karboksylat (116 mg) i metylenklorid ( 3 ml) og pyridin (2*+ ul) og blandingen omrbres ved 0°C i 1 time. \ j Reaksjonsblandingen helles ut i etylacetat, vaskes med 2N saltsyre, vann, vandig 5% natriumhydrogenkarbonatlbsning, og and oxalyl chloride (26 µl) under cooling. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl-7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem-^-carboxylate (116 mg) in methylene chloride ( 3 ml) and pyridine (2+ µl) and the mixture is stirred at 0°C for 1 hour. The reaction mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and
vann, tbrkes over magnesiumsulfat og inndampes. Resten kromatograferes over silikagel (10 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (10:1) til å gi difenylmetyl 7(3-/a-(3-tienyl)-a-(3,^-dimetylfenyl)oksykarbonyl-acetamid 0.7-7a-metoksy-3- (1 -me tyltetrazol-5-yl) tiometyl-1- water, washed over magnesium sulphate and evaporated. The residue is chromatographed over silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl 7(3-/a-(3-thienyl)-a-(3,^ -dimethylphenyl)oxycarbonyl-acetamide 0.7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-
oksadetia-3-cefem-lf-karboksylat (128 mg). Utbytte: 72%.oxadethia-3-cephem-lf-carboxylate (128 mg). Yield: 72%.
IR: y CH<C1>3 3LK)5, 33^, 1790, 1737, 1712 cm'<1>, IR: y CH<C1>3 3LK)5, 33^, 1790, 1737, 1712 cm'<1>,
maks.max.
NMR: é<C>DC132.22s6H, 3.50s3H, 3.76s3H, k. 2hs2R, ^.56s2H, NMR: ε<C>DC132.22s6H, 3.50s3H, 3.76s3H, k. 2hs2R, ^.56s2H,
<>>+.95s1H, (5.00s + 5.02s)1H, 6.86s2H, 6.90s1H. <>>+.95s1H, (5.00s + 5.02s)1H, 6.86s2H, 6.90s1H.
/i?p2'5 -68.1 - 1.1° (c = 1.002, CHC13). ?p2'5 -68.1 - 1.1° (c = 1.002, CHCl 3 ).
Eksempel H- 2^Example H- 2^
Til en losning av a-difenylmetoksykarbonyl-a-(2-tienyl)-For a solution of α-diphenylmethoxycarbonyl-α-(2-thienyl)-
eddiksyre (176 mg) i metylenklorid (1 ml) tilsettes trietylamin (0,055 ml) og oksalylklorid (0,03^ ml) ved 0°C under nitrogen. To acetic acid (176 mg) in methylene chloride (1 ml) is added triethylamine (0.055 ml) and oxalyl chloride (0.03 ml) at 0°C under nitrogen.
Etter omrbring i 15 min. ved 0°C tilsettes blandingen til enAfter stirring for 15 min. at 0°C, the mixture is added to a
losning av difenylmetyl 7(3-amino-7cc-metoksy-3- (1 -metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^f-karboksylat (101 mg) og pyridin i metylenklorid (3 ml) ved 0°C. Blandingen omrores i 30 min., fortynnes med etylacetat, vaskes med vandig 5% natriumhydrogenkarbonatlbsning, vann, 2N saltsyre, og vann, solution of diphenylmethyl 7(3-amino-7cc-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^f-carboxylate (101 mg) and pyridine in methylene chloride (3 ml) at 0° C. The mixture is stirred for 30 min., diluted with ethyl acetate, washed with aqueous 5% sodium bicarbonate solution, water, 2N hydrochloric acid, and water,
tbrkes over natriumsulfat, og konsentreres under redusert trykk.is washed over sodium sulfate, and concentrated under reduced pressure.
Den oppnådde rest kromatograferes på silikagel (10 g)The obtained residue is chromatographed on silica gel (10 g)
inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat C+:1) til å gi difenylmetyl 7(3-/a-difenylmetoksykarbonyl-a- (2-tienyl)acetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-lf-karboksylat (1^+0 mg) som et farvelost skum. Utbytte: 85%. containing 10% water, and eluted with a mixture of benzene and ethyl acetate C+:1) to give diphenylmethyl 7(3-/α-diphenylmethoxycarbonyl-α-(2-thienyl)acetamido7-7α-methoxy-3-(1-methyltetrazole -5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (1^+0 mg) as a colorless foam.Yield: 85%.
IR: v<CH>Cl31785, 1720 ca. 1700 cm"<1>, IR: v<CH>Cl31785, 1720 approx. 1700 cm"<1>,
maks.max.
NMR:£CDC136.93<s>2H, 5.00s2H, ^.50brs2H,<t>f.l5brs2H,NMR: £CDC136.93<s>2H, 5.00s2H, ^.50brs2H,<t>f.15brs2H,
3.80s3H, 3.>+Obrs3H.3.80s3H, 3.>+Obrs3H.
Eksempel 11- 25 ^ . ■_. Example 11- 25 ^ . ■_.
Til en lbsning av'a-(p-benzyloksyfenyl)malonsyre-monobenzylester For a solution of α-(p-benzyloxyphenyl) malonic acid monobenzyl ester
(376 mg) i metylenklorid ( k ml) tilsettes trietylamin' (105 pl)(376 mg) in methylene chloride (k ml) is added triethylamine' (105 pl)
og oksalylklorid (65^1) under isavkjbling. Etter omrbring i 15 min. under isavkjbling tilsettes blandingen til en lbsning av difenylmetyl 7(3-amino-7a-metoksy-3- (1 -metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (25^ mg) og pyridin (60 pl) i metylenklorid (7 ml) under isavkjbling. Etter omr<p>ring i 30 min. ved den samme temperatur helles blandingen ut i etylacetat, vaskes med 2N saltsyre, vann, vandig 5% natriumhydrogenkarbonatlbsning, og vann, tbrkes over magnesiumsulfat, and oxalyl chloride (65^1) under ice cooling. After stirring for 15 min. under ice-cooling, the mixture is added to a solution of diphenylmethyl 7-(3-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (25 mg) and pyridine (60 µl) in methylene chloride (7 ml) under ice-cooling. After stirring for 30 min at the same temperature, the mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and water, dried over magnesium sulfate,
og inndampes. Resten kromatograferes på silikagel (20 g) inneholdende 10% vann, og elueres med en blanding av benzen og etylacetat (10:1) til å gi difenylmetyl 7(3-/cc-(p-benzyloksy-f enyl)-oc-benzyloksykarbonylacetamido7-7a-metoksy-3- (1-metyl-tetrazol-5-yl)tiometyl-i-oksadetia-3-cefem-^f-karboksylat som et farvelost skum, (390 mg). and evaporated. The residue is chromatographed on silica gel (20 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl 7(3-/cc-(p-benzyloxy-phenyl)-oc-benzyloxycarbonylacetamido7 -7α-Methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-β-carboxylate as a colorless foam, (390 mg).
,CDC17, CDC17
NMR:dJ 3-38s3H, 3.62s3H, >+.13s2H, l+A5s2H, lf.56s1H,NMR: dJ 3-38s3H, 3.62s3H, >+.13s2H, 1+A5s2H, lf.56s1H,
<l>+.96s3H, 5.09s2H, 6.82d(9Hz)2H, 6.8>+s1H. <l>+.96s3H, 5.09s2H, 6.82d(9Hz)2H, 6.8>+s1H.
IR: v<CH>C133^11 , 3326, 1789, 1722, 1700shcm"<1>, IR: v<CH>C133^11 , 3326, 1789, 1722, 1700shcm"<1>,
maks.max.
/a?23 -72.O - 2° (c 0.553, CHC13). /α?23 -72.0 - 2° (c 0.553, CHCl 3 ).
Eksempel 11- 26Example 11-26
Til en lbsning av a-difenylmetoksykarbonyl-p-(p-metoksybenzyl)-oksyfenyleddiksyre (193 m§) i metylenklorid (2 ml) tilsettes trietylamin (0,0^-16 ml) og oksalylklorid (0,G$6 ml) ved 0°C og blandingen omrbres i 30 min. Den resulterende lbsning tilsettes til en lbsning av difenylmetyl 7B-amino-7a-metoksy-3-(1-metyl- \ tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-'+-karboksylat (101 ,7 mg) To a solution of α-diphenylmethoxycarbonyl-p-(p-methoxybenzyl)-oxyphenylacetic acid (193 m§) in methylene chloride (2 ml) is added triethylamine (0.0^-16 ml) and oxalyl chloride (0.G$6 ml) at 0 °C and the mixture is stirred for 30 min. The resulting solution is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyl-\tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-'+-carboxylate (101.7 mg )
og pyridin (0,02l+ ml) i metylenklorid ( h ml) ved 0°C. Etter omrbring i 30 min. ved 0°C fortynnes blandingen med etylacetat, vaskes med vann, tbrkes over natriumsulfat og konsentreres. and pyridine (0.02l+ ml) in methylene chloride (h ml) at 0°C. After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with water, washed over sodium sulfate and concentrated.
Resten kromatograferes på silikagel (20 g) inneholdende 10% vannThe residue is chromatographed on silica gel (20 g) containing 10% water
og elueres med en blanding av benzen og etylacetat (*+:1) til åand eluted with a mixture of benzene and ethyl acetate (*+:1) to
gi difenylmetyl 7B-/a-p-(p-metoksybenzyl)oksyfenyl-a-difenyl- give diphenylmethyl 7B-/a-p-(p-methoxybenzyl)oxyphenyl-a-diphenyl-
me toksykarbonylace tamido7-7cc-metoksy-3- (1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-M-karboksylat (190,7 mg) som et farvelost skum. Utbytte: 98%. me toxycarbonylace tamido7-7cc-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-M-carboxylate (190.7 mg) as a colorless foam. Yield: 98%.
IR:Y<CHC1>3 3^20, 3325, 1792, 1730, 1700 sh cm"<1>, IR:Y<CHC1>3 3^20, 3325, 1792, 1730, 1700 sh cm"<1>,
maks.max.
NMR-£CDC13(3.38S<+>3.<l>+Os)3H, 3-70S3H, 3-77s3H,<>>+.20s2H, NMR-£CDCl3(3.38S<+>3.<l>+Os)3H, 3-70S3H, 3-77s3H,<>>+.20s2H,
<!>+.<l>f7s2H, >+.68s1H, l+.95s2H, 5.00s1H. <!>+.<l>f7s2H, >+.68s1H, l+.95s2H, 5.00s1H.
Eksempel 11- 27 ;y,'Example 11- 27 ;y,'
Ved en fremgangsmåte tilsvarende eksempel 11-26 behandles difenylmetyl 76-amino-7a-metoksy-3~(1-mety1tetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (800 mg) med a-p-(p-metoksybenzyl)oksyfenyl-a-p-metoksybenzyloksykarbonyl-acetylklorid fremstilt fra den tilsvarende fri syre (1370 mg) In a method similar to Example 11-26, diphenylmethyl 76-amino-7a-methoxy-3~(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (800 mg) is treated with a-p- (p-Methoxybenzyl)oxyphenyl-a-p-methoxybenzyloxycarbonyl-acetyl chloride prepared from the corresponding free acid (1370 mg)
og oksalylklorid i nærvær av pyridin (190 mg) og trietylaminand oxalyl chloride in the presence of pyridine (190 mg) and triethylamine
(0,33 ml) i metylenklorid ( k2 ml) til å gi difenylmetyl 7(3-/a-p-(p-metoksybenzyl)oksyfenyl-a-p-metoksybenzyloksykarbonyl- ,/ acetamido7-7a-metoksy-3- (1 -me tylte tr azol-5-yl)-tiometyl-1 - oksadetia-3-cefem-i+-karboksylat (1,^5 g). (0.33 mL) in methylene chloride (k2 mL) to give diphenylmethyl 7(3-/α-p-(p-methoxybenzyl)oxyphenyl-α-p-methoxybenzyloxycarbonyl-,/acetamido7-7α-methoxy-3-(1-methyl tr azol-5-yl)-thiomethyl-1-oxadethia-3-cephem-i+-carboxylate (1.5 g).
Utbytte: nesten kvantitativt.Yield: almost quantitative.
IR:vCHC131792, 1725, 1700shcm"<1>.IR:vCHC131792, 1725, 1700shcm"<1>.
maks.max.
NMR: £CDC13 3A5S3H/2, 3.i+8s3H/2, 3-78s6H, 3.82s3K, NMR: £CDCl3 3A5S3H/2, 3.i+8s3H/2, 3-78s6H, 3.82s3K,
lf.27 brs2H, l+.57brs3H,<!>+.98s2H, 5.03s1H,lf.27 brs2H, l+.57brs3H,<!>+.98s2H, 5.03s1H,
5.13S2H. 5.13S2H.
Eksempel 1 1- 28 ''Example 1 1- 28''
iin
- - •• ) i Til en omrort suspensjon av p-(p-metoksybenzyloksy)fenylmalon- - - •• ) i To a stirred suspension of p-(p-methoxybenzyloxy)phenylmalon-
syre (125 mg) i metylenklorid (3 ml) tilsettes trietylamin (55 ul) og oksalylklorid (26 pl) ved -15°C og suspensjonen / omrores i kO min. ved 0°G. Blandingen tilsettes til en losning av difenylmetyl 7B-amino-7a-metoksy-3-(1-metyltetrazol-5-yD-tiometyl-1-oksadetia-3-cefem-l+-karboksylat (100 mg) i metylen- acid (125 mg) in methylene chloride (3 ml), triethylamine (55 ul) and oxalyl chloride (26 ul) are added at -15°C and the suspension / is stirred for kO min. at 0°G. The mixture is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yD-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (100 mg) in methylene-
klorid (3 ml) og pyridin (63 pl) og blandingen omrores i 30 min. ved 0°C. Reaksjonsblandingen fortynnes med etylacetat, vaskes med vandig 2N saltsyre og vann, tbrkes over natriumsulfat og konsentreres til å gi et råprodukt (212 mg) som kromatograferes på silikagel (20 g) og elueres med en blanding av etylacetat og eddiksyre (99:1) til å gi difenylmetyl 7|3-</>a-p-(p-metoksybenzyl-oksy)fenyl-a-karboksyacetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat som et skum (71 mg). Utbytte: k5%. chloride (3 ml) and pyridine (63 µl) and the mixture is stirred for 30 min. at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N hydrochloric acid and water, triturated over sodium sulfate and concentrated to give a crude product (212 mg) which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99:1) to to give diphenylmethyl 7|3-</>a-p-(p-methoxybenzyl-oxy)phenyl-a-carboxyacetamido7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylate as a foam (71 mg). Dividend: k5%.
IR: yCHC133385, 3300-2l+OObr, 1790, 1762, 1711+, 1612 cm<-1>, IR: yCHC133385, 3300-2l+OObr, 1790, 1762, 1711+, 1612 cm<-1>,
maks.max.
NMR:<$<CD>Cl33A3s3H/2, 3A6s3H/2, 3.7^s3H, 3-78s6H,NMR: <$<CD>Cl33A3s3H/2, 3A6s3H/2, 3.7^s3H, 3-78s6H,
l+.22brs2H, >f.56brs3H, l+.96s2H, 5.05s1H.l+.22brs2H, >f.56brs3H, l+.96s2H, 5.05s1H.
Det ovenfor oppnådde produkt ( ho mg) gir 7P~(a-hydroksyfenyl-a-karboksyace tamido) -7<x-metoksy-3- (1 -metyltetrazol-5-yl) tiometyl-1-oksadetia-3-cefem-lf-karboksylsyre ved innvirkning av trifluoreddiksyre (0,2 ml) og anisol (0,<*>+ ml) ved 0°C i 20 min. The product obtained above (ho mg) gives 7P~(α-hydroxyphenyl-α-carboxyacetamido)-7<x-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-lf -carboxylic acid by the action of trifluoroacetic acid (0.2 ml) and anisole (0.<*>+ ml) at 0°C for 20 min.
III. Deproteksjon.III. Deprotection.
Eksempel III- 1Example III-1
Til en lbsning av difenylmetyl-7|3- (a-fenyl^a-dif enylmetoksy-karbonylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (120 mg) i metylenklorid (3 ml) tilsettes anisol (0,3 ml) og trifluoreddiksyre (0,3 ml) i nitrogen- To a solution of diphenylmethyl-7|3-(α-phenylα-diphenylmethoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylate (120 mg ) in methylene chloride (3 ml), anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) are added in nitrogen-
atmosfære ved 0°C og blandingenomrbres i 1,5 timer. Reaksjonsblandingen konsentreres under redusert trykk. Resten renses ved kromatografering på silikagel (10 g) inneholdende 10% vann og elueres med en b]aiding av etylacetat og eddiksyre (9:1) til å gi 7P-(a-fenyl-a-karboksyacetamido)-3-(1-metyltetrazol-5-yl)tiornetyl-1-oksadetia-3-cefem-l+-karboksylsyre (57 mg) som pulver. atmosphere at 0°C and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (10 g) containing 10% water and eluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7P-(α-phenyl-α-carboxyacetamido)-3-(1- methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (57 mg) as powder.
Smp. 157 - 159°C, (spalting). Utbytte: 81%.Temp. 157 - 159°C, (decomposition). Yield: 81%.
IH: Vllll]1778, 1670, 1606cm"<1>. IH: Vllll]1778, 1670, 1606cm"<1>.
IR:V^s. 3^+20, 2520br, 1775, 167^, 1606, 1528,5, 1376 cm"<1>. IR:V^s. 3^+20, 2520br, 1775, 167^, 1606, 1528.5, 1376 cm"<1>.
UV: y1^ NaHC03265.5 nm (£ = 9^+2).UV: y1^ NaHCO3 265.5 nm (£ = 9^+2).
maks.max.
NMR: g1^ NaHC03i D2°l+.02s3H, h. 05<+>)+.32ABq(1 3. 5Hz)2H, NMR: g1^ NaHCO3i D2°l+.02s3H, h.05<+>)+.32ABq(1 3.5Hz)2H,
<l>+.55brs2H, 5.l6d(lfHz)1H/2, 5-21d AHz)m/2, <l>+.55brs2H, 5.l6d(lfHz)1H/2, 5-21d AHz)m/2,
5A8d(l+Hz)1H, 7-37s5H, 5.08brs1H,5A8d(l+Hz)1H, 7-37s5H, 5.08brs1H,
(den siste topp gradvis avtagende)(the last peak gradually decreasing)
/a?<2>)<3>90.3~^.2° (c = 0:310, 1% NaHC03). /α?<2>)<3>90.3~^.2° (c = 0:310, 1% NaHCO 3 ).
CD: A (e) (0.155% NaHC03) 305(0), 285(- 2500), 276.5(0), CD: A (e) (0.155% NaHCO 3 ) 305(0), 285(- 2500), 276.5(0),
258(+11700), 2<1>+9-5(0), 232(- 59100), 258(+11700), 2<1>+9-5(0), 232(- 59100),
210(- 3500). 210 (- 3500).
Eksempel III-2Example III-2
Til en lbsning av difenylmetyl 76-/a-(5-indanyl)oksykarbonyl-a-fenylacetamido7-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat O^Af mg) i metylenklorid (3 ml) tilsettes anisol (0,2 ml) og trifluoreddiksyre ( 0, h ml) under isavkjbling og blandingen omrbres i 2 timer. Reaksjonsblandingen fortynnes med etylacetat, vaskes med vann og vandig natriumhydrogenkarbonat, tbrkes og inndampes. Resten behandles med eter og det resulter- To a solution of diphenylmethyl 76-/α-(5-indanyl)oxycarbonyl-α-phenylacetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate O^Af mg) in methylene chloride (3 ml) anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) are added under ice cooling and the mixture is stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue is treated with ether and the resulting
ende pulver samles ved filtrering til å gi natrium 7P-/«-(5-indanyl)oksykarbonyl-a-fenylacetamid07-3-(1-metyltetrazol-5-yl)-tiometyl-1 -oksadetia-3-cefem-^-karboksyJat (60 mg). final powder is collected by filtration to give sodium 7β-[(5-indanyl)oxycarbonyl-α-phenylacetamide O7-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-3-carboxylate (60mg).
IR: ^Saks1176°'l690sh, 1670 cm"<1>.IR: ^Sax1176°'l690sh, 1670 cm"<1>.
EksempelExample
Til en lbsning av difenylmetyl 7(3-(q-karboksy-a- fenyla cetamido)- ~/} 3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-k-karboksylat (57.6 mg) i metylenklorid (10 ml) tilsettes anisol (1 ml) og trifluoreddiksyre (1 ml) under nitrogenatmosfære og isavkjbling, og blandingen omrores i 70 min. Reaksjonsblandingen konsentreres under redusert trykk til å gi 7(3- (a-fenyl-a-karboksyacetamido) -3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre. Utbytte: nesten kvantitativt. To a solution of diphenylmethyl 7(3-(q-carboxy-a-phenylacetamido)-~/} 3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-k-carboxylate (57.6 mg ) in methylene chloride (10 ml), anisole (1 ml) and trifluoroacetic acid (1 ml) are added under a nitrogen atmosphere and ice cooling, and the mixture is stirred for 70 min. The reaction mixture is concentrated under reduced pressure to give 7(3-(a-phenyl-a- carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid Yield: almost quantitative.
Råprodukt.Raw product.
IR: Vmaks!1778'167°'16°^ cm~1' IR: Vmax!1778'167°'16°^ cm~1'
Eksempel III- WExample III-W
Til en lbsning av 7(3-(a-difenylmetoksykarbonyl-a-fenyl-<K/?>acetamido)-3-(1-metylte trazol-5-yl)tiometyl-1-oksadetia-3-cefem-karboksylsyre (72 mg) i metylenklorid 5(2 ml) tilsettes anisol (0,2 ml) og trifluoreddiksyre (0,2 ml) ved 0°C. Etter 50 min. To a solution of 7(3-(α-diphenylmethoxycarbonyl-α-phenyl-<K/?>acetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-carboxylic acid (72 mg) in methylene chloride 5 (2 ml), anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) are added at 0° C. After 50 min.
under isavkjbling konsentreres reaksjonsblandingen unjer redusert trykk. Resten renses ved kromatografering på silikagel (5 g) inneholdende 10% vann og elueres med en blanding av eddik- during ice cooling, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5 g) containing 10% water and eluted with a mixture of acetic
syre og etylacetat (1:9) til å gi 7P-(a-karboksyca-fenylacet-amido)-3-(>metyltetrazol-5-yl)tiometyl-1-oksadetia-3~cefem-^-karboksylsyre (<!>+1 mg). Smp. 165 - 170°C (spalting). acid and ethyl acetate (1:9) to give 7P-(α-carboxyca-phenylacetamido)-3-(>methyltetrazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylic acid (<!> +1 mg). Temp. 165 - 170°C (decomposition).
Utbytte: 75%.Yield: 75%.
IR:Y<maksl>1778'16?0'1605 cm~1 ' IR:Y<maxl>1778'16?0'1605 cm~1 '
Eksempel III- 5Example III-5
En lbsning av difenylmetyl 7(3- (a-p-nitrobenzyloksykarbonyl-a- /^ 5( fenylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (715 mg) i en blanding av metanol ( ho ml) A solution of diphenylmethyl 7(3-(α-p-nitrobenzyloxycarbonyl-α- /^ 5(phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (715 mg) in a mixture of methanol (ho ml)
og tetrahydrofuran (>+0 ml) rystes i nærvær av på forhånd redusert 5% palladium på kull (700 mg) og 10% saltsyre (2 ml) and tetrahydrofuran (>+0 mL) is shaken in the presence of pre-reduced 5% palladium on charcoal (700 mg) and 10% hydrochloric acid (2 mL)
under hydrogen ved en atmosfære og romtemperatur i 70 min. under hydrogen at one atmosphere and room temperature for 70 min.
Reaksjonsblandingen filtreres for å fjerne katalysatoren,The reaction mixture is filtered to remove the catalyst,
fortynnes med vann (120 ml) inneholdende 10% saltsyre (2 ml), konsentreres for å fjerne det organiske Ibsningsmiddel, og ekstraheres med etylacetat. Ekstrakten vaskes med vann, torkes over magnesiumsulfat, og inndampes under redusert trykk til å diluted with water (120 ml) containing 10% hydrochloric acid (2 ml), concentrated to remove the organic thickener, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to
gi difenylmetyl 7(3-(a-karboksy-a-fenylacetamido)-3-(1-metyl-tetxazol-5-yl)tiometyl-1-oksadetia-3~cefem-^-karboksylat (576 mg). Utbytte: 97,6%. (råprodukt). give diphenylmethyl 7(3-(α-carboxy-α-phenylacetamido)-3-(1-methyl-tetxazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylate (576 mg). Yield: 97 .6% (raw product).
Eksempel III- 6Example III- 6
En blanding av difenylmetyl 7(3-(oc-p-hydroksyf enyl-oc-t-butoksy-kar bonylacetamido)-3-(1-mety1tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat ( yh mg), tiofenol (0,075 mD°g trifluoreddiksyre (0,75 ml) omrbres i 1,5 timer under isav- A mixture of diphenylmethyl 7(3-(oc-p-hydroxyphenyl-oc-t-butoxy-carbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (yh mg), thiophenol (0.075 mD°g trifluoroacetic acid (0.75 ml) is stirred for 1.5 hours under ice-
kjbling. Reaksjonsblandingen inndampes under redusert trykk.kidding The reaction mixture is evaporated under reduced pressure.
Resten renses ved kromatografering på silikagel inneholdendeThe residue is purified by chromatography on silica gel containing
10% vann og elueres med en blanding av eddiksyre og etylacetat10% water and eluted with a mixture of acetic acid and ethyl acetate
(1:9). Eluatet behandles med en blanding av eter og pentan til(1:9). The eluate is treated with a mixture of ether and pentane
å gi 7P- (<*-p-hydroksyf enyl-oc-karboksyacetamido)-3- (1 -metyl- y-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre to give 7P- (<*-p-hydroxyenyl-oc-carboxyacetamido)-3-(1-methyl-γ-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid
(30mg). Utbytte 58,9%.(30mg). Yield 58.9%.
Smp. 130 - 1<1>+'2°C (spalting).Temp. 130 - 1<1>+'2°C (decomposition).
IR: V 3<1>+00'1787'1720 cm~<1>-IR: V 3<1>+00'1787'1720 cm~<1>-
UV: V^s? 273 nm ( f = 7850)-UV: V^s? 273 nm ( f = 7850)-
Eksempel III- 7 r ) ■ Example III- 7 r ) ■
'• Cl-, r 7 Til en lbsning av difenylmetyl 7(3- (a-p-hydroksyfenyl-a-difenyl-metoksykarbonylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1 - oksadetia-3-cefem-V-karboksylat (137 mg) i metylenklorid (3 ml) tilsettes anisol (0,3 ml) og trifluoreddiksyre (0,3 ml) ved 0°C under nitrogen. Etter omrbring i 1 time ved 0°C konsentreres blandingen under redusert trykk, behandles med eter, og vaskes med eter til å gi 7(3- (oc-p-hydroksyf enyl-a- '• Cl-, r 7 To a solution of diphenylmethyl 7(3- (a-p-hydroxyphenyl-a-diphenyl-methoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1 - oxadethia-3-cephem-V -carboxylate (137 mg) in methylene chloride (3 ml) is added anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) at 0° C. under nitrogen. After stirring for 1 hour at 0° C. the mixture is concentrated under reduced pressure, treated with ether, and washed with ether to give 7(3-(oc-p-hydroxy enyl-α-
karboksyacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-<l>+-karboksylsyre som farvelost pulver (81 mg) som spaltes ved 130 - 1<l>f2°C. Utbytte: 59,6%. y~ H carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid as a colorless powder (81 mg) which decomposes at 130 - 1<l>f2°C. Yield: 59.6%. y~ H
IR: vSs. 3<l>f00'1787'1720 cm"<1>'IR: vs. 3<l>f00'1787'1720 cm"<1>'
UV:;YCH30H273nm ( £= 7850). UV:;YCH30H273nm ( £= 7850).
maks.max.
Eksempel III- 8Example III-8
Til en lbsning av difenylmetyl 7^-/ J*-~ (2-tienyl)-a-t-butoksy-kar bonylacetamido7-3-(1-mety1tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-+-karboksylat (<1>+9 mg) i metylenklorid (1 ml) tilsettes anisol (0,*+ ml) i trif luoreddiksyre (1 ml) ved 0°C og blandingen ■./-(■ omrbres under isavkjbling i h timer og ved romtemperatur i ' To a solution of diphenylmethyl 7^-/ J*-~ (2-thienyl)-α-t-butoxy-carbonylacetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-+-carboxylate (<1>+9 mg) in methylene chloride (1 ml) is added anisole (0.*+ ml) in trifluoroacetic acid (1 ml) at 0°C and the mixture ■./-(■ is stirred under ice cooling for h hours and at room temperature i'
kO min. Reaks jonsblandingen konsentreres under redusert trykk. Resten renses ved kromatografering på silikagel (5 g) inneholdende kO min. The react ion mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5 g) containing
10% vann, og elueres med en blanding av etylacetat og eddiksyre (9:1). Eluatet behandles med eter til å gi 76-/et- (2-tienyl)-a-karboksyacetamido7-3-(1-metyltetrazol-5-yl)ti ornetyl-1-oksadetia-3-cefem-if-karboksylsyre (23 mg) som et amorft pulver. 10% water, and eluted with a mixture of ethyl acetate and acetic acid (9:1). The eluate is treated with ether to give 76-(2-thienyl)-α-carboxyacetamido7-3-(1-methyltetrazol-5-yl)thiornetyl-1-oxadethia-3-cephem-if-carboxylic acid (23 mg ) as an amorphous powder.
Smp. 156 - 160°C (spalting ved oppskumming). Utbytte: 33,5%.Temp. 156 - 160°C (decomposition during foaming). Yield: 33.5%.
IR: VSks. 3390'1765'1670'16°8' 1520 cm"1' IR: VSks. 3390'1765'1670'16°8' 1520 cm"1'
/<*<723>- 62.0 - 3-7° (c = 0.279, 1% NaHCO^). /<*<723>- 62.0 - 3-7° (c = 0.279, 1% NaHCO 3 ).
CD: A (6) (0.279, 1% NaHC03) 300(0), 282(- 2600), 276(0), CD: A (6) (0.279, 1% NaHCO 3 ) 300(0), 282(- 2600), 276(0),
259(+ 11100), 21+9(0) , 231 .5(-^7^00) , 210(- 9700). 259(+ 11100), 21+9(0) , 231 .5(-^7^00) , 210(- 9700).
Eksempel III- 9Example III-9
En blanding av difenylmetyl 7P-/a-(3-tienyl)-a-t-butoksykarbonyl-acetamido7-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-lf-karboksylat (56 mg), anisol (0,35 ml), og trif luoreddiksyre (0,35 ml) omrbres ved 0°C i 2 timer. Reaksjonsblandingen A mixture of diphenylmethyl 7β-[α-(3-thienyl)-α-t-butoxycarbonyl-acetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (56 mg), anisole (0.35 ml), and trifluoroacetic acid (0.35 ml) are stirred at 0°C for 2 hours. The reaction mixture
inndampes under redusert trykk. Resten renses vedevaporated under reduced pressure. The rest is cleaned with wood
kromatografering på silikagel (5 g) inneholdende 10% vann,chromatography on silica gel (5 g) containing 10% water,
elueres med en blanding av etylacetat og eddiksyre (9:1) og behandles i en blanding av n-pentan og eter (2:1) til å gi ,/7P-/oc-(3-tienyl)-a-karboksyacetamido7-3-(1 -metyltetrazol-5-yl)- Y " tiometyl-1-oksadetia-3-cefem-l+-karboksylsyre (37 mg) som farvelost pulver. Smp. 155 - 160°C. Utbytte: 96,8%. eluted with a mixture of ethyl acetate and acetic acid (9:1) and treated in a mixture of n-pentane and ether (2:1) to give ,/7P-/oc-(3-thienyl)-α-carboxyacetamido7-3 -(1-methyltetrazol-5-yl)-Y" thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (37 mg) as colorless powder. M.p. 155 - 160°C. Yield: 96.8%.
IR: Vjj^g^ 3<>>+00, 1770, 1692, 1610 cm"<1>.IR: Vjj^g^ 3<>>+00, 1770, 1692, 1610 cm"<1>.
Eksempel 111- 10Example 111-10
Til en losning av difenylmetyl 76-(a-difenylmetoksykarbonyl-a-fenylacetamido)-3-(1-t-butoksykarbonylmety1tetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-<l>+-karboksylat (60 mg) i anisol (0,5 ml) tilsettes trif luoreddiksyre (1 ml) under isavkjbling under nitrogen, og blandingen holdes ved 0°C over natten. Reaksjonsblandingen konsentreres under redusert trykk, resten To a solution of diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylate (60 mg ) in anisole (0.5 ml), trifluoroacetic acid (1 ml) is added under ice-cooling under nitrogen, and the mixture is kept at 0°C overnight. The reaction mixture is concentrated under reduced pressure, the residue
behandles med etylacetat til å gi rå 7S-(a-karboksy-a-fenyl- J acetamido)-3-(1-karboksymetyltetrazol-5-yl)tiometyl-1-oksadetia- v 3-cefem-^f-karboksylsyre (22 mg) som pulver. Utbytte: 6k%. treated with ethyl acetate to give crude 7S-(α-carboxy-α-phenyl- J acetamido)-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia- v 3-cephem-^f-carboxylic acid (22 mg) as powder. Yield: 6k%.
IR: xSSs. 1775'1725 cra"<1>-IR: xSSs. 1775'1725 cra"<1>-
Eksempel III- 11Example III-11
Til en lbsning av difenylmetyl 76-Za-t-butoksykarbonyl-a-(2-tienyl)acetamidq7-3-(1-t-butoksykarbonylmetyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (96 mg) i anisol (0,5 ml) tilsettes trifluoreddiksyre (1,5 ml) under nitrogenatmosfære under isavkjbling og blandingen får stå over natten under isavkjbling. Reaksjonsblandingen konsentreres under/redusert trykk. Resten behandles med en blanding av eter og 7 etylacetat til å gi rå 7P-/a-(2-tienyl)-a-karboksyacetamido7-3-(1-karboksymety1tetrazol-5-yl)tiometyl-1-oksadetia-3-cef em- k-karboksylsyre (30 mg). Smp. med spalting fra 160°C To a solution of diphenylmethyl 76-Za-t-butoxycarbonyl-α-(2-thienyl)acetamide q7-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate ( 96 mg) in anisole (0.5 ml), trifluoroacetic acid (1.5 ml) is added under a nitrogen atmosphere under ice cooling and the mixture is allowed to stand overnight under ice cooling. The reaction mixture is concentrated under/reduced pressure. The residue is treated with a mixture of ether and 7 ethyl acetate to give crude 7β-β-(2-thienyl)-α-carboxyacetamido7-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em - k-carboxylic acid (30 mg). Temp. with cleavage from 160°C
Utbytte: h8%.Yield: h8%.
IR: ^maL. 1780'172? cm"<1>'IR: ^maL. 1780'172? cm"<1>'
Eksempel 111- 12Example 111-12
Til en losning av difenylmetyl 7(3- (a-fenyl-a-difenylmetoksy-karbonylacetamido)-3-(2-mety1-1,3 A~tiadiazol-5-yl)tiometyl-1 -oksadetia-3-cefem-l+-karboksylat (170 mg) i metylenklorid (3 ml) tilsettes anisol (0,2 mi) og trifluoreddiksyre ( 0 , h ml) To a solution of diphenylmethyl 7(3-(α-phenyl-α-diphenylmethoxy-carbonylacetamido)-3-(2-methyl-1,3 A~thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-l+ -carboxylate (170 mg) in methylene chloride (3 ml), anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) are added
ved 0°C og blandingen omrores ved 0°C i 1,5 timer. Reaksjonsblandingen konsentreres under redusert trykk. Resten renses på silikagel (10 g) inneholdende 10% vann, elueres med en blanding av etylacetat og eddiksyre (9:1) og behandles med en blanding av A etylacetat og eter til å gi 7(3- (a-_feny_l-a-karboksyacetamido)-3-£2^metyl-1 ,3 ,*+-tiadjUz_ol-_5-yl) tiometyl-1 -oksadetia-3-cef em- h-karboksylsyre C+5,8 mg) som et farvelost pulver. Utbytte: >+5,1%. at 0°C and the mixture is stirred at 0°C for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified on silica gel (10 g) containing 10% water, eluted with a mixture of ethyl acetate and acetic acid (9:1) and treated with a mixture of A ethyl acetate and ether to give 7(3- (a-_pheny_l-a- carboxyacetamido)-3-£2^methyl-1,3,*+-thiadjUz_ol-_5-yl)thiomethyl-1-oxadethia-3-cef em-h-carboxylic acid C+5.8 mg) as a colorless powder. Dividend: >+5.1%.
Smp. 130 - 132°C. Temp. 130 - 132°C.
IR:</>maks. 3<l>f10'1772'1600 cm~<1>'IR:</>max. 3<l>f10'1772'1600 cm~<1>'
Eksempel 111- 13Example 111-13
Til en lbsning av difenylmetyl 7(3-(a-difenylmetoksy-karbonyl-a-fenylacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefemA-karboksylat (121,2 mg) i metylenklorid (2 ml) tilsettes anisol (0,2 ml) og trifluoreddiksyre ( 0, h ml) ved 0°C. To a solution of diphenylmethyl 7(3-(α-diphenylmethoxy-carbonyl-α-phenylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem A-carboxylate (121, 2 mg) in methylene chloride (2 ml) add anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) at 0°C.
Etter omrbring ved 0°C i 1 time konsentreres reaksjons- ^>blandingen under redusert trykk og behandles med eter til gi /uA 7(3-(a-karboksy-a-. - feny_lacetamido)-7a-metoksy-3-(1 -metyltetrazol-5-yDtiometyl-1 -oksadetia-3-cefem-^-karboksylsyre A6,5 mg) som et farvelost pulver. Utbytte: 59,8%. Smp. 110 - 116°C. After stirring at 0°C for 1 hour, the reaction mixture is concentrated under reduced pressure and treated with ether to give /uA 7(3-(α-carboxy-α-.-phenyl_lacetamido)-7α-methoxy-3-(1 -methyltetrazol-5-ylDithiomethyl-1-oxadethia-3-cephem-^-carboxylic acid A6.5 mg) as a colorless powder. Yield: 59.8%. M.p. 110 - 116°C.
UV:)fCH30H 275.5 nm 9<l>+00). - 19 A - 2.8°(c=211, UV:)fCH 3 OH 275.5 nm 9<l>+00). - 19 A - 2.8°(c=211,
maks* CH30H).max* CH30H).
IR: V^s. 178o>1717>1631 cm"<1>.IR: V^s. 178o>1717>1631 cm"<1>.
NMR: 5<D>2° +NaHC03(3.<l>+6s + 3.53s)P, (3-99s +<>>+.02s)3H,NMR: 5<D>2° +NaHCO3(3.<l>+6s + 3.53s)P, (3-99s +<>>+.02s)3H,
k. O -<l>+.2m2H,<l>+.<l>f8s2H,<l>+.53s1H, 5.13s1H, k. O -<l>+.2m2H,<l>+.<l>f8s2H,<l>+.53s1H, 5.13s1H,
7-38s5H. 7-38s5H.
Eksempel III- A tcd?'^Example III- A tcd?'^
Til en losning av difenylmetyl 78-(a-difenylmetoksykarbonyl-a-p-acetoksyfenylacetamido)-7a-metoksy-3-(1 -metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat 033A mg) i metylenklorid (2 ml) tilsettes anisol (0,2 ml) og trifluor- 1 1^ eddiksyre (0 ,hml) ved 0°C Blandingen omrores i *+5 min., Nv inndampes og behandles med en blanding av eter og pentan, og eter til å gi 78-(a-karboksy-a-p-acetoksyfenylacetamido)-7a- j metoksy-3- (1 -me tyl te tr azol-5-yl) tiometyl-1 - oksad e tia-3-cef em-l+-karboksylsyre (77 mg) som et farvelost skum. Smp. 110 - 115°C. Utbytte 91 ,9%. To a solution of diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-acetoxyphenylacetamido)-7a-methoxy-3-(1 -methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate 033A mg) in methylene chloride (2 ml), anisole (0.2 ml) and trifluoroacetic acid (0.hml) are added at 0°C. The mixture is stirred for *+5 min., Nv is evaporated and treated with a mixture of ether and pentane, and ether to give 78-(α-carboxy-α-β-acetoxyphenylacetamido)-7α-j methoxy-3-(1-methyl tetrazol-5-yl)thiomethyl-1-oxad e thia-3-cef em- l+-carboxylic acid (77 mg) as a colorless foam. Temp. 110 - 115°C. Yield 91.9%.
UV: ><CH>3<0H>275 nm ( 6=9300) . UV: <CH>3<OH>275 nm ( 6=9300) .
maks .• max.•
[ vj^ 27,5 - 2,6° (c = 0,258, CH30H). [vj^ 27.5 - 2.6° (c = 0.258, CH 3 OH).
IR: V Ss. 1782'1728'1635 cm"<1->IR: V Ss. 1782'1728'1635 cm"<1->
NMR:£<D>2° + NaHC032.33s3H, ( 3Ms + 3-53s)3H,NMR: £<D>2° + NaHC032.33s3H, (3Ms + 3-53s)3H,
(3.99s + lf.02s)3H, ca. l+.13brs2H,(3.99s + lf.02s)3H, approx. l+.13brs2H,
*+A6brs2H, 5.13s1H, 7.12 + 7.*+7ABq(8Hz)>+H. *+A6brs2H, 5.13s1H, 7.12 + 7.*+7ABq(8Hz)>+H.
Eksempel 111-<1>5^ . / Example 111-<1>5^ . /
V V
Til en losning av difenylmetyl 78-(a-difenylmetoksykarbonyl-a-p-hydroksyf enylacetamido)r-7a-metoksy-3- (1-me tylte tr azol-5-yl)- rj tiometyl-1-oksadetia-3-cefem-l+-karboksylat (8^,6 mg) i metylen- M° klorid (2 ml) tilsettes anisol (0,1 ml) og trifluoreddiksyre (0,3 ml) ved 0°C. Etter omrbring i.>5 min. i 0°C inndampes blandingen under redusert trykk og behandles med en blanding av eter og n-pentan, og eter til å gi 7P-(a-karboksy-a-p-hydroksyf enylace tamido)-7<x-metoksy-3- (1-me tylte tr azol-5-yl) tiometyl-1 - oksadetia-3-cefem-<1>+-karboksylsyre ( U- 6, h mg) som et farvelost pulver. Utbytte: 89,9%. Smp. 117 - 122°C (spalting). To a solution of diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-hydroxyphenylacetamido)r-7a-methoxy-3-(1-methyl trazol-5-yl)-rj thiomethyl-1-oxadethia-3-cephem-l+ -carboxylate (8^.6 mg) in methylene chloride (2 ml) is added anisole (0.1 ml) and trifluoroacetic acid (0.3 ml) at 0°C. After rotation for >5 min. at 0°C, the mixture is evaporated under reduced pressure and treated with a mixture of ether and n-pentane, and ether to give 7P-(α-carboxy-α-β-hydroxyphenylacetamido)-7<x-methoxy-3-(1 -me tylte tr azol-5-yl) thiomethyl-1 - oxadethia-3-cephem-<1>+-carboxylic acid (U- 6, h mg) as a colorless powder. Yield: 89.9%. Temp. 117 - 122°C (decomposition).
UV:J\CH30H276 nm ( 10200) UV: J\CH30H276 nm ( 10200)
maks.max.
foj<2>^15.3 2.6° (c =0.216,CH^OH). fj<2>^15.3 2.6° (c = 0.216, CH^OH).
IR: Vmaks. 1780'1719'1632 cm"1' IR: Vmax. 1780'1719'1632 cm"1'
NMR: £<D>2° + NaCH03(3-^5s+3-53s)3H, (<l>+.00s+<l>+.02s)3-H,NMR: £<D>2° + NaCH03(3-^5s+3-53s)3H, (<l>+.00s+<l>+.02s)3-H,
(<!>+.08s ' l+.13m)2H, ( k. k5s + *f .*t8s)2-3H, 5.12s1H, 6.87 + 7.28ABq(8Hz)lfK. (<!>+.08s ' l+.13m)2H, ( k. k5s + *f .*t8s)2-3H, 5.12s1H, 6.87 + 7.28ABq(8Hz)lfK.
Eksempel III- 16 7c/:33Example III- 16 7c/:33
Til en lbsning av difenylmetyl 7(3-/oe-p-hydroksyfenyl-oc- (5-indanyl)oksykarbonylacetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-l-oksadetia-S-cefem-^-karboksylat (1 50 mg) i metylenklorid-(12 ml) tilsettes anisol (0,^ ml) og trifluoreddiksyre (0,<*>+ ml) ved 0°C i nitrogen. Etter omrbring i 20 min. ved 0°C konsentreres reaksjonsblandingen under redusert trykk, fortynnes med benzen og konsentreres. Resten behandles med eter til gi 7(3-/a-p-hydroksyf enyl-a- (5-indanyl) oksykarbonylacetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1 -oksadetia-3-cefem-^-karboksylsyre som et pulver (91 mg) som smelter ved 123 - 126°C med spalting. Utbytte: 76,5%. To a solution of diphenylmethyl 7(3-/oe-p-hydroxyphenyl-oc-(5-indanyl)oxycarbonylacetamido7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-S-cephem- ^-carboxylate (150 mg) in methylene chloride (12 ml) is added anisole (0.5 ml) and trifluoroacetic acid (0.<*>+ ml) at 0° C. in nitrogen. After stirring for 20 min at 0° C, the reaction mixture is concentrated under reduced pressure, diluted with benzene and concentrated. The residue is treated with ether to give 7(3-/α-β-hydroxyphenyl-α-(5-indanyl)oxycarbonylacetamido7-7α-methoxy-3-(1-methyltetrazol-5 -yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid as a powder (91 mg) melting at 123-126°C with cleavage.Yield: 76.5%.
IR: Vmaks. 3385' 1785' 1727' 1705' 1631 ' 1613' 1 595 cm"<1>'IR: Vmax. 3385' 1785' 1727' 1705' 1631' 1613' 1,595 cm"<1>'
UV: > CH30H271.5 ( £= 12950), 276.5 ( e= 12700) nm. UV: > CH30H271.5 ( £= 12950), 276.5 ( e= 12700) nm.
maks.max.
foijf + 1.3- 0,8°, A7^<2>6- 25.1- 1.2°, Oti% ~ 5.2 1.2° foijf + 1.3- 0.8°, A7^<2>6- 25.1- 1.2°, Oti% ~ 5.2 1.2°
(c = 0,5>+1 , CH^OH).(c = 0.5>+1, CH 2 OH).
Eksempel 111- 17 °^ ^ i'! ;,Example 111- 17 °^ ^ i'! ;,
Til en lbsning av difenylmetyl 7P-^o-(p-benzyloksyfenyl)-a- / benzyloksykarbonylacetamidQ7-7a-metoksy-3-(1-metyltetrazol-5- \jyl)tiometyl-l-oksadetia-3-cefem-^-karboksylat (100 mg) i metylenklorid (2 ml) tilsettes anisol (0,2 ml) og en lbsning av q aluminiumklorid (250 mg) i nitrometan (1,2 ml) under isavkjbling. y'^' Etter omrbring i 2 timer under isavkjbling og i 1 time ved romtemperatur helles blandingen ut i en blanding av etylacetat og metanol (5:1), vaskes med 2N saltsyre og mettet saltlake, To a solution of diphenylmethyl 7β-α-(p-benzyloxyphenyl)-α-/benzyloxycarbonylacetamide Q7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylate (100 mg) in methylene chloride (2 ml) is added anisole (0.2 ml) and a solution of q aluminum chloride (250 mg) in nitromethane (1.2 ml) under ice cooling. y'^' After stirring for 2 hours under ice cooling and for 1 hour at room temperature, the mixture is poured into a mixture of ethyl acetate and methanol (5:1), washed with 2N hydrochloric acid and saturated brine,
tbrkes over natriumsuli&og konsentreres. Resten vaskes med eter til å gi 7P- (a-p-hydroksyf enyl-a-karboksyacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-H-karboksyl- tbruk over sodium sul& and concentrate. The residue is washed with ether to give 7β-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-H-carboxyl-
syre (35 mg)• acid (35 mg)•
IR: Vj^s. 1?80, 1719, 1632 cm<-1>. IR: Vj^s. 1?80, 1719, 1632 cm<-1>.
E ksempel 111- 18 T. yjs l°( lJ $'"• Example 111-18 T. yjs l°( lJ $'"•
Til en lbsning av difenylmetyl 7P-/a-t-butoksykarbonyl-a-(3-tienyl) acetamido_7-7a-metoksy-3- (1-mety1tetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-!+-karboksylat (1M+ mg) i anisol To a solution of diphenylmethyl 7β-[α-t-butoxycarbonyl-α-(3-thienyl)acetamido_7-7α-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-!+- carboxylate (1M+ mg) in anisole
(0,3 ml) tilsettes trifluoreddiksyre (1,7 ml) ved 0°C under nitrogengass. Etter omrbring i 3 timer konsentreres blandingen (0.3 ml) is added trifluoroacetic acid (1.7 ml) at 0°C under nitrogen gas. After stirring for 3 hours, the mixture is concentrated
til tbrrhet under redusert trykk, behandles med eter, og vaskesto dryness under reduced pressure, treated with ether, and washed
med etylacetat og eter til å gi 7P~/a-karboksy-a-(3-tienyl)-acetamidg>7-7a-metoksy-3- (1 -metyltetrazol-5-yl) tiometyl-1 -oksa-detia-3-cefem-^-karboksylsyre (61 mg) som et svakt gult pulver. Utbytte: 61%. Smp. 118 - 125°C (spalting) fra aceton. with ethyl acetate and ether to give 7β-α-carboxy-α-(3-thienyl)-acetamide 7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3 -cephem-^-carboxylic acid (61 mg) as a pale yellow powder. Yield: 61%. Temp. 118 - 125°C (decomposition) from acetone.
A7<25>12.8 - 2.5° (c 0.211, CH^OH). Δ7<25>12.8 - 2.5° (c 0.211, CH 2 OH).
UV: > CH3°<H>276 nm (£<=>10200). UV: > CH3°<H>276 nm (£<=>10200).
maks.max.
IR: V maks. 1780'1^5 cm"<1.>IR: V max. 1780'1^5 cm"<1.>
NMR:^D2°+NaHC03lf.03s3H, (<l>+.11s + l+.21m)2H, ( h. 51 s+ h. 53s) 2-3H, 5-15s1H, 7.05-7.25m1H, 7.27-7.52m2H. NMR: ^D2°+NaHC03lf.03s3H, (<l>+.11s + 1+.21m)2H, ( h. 51 s+ h. 53s) 2-3H, 5-15s1H, 7.05-7.25m1H, 7.27-7.52m2H .
Eksempel 111- 19Example 111-19
Til en losning av difenylmetyl 7P-/Joe-(3-ti enyl)-a-dif enylme toksykarbonylacetamido7-7a-metoksy-3- (1 -me tylte trazol-5-yl) - tiometyl-1-oksadetia-3-cefem-^-karboksylat (830 mg) i , metylenklorid (15 ml) tilsettes anisol (2 ml) og trifluor- \ eddiksyre (2 ml) under isavkjbling. Etter omrbring i 1 time ved den samme temperatur konsentreres blandingen under redusert ,•; /Utrykk. Resten vaskes med eter til å gi 7S-/a-(3-tienyl)-a-karboksyacetamido7-7o:-metoks<y->3- (1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylsyre som et pulver (383 mg) som smelter ved 110-11^°C, identifisert med en autentisk prove ved sammenligning av IR-spektra i KBr skive og tynnskiktkrornatogram. To a solution of diphenylmethyl 7P-[Joe-(3-thienyl)-a-diphenylme toxycarbonylacetamido7-7a-methoxy-3-(1-methyl trazol-5-yl)-thiomethyl-1-oxadethia-3-cephem -^-carboxylate (830 mg) in methylene chloride (15 ml) is added to anisole (2 ml) and trifluoroacetic acid (2 ml) under ice cooling. After stirring for 1 hour at the same temperature, the mixture is concentrated under reduced pressure. /Expression. The residue is washed with ether to give 7S-[α-(3-thienyl)-α-carboxyacetamido7-7o:-methoxy<y->3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3- cephem-^-carboxylic acid as a powder (383 mg) melting at 110-11^°C, identified with an authentic sample by comparison of IR spectra in KBr slice and thin-layer chromatogram.
Eksempel 111- 20 ' J fJ^ ( tExample 111- 20 ' J fJ^ ( t
Til en lbsning av difenylmetyl 7P-/a-(3-tienyl)-a-fenoksy-karbonylacetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiomety1-1-oksadetia-3-cefem-^-karboksylat (100 mg) i metylenklorid (2 ml) tilsettes anisol (0,2 ml) og trifluoreddiksyre (0,2 ml) under isavkjbling. Etter omrbring i 1 time konsentreres blandingen To a solution of diphenylmethyl 7β-[α-(3-thienyl)-α-phenoxy-carbonylacetamido 7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (100 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) under ice cooling. After stirring for 1 hour, the mixture is concentrated
og behandles i eter til å gi 7(3-/a-(3-tienyl)-a-f enoksykarbonyl-acetamido7-7a-metoksy-3-(1-me tyltetrazol-5-yl)tiomety1-1-oksadetia-3-cefem-^-karboksylsyre som et pulver (38 mg) som smelter ved 108-111°C. Utbytte: 50%. and treated in ether to give 7(3-[α-(3-thienyl)-α-phenoxycarbonyl-acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-1-oxadethia-3-cephem -^-carboxylic acid as a powder (38 mg) melting at 108-111° C. Yield: 50%.
IR: yCH<C1>3 3<l>f00sh, 3325, 1788, 17^5, 1705 cm"<1>. ijU IR: yCH<C1>3 3<l>f00sh, 3325, 1788, 17^5, 1705 cm"<1>. ijU
maks. yJj ^ max. yJj ^
/q7<23>- 61.3 i 2.0° (c = 0.517, CHC13). /q7<23>- 61.3 in 2.0° (c = 0.517, CHCl3).
Eksempel 111- 21 Example 111-21
Til en losning av 7B-/a-(3-tienyl)-a-(3,<l>+-dimetylfenyl)oksy-karbonylacetamido_7-7a-metoksy-3- (1-metylte trazol-5-yl)tiometyl-1-oksadetia-3-cefem-+-karboksylat (105 mg) i metylenklorid (2 ml) tilsettes anisol (0,2 ml) og trifluoreddiksyre (0,2 ml) To a solution of 7B-/α-(3-thienyl)-α-(3,<l>+-dimethylphenyl)oxy-carbonylacetamido_7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-+-carboxylate (105 mg) in methylene chloride (2 ml) is added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml)
under isavkjoling. Etter omrbring i 1 time konsentreres blandingen under redusert trykk, behandles med eter, og / filtreres. Faststoffet vaskes med eter og torkes til å gi 78-/cx-(3-tienyl)-a-(3,^-dimetylf enyl)oksykarbonylacetamido7-7a- / J j metoksy-3-(1-metyltetøzol-5-yl)tiometyl-1-oksadetia-3 cefem-^- ' karboksylsyre som et pulver (6^ mg) som smelter ved 110-113°C. Utbytte: 77%. during ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure, treated with ether, and filtered. The solid is washed with ether and dried to give 78-[cx-(3-thienyl)-a-(3,^-dimethylphenyl)oxycarbonylacetamido7-7a- / J j methoxy-3-(1-methyltetozol-5-yl) thiomethyl-1-oxadethia-3 cephem-^-' carboxylic acid as a powder (6^ mg) melting at 110-113°C. Yield: 77%.
IR: V<CHC1>3 3^00sh, 3325, 1787, 1737 cm"<1>, IR: V<CHC1>3 3^00sh, 3325, 1787, 1737 cm"<1>,
maks.max.
/«7d3 "53A - 1.9° (c 0.50<!>+, CHCl3). /«7d3 "53A - 1.9° (c 0.50<!>+, CHCl3).
Eksempel 111- 22 yjr . ( i'Example 111- 22 years. (i'
Til en losning av dif enylmetyl-73-/a-(3-tienyl)-ct-(Lndan-5-yl)-oksykarbonylaeetamidq7-7a-metoksy-3-(1 -metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat (97 mg) i metylen- To a solution of diphenylmethyl-73-/a-(3-thienyl)-ct-(lndan-5-yl)-oxycarbonylacetamide q7-7a-methoxy-3-(1 -methyltetrazol-5-yl)-thiomethyl-1- oxadethia-3-cephem-^-carboxylate (97 mg) in methylene-
klorid (2 ml) tilsettes anisol (0,3 ml) og trifluoreddiksyre (0,3 ml) under isavkjbling. Etter omroring i 1 time konsentreres blandingen under redusert trykk og resten behandles med eter til å gi 7P-/a-(3-tienyl)-a-(5-indanyl)oksykarbonylacetamido/-7a-metoksy-3- (1 -me tyl te tr azol- 5-yl) tiometyl-1 - oksadetia- 3-cef em-^f- ^' karboksylsyre som pulver (3^ mg) som smelter ved 111-113°C j-Utbytte: h$%. chloride (2 ml), anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) are added under ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure and the residue is treated with ether to give 7β-[α-(3-thienyl)-α-(5-indanyl)oxycarbonylacetamido/-7α-methoxy-3-(1-methyl te tr azol-5-yl) thiomethyl-1 - oxadethia- 3-cef em-^f- ^' carboxylic acid as powder (3^ mg) melting at 111-113°C j-Yield: h$%.
IR: V<CH>C133l+06sh, 3335, 1789, 17^+, 170^ cm"<1>, IR: V<CH>C133l+06sh, 3335, 1789, 17^+, 170^ cm"<1>,
maks.max.
Æ*.7j53"57.5<1>2. k° (c = 0.^+02, CHC1Æ*.7j53"57.5<1>2. k° (c = 0.^+02, CHC1
Eksempel 111- 23 IA17Example 111- 23 IA17
Til en losning av difenylmetyl 7P-/a-difénylmetoksykarbonyl-a-(2-tienyl)acetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-^-karboksylat ('[ ko mg) i metylen- To a solution of diphenylmethyl 7β-/α-diphenylmethoxycarbonyl-α-(2-thienyl)acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate ('[ ko mg) in methylene-
klorid tilsettes anisol (0,2 ml) og trif luoreddiksyre (0,1* ml) vedi0°C under nitrogengass. Etter omroring i 1 time ved 0°C inndampes blandingen under redusert trykk, behandles med eter, chloride, anisole (0.2 ml) and trifluoroacetic acid (0.1* ml) are added at 0°C under nitrogen gas. After stirring for 1 hour at 0°C, the mixture is evaporated under reduced pressure, treated with ether,
og vaskes med eter til å gi 7P-/«-karboksy-a-(2-tienyl)acetamidoj<7->7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-k-karboksylsyre (60 mg) som et farvelost pulver. Utbytte: 70%. , Smp. 10^ - 109°C (spalting); \jand washed with ether to give 7β-β-carboxy-α-(2-thienyl)acetamido<7->7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -k-carboxylic acid (60 mg) as a colorless powder. Yield: 70%. , Smp. 10^ - 109°C (decomposition); \j
UV: ^<CH>3<0H>275 nm ( £= 8800). ! i \J UV: ^<CH>3<OH>275 nm ( £= 8800). ! in \J
maks.<1>max.<1>
fij^ 7 15.0 - 1.5° (c 0.37^, ch3oh). fij^ 7 15.0 - 1.5° (c 0.37^, ch3oh).
IR;<y>Ss,1?85> 1715 cm"<1>. IR;<y>Ss,1?85> 1715 cm"<1>.
NMR: gD2°<+><NaH>C037_<0>Q _ 7>5m3Hj5 . t 5 s 1 h , l+.O^H,NMR: gD2°<+><NaH>C037_<0>Q _ 7>5m3Hj5 . t 5 s 1 h , l+.O^H,
(3.5^s + 3-1+8s)3H. (3.5^s + 3-1+8s)3H.
E ksempel III - 2 + - ov- ^Example III - 2 + - ov- ^
Til en losning av difenylmetyl 7P~Za-(5-indanyl)oksykarbonyl-a-f enylacetamidoJ7-7a-metoksy-3- (1 -metyltetrazol-5-yl) tiometyl-l-oksadetia-3-cefem-^-karboksylat (116,1 mg) i metylenklorid tilsettes anisol (0,1 ml) og trifluoreddiksyre (0,2 ml). Etter j omroring i 30 min. ved 0°C inndampes blandingen under redusert/-^ trykk, kromatograferes på silikagel (10 g) inneholdende 10% vann, elueres med etylacetat inneholdende 5% eddiksyre, og To a solution of diphenylmethyl 7P~Za-(5-indanyl)oxycarbonyl-α-phenylacetamidoJ7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (116, 1 mg) in methylene chloride, anisole (0.1 ml) and trifluoroacetic acid (0.2 ml) are added. After j stirring for 30 min. at 0°C, the mixture is evaporated under reduced pressure, chromatographed on silica gel (10 g) containing 10% water, eluted with ethyl acetate containing 5% acetic acid, and
krystalliseres fra en blanding av eter og pentan til å gi 7(3-/a- (indan-5-yl) oksykarbonyl-q^f e nylacetamido7-7a-metoksy-3-(1 -metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre (7^,5 mg) som farvelose krystaller. Utbytte: 81 , h%. crystallized from a mixture of ether and pentane to give 7(3-/a-(indan-5-yl)oxycarbonyl-q^f e nylacetamido7-7a-methoxy-3-(1 -methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-^-carboxylic acid (7^.5 mg) as colorless crystals.Yield: 81, h%.
Smp. 123 - 125°C (spalting).Temp. 123 - 125°C (decomposition).
IR: VmSs. 177°>1702cra'<1>'IR: VmSs. 177°>1702cra'<1>'
/o7<25>- 8A - 1A° ( c = 0.286, CR^OH). /o7<25>- 8A - 1A° (c = 0.286, CR^OH).
NMR: CDC132.07s2H, 2.855^,. (3.32s + 3A3s)3H, 3-79s3H, NMR: CDCl32.07s2H, 2.855. (3.32s + 3A3s)3H, 3-79s3H,
!f.25s2H,<l>f.50s2H,<1>+.69S1H, ^f.97s1H. !f.25s2H,<l>f.50s2H,<1>+.69S1H, ^f.97s1H.
Eksempel 111- 25Example 111-25
Til en losning av difenylmetyl 7(3- (a-p-karbamoyloksyf enyl-a-dif enylmet oksykarbonylace-tamido)-7a-metoksy-3- (1 -metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-V-karboksylat (170,1 mg) i metylenklorid (2 ml) tilsettes anisol (0 ,>+ ml) og trifluor- To a solution of diphenylmethyl 7(3-(α-β-carbamoyloxyphenyl-α-diphenylmetoxycarbonylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V -carboxylate (170.1 mg) in methylene chloride (2 ml) is added anisole (0.>+ ml) and trifluoro-
eddiksyre (0,*+ ml) ved 0°C og blandingen omrSres i U- 5 min., y'inndampes til torrhet under redusert trykk, og behandles med ■ eter til å gi 7P-(a-p-karbamoyloksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1-metylte trazol-5-yl)tiometyl-1 - oksadetia-3-cefem-V-karboksylsyre (98,2 mg) som et farvelost pulver. acetic acid (0.*+ ml) at 0°C and the mixture is stirred for 5 min., evaporated to dryness under reduced pressure, and treated with ■ ether to give 7P-(α-β-carbamoyloxyphenyl-α-carboxyacetamido) -7α-Methoxy-3-(1-methyl terazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (98.2 mg) as a colorless powder.
Smp. 128 - 132°C. Temp. 128 - 132°C.
IR: V^s. 1?8<1>+'1^(sh), cm"<1>.IR: V^s. 1?8<1>+'1^(sh), cm"<1>.
UV:<CH>30H273nm ( C= 9500). UV:<CH>30H273nm (C=9500).
maks.max.
/o/p<5>23-1<->0,7° (c 0.900, CH30H). /o/p<5>23-1<->0.7° (c 0.900, CH 3 OH).
Ek sempel 111- 26Oak sample 111-26
Ved en fremgangsmåte tilsvarende eksempel 111-25 behandles difenylmetyl 7(3- (q-p-N-metylk arbamoyloksyf enyl-a-dif enyl - metoksykarbonylacetamido)-7a-metoksy-3-(1 -metyltetrazol-5-yl)-tiometyl-1-oksadetia-3-cefem-lf-karboksylat (100 mg) med anisol (0,1 ml) og trifluoreddiksyre (0,1 ml) i metylenklorid (1 ml)Jved 0 O C i 1 time til a ogi 7(3- (a-p-N-metylkarbamoyloksyf enyl-a-karboksyacetamido) -7a-metoksy-3-(1-metyltetrazol-5-yl)tiorne ty1-1-oksadetia-3-cefear-^-karboksylsyre (52 mg) med hy% utbytte. In a method corresponding to example 111-25, diphenylmethyl 7(3-(q-p-N-methylcarbamoyloxyphenyl-a-diphenyl-methoxycarbonylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia is treated -3-cephem-1f-carboxylate (100 mg) with anisole (0.1 ml) and trifluoroacetic acid (0.1 ml) in methylene chloride (1 ml) at 0 O C for 1 hour to a ogi 7(3-(a-p-N- methylcarbamoyloxy enyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiorne ty1-1-oxadethia-3-cefear-3-carboxylic acid (52 mg) in high% yield.
Smp. 117 - 125°C Temp. 117 - 125°C
IR: V^ks. 3385'1786'1725 cm"<1>'IR: Growth 3385'1786'1725 cm"<1>'
UV; ><CH>3<0H>271 nm ( £= 9532). UV; <CH>3<OH>271 nm (£= 9532).
maks.max.
Eksempel 111- 27 i"/Example 111-27 i"/
i / / /■J■r rVed en fremgangsmåte tilsvarende eksempel 111-25 behandles difenylmetyl 78- (a-pjMir^i^pJtaxbjsnyloksyfenyl-a-difenylmetoksy-karbonylacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiornetyl-■ 1-oksadetia-3-cefem-U-karboksylat (213 mg) med anisol ( 0, k ml) In a method similar to example 111-25, diphenylmethyl 78- (a-pjMir^i^pJtaxbjsnyloxyphenyl-a-diphenylmethoxy-carbonylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl) is treated )thiomethyl-■ 1-oxadethia-3-cephem-U-carboxylate (213 mg) with anisole (0.k ml)
og trifluoreddiksyre (O,^ ml) i metylenklorid (3 ml) i 1 timeand trifluoroacetic acid (0.5 ml) in methylene chloride (3 ml) for 1 hour
ved 0°C til å gi 7P- (a-p-ureidokarbonyloksyf enyl-a-karboksyace tamido)-7a-metoksy-3- (1 - me tyl te tr azol-5-yl) tiometyl-1 -oks a-detia-3-cefem-^-karboksylsyre (125 mg) med 91% utbytte. at 0°C to give 7β-(α-β-ureidocarbonyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxα-dethia-3 -cephem-^-carboxylic acid (125 mg) in 91% yield.
Smp. 137 - -|<l>f2°C.Temp. 137 - -|<l>f2°C.
IR:<Y>maks. 3^°'3330'1780'1712 crn"<1>'IR:<Y>max. 3^°'3330'1780'1712 crn"<1>'
NMR: ^<CD>3)2<SO>(3-25s + 3Als)3H, (3-90s + 3-93s)3H,NMR: ^<CD>3)2<SO>(3-25s + 3Als)3H, (3-90s + 3-93s)3H,
<»>+.21brs2H, +.98brs2H,<l>+.85brslH, 5.05s1H,<»>+.21brs2H, +.98brs2H,<l>+.85brslH, 5.05s1H,
7.20 - 7.l5m2H, 7.13d(8Hz)2H, 7. *+2d(8Hz) 2H, (9-l5brs + 9.27 brs)1H, 10.25brs1H. 7.20 - 7.l5m2H, 7.13d(8Hz)2H, 7. *+2d(8Hz) 2H, (9-l5brs + 9.27 brs)1H, 10.25brs1H.
UV:<CH>3°H 276 nm ( £= 9105). UV: <CH>3°H 276 nm ( £= 9105).
maks.max.
Eksempel 111-2,8 "V o"^ JExample 111-2.8 "V o"^ J
<■ - -; ;rTil en losning av difenylmetyl 7?-/Ja-p- (p-metoksybenzyl) oksy-fenyl-a-difenylmetoksykarbonylacetamido7-7a-metoksy-3-(1 - metyltetrazol-5-yl)tiometyl-1 -oksadetia-3-cefem->+-karboksylat y' <■ - -; ;rTo a solution of diphenylmethyl 7?-/Ja-p-(p-methoxybenzyl)oxy-phenyl-a-diphenylmethoxycarbonylacetamido7-7a-methoxy-3-(1 - methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3- cephem->+-carboxylate y'
(170 mg) i metylenklorid (3,5 ml) tilsettes anisol (0,35 ml) og trifluoreddiksyre (0,35 ml) ved 0°C, og blandingen omrores i | f\ kS min. ved 0°C. Etter avdamping av losningsmidlet behandles produktet med eter til å gi 7B~(a-p-hydroksyfenyl-a-karboksyace tamido)-7a-metoksy-3"(1-metyltetrazol-5-yl)tiomety1-1-oksa-detia-3-cefem-^-karboksylsyre (91 mg) som er farvelost pulver. (170 mg) in methylene chloride (3.5 ml) is added anisole (0.35 ml) and trifluoroacetic acid (0.35 ml) at 0°C, and the mixture is stirred in | f\ kS min. at 0°C. After evaporation of the solvent, the product is treated with ether to give 7B~(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3"(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem -^-carboxylic acid (91 mg) which is a colorless powder.
Utbytte: nesten kvantitativt. Smp. 125 - 132°C (spalting).Yield: almost quantitative. Temp. 125 - 132°C (decomposition).
Eksempel III- 29 f <n&-■ MExample III- 29 f <n&-■ M
Ved en fremgangsmåte tilsvarende som i eksempel 111-28, 3- r behandles difenylmetyl 7P-/oc-p-(p-metoksybenzyl)oksyfenyl-a-p-metdksybenzyloksykarbonylacetamido7-7a-metoksy-3-(1-metyl- \ I tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-l+-karboksylat (1,1+5 g) , ., med anisol (1+ ml) og trif luoreddiksyre (1+ ml) i metylenklorid j\J j (8 ml) ved 0°C i 1+0 min. til å gi 70-(oc-p-hydroksyfenyl-a-karboksyace tamido)-7a-metoksy-3-(1-mety1tetrazol-5-yl)tiornety1-1-oksadetia-3-cefem-<l>+-karboksylsyre. Smp. 125 - 132°C In a method similar to that in example 111-28, 3-r, diphenylmethyl 7P-/oc-p-(p-methoxybenzyl)oxyphenyl-a-p-metdoxybenzyloxycarbonylacetamido7-7a-methoxy-3-(1-methyl-\I tetrazol-5) is treated -yl)thiomethyl-1-oxadethia-3-cephem-l+-carboxylate (1.1+5 g) , ., with anisole (1+ ml) and trifluoroacetic acid (1+ ml) in methylene chloride j\J j (8 ml) at 0°C for 1+0 min. to give 70-(oc-p-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid. Temp. 125 - 132°C
(spalting). Utbytte: kvantitativt.(cleavage). Yield: quantitative.
Eksempel 111- 30 \ ^ i' .'; yw ** y Example 111- 30 \ ^ i' .'; yw **y
1) Til en losning av difenylmetyl 7(3-/bc-p-(p-metoksybenzyl-oksy-fenyl-a-p-metoksybenzyloksykarbonyl-acetamido7-7a-metoksy-3- (1 -me ty 1te tr azol-5-yl) tiometyl-1 - oksad eti a-3-cef em-l+- 1) To a solution of diphenylmethyl 7(3-/bc-p-(p-methoxybenzyl-oxy-phenyl-a-p-methoxybenzyloxycarbonyl-acetamido7-7a-methoxy-3-(1-methy 1te tr azol-5-yl) thiomethyl-1 - oxad eti a-3-cef em-l+-
karboksylat (1,20 g) i metylenklorid ( 2k ml) tilsettes anisol (2,<1>+ ml) og en losning av aluminiumklorid (2,58 g) i nitrometan (12 ml) ved 0°C under nitrogen. Etter omroring 15 min. ved 0°C helles blandingen ut i kald vandig 5% natriumhydrogenkarbonatlosning (100 ml) og filtreres for å fjerne det dannede bunnfall. Filtratet vaskes to ganger med metylenklorid (2 x 100 ml), gjores v surt med 2N saltsyre til pH 2.60 og helles ut i en kolonne fylt med hbyporos polymer "HP-20" (60 ml) (selges av Mitsubishi Chemical Industries Ltd.). Kolonnen vaskes med vann, (300 ml) carboxylate (1.20 g) in methylene chloride (2k ml) is added anisole (2.<1>+ ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0°C under nitrogen. After stirring for 15 min. at 0°C, the mixture is poured into cold aqueous 5% sodium bicarbonate solution (100 ml) and filtered to remove the precipitate formed. The filtrate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N hydrochloric acid to pH 2.60 and poured into a column filled with hyperporous polymer "HP-20" (60 ml) (sold by Mitsubishi Chemical Industries Ltd.) . The column is washed with water, (300 ml)
og elueres med metanol. Eluatet konsentreres under redusert trykk ved romtemperatur. Resten opploses i metanol, behandles med aktivt karbon og konsentreres under redusert trykk til å gi 7B-(a-p-hydroksyfenyl-a-karboksyacetamido)-7a-metoksy-3-(1 - me tyl te tr azol-5-yl) tiome tyl-1 - oks ad eti a-3-cef em-lf-karboksyl syre som et pulver (595 mg) som spaltes ved 125 - 132°C. and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methanol, treated with activated carbon and concentrated under reduced pressure to give 7B-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyl tetrazol-5-yl)thiomethyl -1 - ox ad eti a-3-cef em-lf-carboxylic acid as a powder (595 mg) which decomposes at 125 - 132°C.
Utbytte: 88,5%.Yield: 88.5%.
2) Det samme produkt kan fremstilles ved en metode2) The same product can be produced by a method
tilsvarende 1) ovenfor, hvoricorresponding to 1) above, in which
a) p-metoksy-benzyleter erstattes med benzyletera) p-methoxy-benzyl ether is replaced by benzyl ether
b) p-metoksybenzyloksykarbonylgruppen erstattes med benzyloksykarbonylgruppen og/eller b) the p-methoxybenzyloxycarbonyl group is replaced by the benzyloxycarbonyl group and/or
c) difenylmetylesteren erstattes med benzylester.c) the diphenyl methyl ester is replaced by benzyl ester.
IV. O-acylering.IV. O-acylation.
Eksempel IV-1 Example IV-1
Til en losning av difenylmetyl 7(3- (a-p-hydroksyf enyl-a-dif enylme toksykarbonylace tamido) ^7cc-metoksy-3- (1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3_cefem-<!>+-karboksylat (286 mg) i metylenklorid (2 ml) tilsettes trikloracetylisocyanid (0,5 ml) To a solution of diphenylmethyl 7(3-(α-β-hydroxyf enyl-α-dif enylme toxycarbonylace tamido) ^7cc-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3_cephem-<!>+ -carboxylate (286 mg) in methylene chloride (2 ml) is added trichloroacetyl isocyanide (0.5 ml)
under avkjbling ved -78°C. Etter omrbring ved -78°C i 30 min.during cooling at -78°C. After incubating at -78°C for 30 min.
og ved 0°C i 1 time fortynnes blandingen med benzen (20 ml) og etylacetat (20 ml), vaskes med vann, tbrkes og konsentreres. Den oppnådde rest kromatograferes på silikagel (30 g) inneholdende a 10% vann og elueres med en blanding av benzen og etylacetat and at 0°C for 1 hour, the mixture is diluted with benzene (20 ml) and ethyl acetate (20 ml), washed with water, dried and concentrated. The obtained residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate
(1:1) til å gi difenylmetyl 7P-(oe-p-karbamoybksyf enyl-a-dif eny Ime toksykarbonylace tamido) -7a-metoksy-3- (1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (179,9 mg) som et farvelost skum. Utbytte: 59,5%. (1:1) to give diphenylmethyl 7P-(oe-p-carbamoybxyphenyl-a-dipheny Ime toxycarbonylace tamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3 -cephem-^-carboxylate (179.9 mg) as a colorless foam. Yield: 59.5%.
IR: V<CH>C133530, 3^25, 3325, 1790, 1750, 1728, 1700sh cm<-1>, IR: V<CH>C133530, 3^25, 3325, 1790, 1750, 1728, 1700sh cm<-1>,
maks.max.
NMR:6CDC13(3A2s + 3A5s)3H, 3.73s3H, ^+.22s2H,<l>+A2s2H,NMR: 6CDCl3(3A2s + 3A5s)3H, 3.73s3H, ^+.22s2H,<l>+A2s2H,
<t>+.80slH, 5.03s1H, 5-33s2H. <t>+.80slH, 5.03s1H, 5-33s2H.
Ek sempel IV- 2 ) :) ' ■ Ek sample IV- 2 ) :) ' ■
£ ■> i i Ved en fremgangsmåte tilsvarende den som er beskrevet ovenfor £ ■> i i By a method similar to that described above
under eksempel IV-1 , behandles difenylmetyl 7(3- (a-p-hydroksy- under Example IV-1, diphenylmethyl 7(3-(α-β-hydroxy-
fenyl-a-difenylmetoksykarbonylacetamido)-7a-metoksy-3-(1-me tylte tr azol-5-yl) tiome tyl-1-oksadetia-3-cef ern-^-- phenyl-α-diphenylmethoxycarbonylacetamido)-7α-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cef ern-^--
karboksylat (100 mg) med metylisocyanat (0,2 ml) i tetrahydro-carboxylate (100 mg) with methyl isocyanate (0.2 ml) in tetrahydro-
furan (1 ml) i nærvær av 1,5-diazabicyklo/3,5p7undecen ved 0°C * i h, 5 timer til å gi difenylmetyl 7(3-(a-p-N-metylka rbamoyloksy-/<*>Hf fenyl-a-difenyImetoksykarbonylacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (52 mg). Utbytte:<1>+9%. furan (1 ml) in the presence of 1,5-diazabicyclo/3,5p7undecene at 0°C * for h, 5 h to give diphenylmethyl 7(3-(a-p-N-methylcarbamoyloxy-/<*>Hf phenyl-a-diphenylImethoxycarbonylacetamido )-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (52 mg).Yield: <1>+9%.
IR: V<CH>C133^60, 1785, 1725, 1700 cm'<1>, IR: V<CH>C133^60, 1785, 1725, 1700 cm'<1>,
maks.max.
NMR:JCD<C1>3 2.87d(5Hz)3H', 3.<1>+5brs3H, 3.80s3H, l+.23brs2H, NMR: JCD<C1>3 2.87d(5Hz)3H', 3.<1>+5brs3H, 3.80s3H, 1+.23brs2H,
^A7brs2H, If.77brs1H, 5-00s1H, it.95 - 5.i+0m1H, 6.97s2H. ^A7brs2H, If.77brs1H, 5-00s1H, it.95 - 5.i+0m1H, 6.97s2H.
Eksempel IV- 3Example IV- 3
Ved en fremgangsmåte tilsvarende den som er beskrevet ovenforBy a method similar to that described above
i eksempel IV-1 , behandles difenylmetyl 7(3- (a-p-karbamoyloksy-fenyl-a-difenyImetoksykarboksylacetamido)-7a-metoksy-3-(1 -metyl-tetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-lf-karboksylat (1 75 mg) in Example IV-1, diphenylmethyl 7(3-(α-β-carbamoyloxy-phenyl-α-diphenyImethoxycarboxylacetamido)-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem is treated -lf-carboxylate (1 75 mg)
méd trikloracetylisocyanid ( 0, k ml) ved 0°C i metylenklorid (2 ml) og ved romtemperatur i k timer til å gi N<3->trikloro-acetylureidokarbonyloksyfenylderivatet, som hydrolyseres med fuktig silikagel (10 g) i en time i metylenklorid ved , romtemperatur til å gi difenylmetyl 7(3- (a-jD-ureidokarbonyloksy- [//jfenyl-a-difenylmetoksykarbonylacetamido)-7a-metoksy~3-(1 -metyl-te tr azol-5-yl) tiome tyl-1-oksad etia-3-cef em->+-karboksylat (1*+5 mg). Farvelost skum. Utbytte: 79%. with trichloroacetylisocyanide (0.k ml) at 0°C in methylene chloride (2 ml) and at room temperature for k hours to give the N<3->trichloro-acetylureidocarbonyloxyphenyl derivative, which is hydrolyzed with moist silica gel (10 g) for one hour in methylene chloride at , room temperature to give diphenylmethyl 7(3-(α-jD-ureidocarbonyloxy-[//jphenyl-α-diphenylmethoxycarbonylacetamido)-7α-methoxy~3-(1-methyl-tetrazol-5-yl)thiomethyl-1 -oxad etia-3-cef em->+-carboxylate (1*+5 mg). Colorless foam. Yield: 79%.
IR: yCHC133500, 1790, 1758, 1725, 1700sh cm"<1>, IR: yCHC133500, 1790, 1758, 1725, 1700sh cm"<1>,
maks .-max.-
NMR: g<CD>C133A3<s>3H, 3.68s3H,<l>+.21brs2H,<l>+.<l>+3brs2H, l+.83brs1H, NMR: g<CD>C133A3<s>3H, 3.68s3H,<l>+.21brs2H,<l>+.<l>+3brs2H, 1+.83brs1H,
5.03s1H, 5.80 - 6.70m2H, 6.95s2H, 8.23brs1H, 5.03s1H, 5.80 - 6.70m2H, 6.95s2H, 8.23brs1H,
9.20brs1H, 6.95s2H. 9.20brs1H, 6.95s2H.
V. Beskyttelse.V. Protection.
Eksempel V- 1Example V-1
Til en suspensjon av 7(3-(a-karboksy-a-f enylacetamido)-3-(1-me tylte tr azol-5-yl) tiome tyl-1-oksadetia-3-cef em-l+- To a suspension of 7(3-(α-carboxy-α-phenylacetamido)-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cef em-l+-
karboksylsyre ( hOO mg) i metylenklorid (20 ml) tilsettes difenyldiazometan (700 mg) og blandingen omrbres ved rom- carboxylic acid (hOO mg) in methylene chloride (20 ml) is added to diphenyldiazomethane (700 mg) and the mixture is stirred at room
temperatur i 30 min. Den oppnådde rest ved konsentrering under redusert trykk kromatograferes på silikagel ( kO g) inneholdende 10% vann og elueres med en blanding av benzen og etylacetat (1:1) til.å gi difenylmetyl 76(a-difenylmetoksykarbonyl-a- //u^' fenylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-l+-karboksylat (322 mg). Smp. 107 - 109°C. Utbytte: 1+7 A%. temperature for 30 min. The residue obtained by concentration under reduced pressure is chromatographed on silica gel (kO g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl 76(α-diphenylmethoxycarbonyl-α- //u^ phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (322 mg). Temp. 107 - 109°C. Yield: 1+7 A%.
(Ved et annet forsbk ble det oppnådd 95% utbytte av produktet). (In another trial, a 95% yield of the product was achieved).
E ksempel V- 2Example V-2
Til en suspensjon av 76-(a-karboksy-a-fenylacetamido)~3-(1 - mety1tetrazol-5-yl) tiometyl-1 - oksad e tia-3-cef emA-kar boksylsyre (50 mg) i en blanding av aceton (30 ml) og metanol (5 ml) To a suspension of 76-(α-carboxy-α-phenylacetamido)~3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad e thia-3-cef emA-carboxylic acid (50 mg) in a mixture of acetone (30 mL) and methanol (5 mL)
tilsettes en lbsning av natriumacetat (1756 mg) i metanol (2 ml)a solution of sodium acetate (1756 mg) in methanol (2 ml) is added
og blandingen-omrbres ved romtemperatur i 1 time. Reaksjonsblandingen inndampes under redusert trykk og resten vaskes med aceton til å gi dinatrium 7P- (a-karboksy-a-f enylacetamido)-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylat (57 mg).and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated under reduced pressure and the residue is washed with acetone to give disodium 7P-(α-carboxy-α-phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate ( 57 mg).
IR: Vmaks3lf25' 17^6' l66obr>1°10br, A10 cm"<1>.IR: Vmax3lf25' 17^6' l66obr>1°10br, A10 cm"<1>.
Eksempel V- 3Example V-3
Produktene fra de ovejinejmte eksempler med fri karboksy opplbsesThe products from the above examples with free carboxy are resolved
i vandig natriumhydrogenkarbonatlbsning til å gi de tilsvarende natriumsalter som utprbves med hensyn til antibakteriell virkning. in aqueous sodium bicarbonate solution to give the corresponding sodium salts which are tested with respect to antibacterial action.
Disse forbindelser er mer aktive enn de tilsvarende forbindelserThese compounds are more active than the corresponding compounds
med svovelatom^i stedet for oksygena tom i tilling en av fr* ringsystemet. Forbindelsene med 7a-metoksy er sterkere~" -^'^ antibiotika mot gramnegative bakterier som er resistente^ mot j<J>^ S"62*^/" vanlige cefalosporiner og også sterkt aktive mot pseudomonas j with a sulfur atom^instead of the oxygena empty in tilling one of the fr* ring system. The compounds with 7a-methoxy are stronger~" -^'^ antibiotics against gram-negative bacteria that are resistant^ to j<J>^ S"62*^/" common cephalosporins and also strongly active against pseudomonas j
aeruginosa-stammer.aeruginosa strains.
Eksempel V - k f ^ ,0jQExample V - k f ^ ,0jQ
Til en lbsning av 70-Za-(3-tienyl)-a-karboksyacetamido7-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cef em- h-karboksylsyre (2,0^ g) i metanol (20 ml) tilsettes en lbsning av natrium-2-etylheksanoat i metanol (2 mol/l, 10 ml) ved romtemperatur. Etter omrbring i 10 min. fortynnes reaksjons- / blandingen med etylacetat (100 ml) omrbres i 5 min. og ^ filtreres for oppsamling av utskilt faststoff, som vaskes med etylacetat og tbrkes til å gi dinatriumsaltet av 73-/a-(3-tienyl)-a-karboksyacetamido7-7cc-metoksy-3- (1 -metylte trazol-5-yl)-tiometyl-1-oksadetia-3-cefem-<l>+-karboksylsyre (1,90 g) To a solution of 70-Za-(3-thienyl)-α-carboxyacetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-h-carboxylic acid (2, 0^ g) in methanol (20 ml) is added to a solution of sodium 2-ethyl hexanoate in methanol (2 mol/l, 10 ml) at room temperature. After stirring for 10 min. dilute the reaction/mixture with ethyl acetate (100 ml) and stir for 5 min. and ^ is filtered to collect the separated solid, which is washed with ethyl acetate and used to give the disodium salt of 73-[α-(3-thienyl)-α-carboxyacetamido7-7cc-methoxy-3-(1-methyltetrazol-5-yl )-thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid (1.90 g)
Utbytte: 86, J%. Farvelost pulver som smelter ved spalting fra 150°C Yield: 86.J%. Colorless powder that melts on cleavage from 150°C
IR:V^s. 1768'1680'1612 cm"<1>-IR:V^s. 1768'1680'1612 cm"<1>-
UV: ]\CH30H271 nm ( é = 9>+20) . UV: ]\CH30H271 nm ( ε = 9>+20) .
maks.max.
Eksempel V-? ^ %{ j j p<\><p>^ ^.}.' tY Example V-? ^ %{ j j p<\><p>^ ^.}.' tY
Til en lbsning av 70- (a-p-hydroksyfenyl-a-karboksyacetamido)-7oc-metoksy-3-(1 -metylte trazol-5-yl)tiometyl-1-oksadetia-3-cefem-V-karboksylsyre (359 mg) i metanol (7 ml) tilsettes en lbsning av natrium-2-etylheksanoat i metanol (2 mol/l, 1,73 ml) ved romtemperatur. Etter omrbring i 10 min. fortynnes reaksjons-\/ blandingen med etylacetat, omrbres i 5 min. og filtreres for oppsamling av utskilt faststoff som vaskes med etylacetat og tbrkes til å gi dinatriumsaltet av 7(3- (oc-p-hydroksyf enyl-a-karboksyace tamidc)r7a-metoksy-3-(1-metyl-tetrazol-5-yl)- To a solution of 70-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (359 mg) in methanol (7 ml) is added to a solution of sodium 2-ethyl hexanoate in methanol (2 mol/l, 1.73 ml) at room temperature. After stirring for 10 min. dilute the reaction mixture with ethyl acetate, stir for 5 min. and filtered to collect the separated solid, which is washed with ethyl acetate and used to give the disodium salt of 7(3-(oc-p-hydroxyphenyl-a-carboxyacetamido)r7a-methoxy-3-(1-methyl-tetrazol-5- yl)-
tiometyl-1-oksadetia-3-cefem-^-karboksylsyre (3^2 mg).thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (3^2 mg).
Utbytte: 88,8%. Farvelost pulver som smelter under spaltingYield: 88.8%. Colorless powder that melts during cleavage
fra 170°C.from 170°C.
IR: vHl0s] 1768, 1675, 1608 cm<-1>. IR: vH10s] 1768, 1675, 1608 cm<-1>.
UV:i>CH30<H>273 nm (£= 11100). UV: i>CH 3 O<H>273 nm (£= 11100).
maks.max.
Eksempel V- 6 fifdj- ■ ZZ '\Example V- 6 fifdj- ■ ZZ '\
Til en lbsning av 7(3-/a-p-hydroksyfenyl-a-karboksyacetamidoy<7->7a-metoksy-3~(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre (836 mg) i en blanding av metylenklorid (15 ml), To a solution of 7-(3-[a-p-hydroxyphenyl-a-carboxyacetamidoy<7->7a-methoxy-3~(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (836 mg) in a mixture of methylene chloride (15 ml),
etylacetat 0 5 ml) og metanol (10 ml) tilsettes difenyldiazo-ethyl acetate 0 5 ml) and methanol (10 ml) are added to diphenyldiazo-
metan (950 mg) . Etter omrbring 30 min. ved romtemperatur methane (950 mg) . After transfer 30 min. at room temperature
konsentreres blandingen under redusert trykk og vaskes med n-heksan. Produktet kromatograferes på silikagel (90 g) the mixture is concentrated under reduced pressure and washed with n-hexane. The product is chromatographed on silica gel (90 g)
inneholdende 10% vann og elueres med en blanding av benzen og etylacetat (1:1) til å gi difenylmetyl 7(3- (a- p-hydroksyf enyl-a-dif enyImetoksykarbonylacetamido)-7a-metoksy-3-(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-l+-karboksylat (1,270 g). containing 10% water and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl 7(3-(α-β-hydroxyphenyl-α-diphenyImethoxycarbonylacetamido)-7α-methoxy-3-(1-methyltetrazole -5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (1.270 g).
Utbytte: 95%.Yield: 95%.
IR: yCHC133585, 3315, 1790, 1722, 1700sh cm*1, IR: yCHC133585, 3315, 1790, 1722, 1700sh cm*1,
maks.max.
VI. Preparater og deres bruk.WE. Preparations and their use.
Eksempel VI- 1 jOY\22-3 " i 1 Example VI- 1 jOY\22-3 " in 1
Dinatriumsaltet av 70-(a-p-hydroksyfenyl-a-karboksyacetamido)-7a-metoksy-3~(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-l+-karboksylsyre (100 mg) i en 5 ml beholder opplbses i \lsterilisert vann for injeksjon (1 ml) for bruk og gis til en voksen pasient som lider av pyelitis ved intravenbs injeksjon. The disodium salt of 70-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (100 mg) in a 5 ml container is dissolved in sterile water for injection (1 ml) for use and given to an adult patient suffering from pyelitis by intravenous injection.
Eksempel VI-2 ^y 2;.;. 7? Example VI-2 ^y 2;.;. 7?
Det frysetbrkede produkt fra en lbsning av 7P-/oc- (3-tienyl)-oc-karboksyacet amid q7-7oc-metoksy-3- (1-me tyl te trazol-5-yl) tiome tyl-l-oksadetia-3-cefem-^-karboksylsyre (1 g) nbytralisert til pH 7,0 med natriumhydrogenkarbonat anbringes i en 150 ml kolbe. - j Produktet opplbses i sterilisert vann for injeksjon (100 ml) og tildryppes intravenbst til en voksen pasient umiddelbart etter eller under en kirurgisk operasjon av kreft for å forhindre og behandle postoperativ bakterieinfeksjon. The freeze-fractured product from a solution of 7P-[oc-(3-thienyl)-oc-carboxyacetamide q7-7oc-methoxy-3-(1-methyl te trazol-5-yl)thiomethyl-l-oxadethia-3 -cephem-^-carboxylic acid (1 g) neutralized to pH 7.0 with sodium bicarbonate is placed in a 150 ml flask. - j The product is dissolved in sterilized water for injection (100 ml) and instilled intravenously to an adult patient immediately after or during a surgical operation for cancer to prevent and treat post-operative bacterial infection.
Eksempel VI- 3 / " ' Example VI- 3 / " '
)-v. o.v /. )-v. etc.
Mikr okrys tall insk 7(3-/a-karbamoyl oksyf enyl-oc-karboksyacet amid q7-7a-metoksy-3~(1-metyltetrazol-5-yl)tiometyl-1-oksadetia-3-cefem-.»^-karboksylsyre (200 mg) i en 5 ml beholder suspenderes i ly sterilisert vann for injeksjon inneholdende 2 mg prokain (2 ml) Micr ochrys tall insk 7(3-/a-carbamoyl oxyphenyl-oc-carboxyacet amide q7-7a-methoxy-3~(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-.»^- carboxylic acid (200 mg) in a 5 ml container is suspended in sheltered sterilized water for injection containing 2 mg procaine (2 ml)
og gis intramuskulært til en pasient som lider av materie-betennelse bevirket av staphylococcus aureus. and is given intramuscularly to a patient suffering from matter-inflammation caused by staphylococcus aureus.
Eksempel VI-^ '■ >'' y Example VI-^ '■ >'' y
r'y::Krystallinsk 7s-/a- (3~tienyl)-a- (5^indanyl)oksykarbonylacetamido.7-3-(1-metylte trazol-5-yl)tiometyl-1-oksadetia-3-cefem-^-karboksylsyre (200 mg) opplbses i sesamolje (0,25 ml)°g fylles r'y::Crystalline 7s-/a-(3~thienyl)-a-(5^indanyl)oxycarbonylacetamido.7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylic acid (200 mg) is dissolved in sesame oil (0.25 ml) and filled
i en hård gelatinkapsel. Hver kapsel gis oralt med h timersin a hard gelatin capsule. Each capsule is given orally with h hours
, mellomrom til en pasient som lider av infeksjon i den ovre åndedrettskanal bevirket av streptococcus pyogenes. , space to a patient suffering from an upper respiratory tract infection caused by streptococcus pyogenes.
Eksempel VI- 5 M v v . ■■7Example VI- 5 M v v . ■■7
Pulverisert 7(3-/ot-p-hydroksyf enyl-a- (5-indanyl) oksykarbonyl-acetamidQ_7-7a-metoksy-3- (1 -me tylte tr azol-5-yl) tiometyl-1 - oksa-detia- 3-cefem-^-karboksylsyre (100 mg) behandles med maisstivelse 0 50 mg) og talkum (10 mg), pulveriseres og innkapsles i en hård gelatinkapsel (250 mg) volum). Hver kapsel tilfores oralt med 3 timers mellomrom til en voksen pasient som lider av urinveisinfeksjon bevirket av Escherichia coli. Powdered 7-(3-β-hydroxyphenyl-α-(5-indanyl)oxycarbonyl-acetamide Q_7-7α-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxa-dethia- 3-cephem-^-carboxylic acid (100 mg) is treated with corn starch (0 50 mg) and talc (10 mg), powdered and encapsulated in a hard gelatin capsule (250 mg) volume). Each capsule is administered orally at 3-hour intervals to an adult patient suffering from a urinary tract infection caused by Escherichia coli.
Eksempel VI- 6 J ' '/£ Example VI- 6 J ' '/£
Blandet pulver av 7P-/g<->p-karbamoyloksyfényl-a-(5-lndanyloksy)-karbonylacetamido7-7cx-metoksy-3- (1-me tylte trazol-5-yl) tiometyl-1-oksadetia-3-cefem-<>>+-karboksylsyre (10 g) lactose (50 g), maisstivelse (2 g), magnesiumstearat (0,3 g) sucrose (10 g) og nbdvendig mengde av acacia og talkum granuleres. Granulen Mixed powder of 7P-[g<->p-carbamoyloxyphenyl-a-(5-lndanyloxy)-carbonylacetamido7-7cx-methoxy-3-(1-methyltrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -<>>+-carboxylic acid (10 g) lactose (50 g), corn starch (2 g), magnesium stearate (0.3 g) sucrose (10 g) and the required amount of acacia and talc are granulated. The granule
44
blandes med vann for bruk for å oppnå en suspensjon, og en teskje av suspensjonen gis oralt til et barn som lider av pneumonia bevirket av Klebsiella pneumoniae. is mixed with water for use to obtain a suspension, and a teaspoonful of the suspension is given orally to a child suffering from pneumonia caused by Klebsiella pneumoniae.
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NL178005C (en) * | 1972-11-06 | 1986-01-02 | Merck & Co Inc | METHOD FOR PREPARING A PHARMACEUTICAL PREPARATION WITH ANTIBACTERIAL ACTION, AND METHOD FOR PREPARING A CEPHALOSPORINE ANTIBIOTIC. |
US3962232A (en) * | 1973-11-05 | 1976-06-08 | Eli Lilly And Company | 7-methoxycephalosporins |
GB1449420A (en) * | 1973-11-26 | 1976-09-15 | Sankyo Co | 7alpha-methoxycephalosporing derivatives |
-
1977
- 1977-03-23 GR GR53086A patent/GR61146B/en unknown
- 1977-03-23 SE SE7703325A patent/SE443143B/en not_active IP Right Cessation
- 1977-03-23 CY CY1158A patent/CY1158A/en unknown
- 1977-03-23 NO NO771023A patent/NO158505C/en unknown
- 1977-03-24 DK DK131277A patent/DK161331C/en not_active IP Right Cessation
- 1977-03-24 HU HU77SI00001565A patent/HU172720B/en not_active IP Right Cessation
- 1977-03-24 RO RO7789781A patent/RO71742A/en unknown
- 1977-03-24 IE IE622/77A patent/IE44794B1/en not_active IP Right Cessation
- 1977-03-24 DD DD7700198053A patent/DD129792A5/en unknown
- 1977-03-24 ES ES457174A patent/ES457174A1/en not_active Expired
- 1977-03-24 NZ NZ183687A patent/NZ183687A/en unknown
- 1977-03-24 RO RO7799076A patent/RO78228A/en unknown
- 1977-03-24 PT PT66346A patent/PT66346B/en unknown
- 1977-03-24 BG BG7735796A patent/BG31074A3/en unknown
- 1977-03-25 MX MX775582U patent/MX4348E/en unknown
- 1977-03-25 IL IL51743A patent/IL51743A/en unknown
- 1977-03-25 AR AR266992A patent/AR224606A1/en active
- 1977-03-25 DE DE2713370A patent/DE2713370C2/en not_active Expired - Lifetime
-
1978
- 1978-04-28 ES ES469286A patent/ES469286A1/en not_active Expired
- 1978-04-28 ES ES469285A patent/ES469285A1/en not_active Expired
- 1978-04-28 ES ES469287A patent/ES469287A1/en not_active Expired
- 1978-04-28 ES ES469284A patent/ES469284A1/en not_active Expired
-
1982
- 1982-11-11 HK HK468/82A patent/HK46882A/en unknown
-
1983
- 1983-08-23 YU YU1738/83A patent/YU44039B/en unknown
- 1983-08-23 YU YU1737/83A patent/YU44038B/en unknown
-
1986
- 1986-05-28 NO NO862107A patent/NO862107L/en unknown
Also Published As
Publication number | Publication date |
---|---|
MX4348E (en) | 1982-04-05 |
YU173883A (en) | 1983-12-31 |
ES457174A1 (en) | 1978-08-16 |
YU44039B (en) | 1990-02-28 |
NO158505B (en) | 1988-06-13 |
DK131277A (en) | 1977-09-26 |
GR61146B (en) | 1978-09-27 |
HU172720B (en) | 1978-11-28 |
SE7703325L (en) | 1977-09-26 |
CY1158A (en) | 1983-01-28 |
ES469285A1 (en) | 1979-09-16 |
NO771023L (en) | 1977-09-27 |
YU173783A (en) | 1983-12-31 |
ES469284A1 (en) | 1978-11-16 |
PT66346B (en) | 1978-08-16 |
IE44794B1 (en) | 1982-04-07 |
DK161331C (en) | 1991-12-09 |
IL51743A (en) | 1980-10-26 |
IE44794L (en) | 1977-09-25 |
BG31074A3 (en) | 1981-10-15 |
DE2713370C2 (en) | 1994-04-21 |
PT66346A (en) | 1977-04-01 |
HK46882A (en) | 1982-11-19 |
YU44038B (en) | 1990-02-28 |
DD129792A5 (en) | 1978-02-08 |
ES469286A1 (en) | 1979-09-16 |
RO78228A (en) | 1982-02-01 |
SE443143B (en) | 1986-02-17 |
ES469287A1 (en) | 1979-09-16 |
RO71742A (en) | 1982-02-26 |
DE2713370A1 (en) | 1977-09-29 |
NO158505C (en) | 1988-09-21 |
NZ183687A (en) | 1979-01-11 |
DK161331B (en) | 1991-06-24 |
AR224606A1 (en) | 1981-12-30 |
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