NO148375B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-CHLORO-7-ALFA-AMINO-ACYLCEPHALOSPORINE - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-CHLORO-7-ALFA-AMINO-ACYLCEPHALOSPORINEInfo
- Publication number
- NO148375B NO148375B NO740606A NO740606A NO148375B NO 148375 B NO148375 B NO 148375B NO 740606 A NO740606 A NO 740606A NO 740606 A NO740606 A NO 740606A NO 148375 B NO148375 B NO 148375B
- Authority
- NO
- Norway
- Prior art keywords
- chloro
- cephem
- carboxylic acid
- amino
- ester
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 10
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 3-chloro-3-cephem ester Chemical class 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 14
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 6
- 231100000252 nontoxic Toxicity 0.000 claims description 6
- 230000003000 nontoxic effect Effects 0.000 claims description 6
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000002081 enamines Chemical group 0.000 claims description 5
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 4
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [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 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002221 trityl group Chemical group [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 claims description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000000203 mixture Substances 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 150000002148 esters Chemical class 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000010521 absorption reaction Methods 0.000 description 16
- 150000001408 amides Chemical class 0.000 description 16
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 11
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- QYIYFLOTGYLRGG-KWBIFUEGSA-N (6r)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@H](C(=O)NC2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-KWBIFUEGSA-N 0.000 description 9
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000007795 chemical reaction product Substances 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- YLIOIMWNSIRKDG-ZWNOBZJWSA-N (4-nitrophenyl)methyl (6r,7r)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1[C@@H](C(N11)=O)N)CC(Cl)=C1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 YLIOIMWNSIRKDG-ZWNOBZJWSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 8
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- MJSLXMHHSSCUOK-LRTDYKAYSA-N (4-nitrophenyl)methyl (6r)-3-chloro-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1COC(=O)C1=C(Cl)CS[C@H]2N1C(=O)C2NC(=O)CC1=CC=CS1 MJSLXMHHSSCUOK-LRTDYKAYSA-N 0.000 description 7
- 230000010933 acylation Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- OAZLXJCFUYYYGO-ZCFIWIBFSA-N (6r)-3-chloro-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class S1CC(Cl)=CN2C(=O)C[C@H]21 OAZLXJCFUYYYGO-ZCFIWIBFSA-N 0.000 description 6
- OQSAFIZCBAZPMY-UHFFFAOYSA-N 7-azaniumyl-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(Cl)=C(C(O)=O)N2C(=O)C(N)C21 OQSAFIZCBAZPMY-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940124587 cephalosporin Drugs 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical class ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- FBZDCMZXVFLUJS-LRTDYKAYSA-N (4-nitrophenyl)methyl (6r)-3-hydroxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(=C(CS2)O)C(=O)OCC=1C=CC(=CC=1)[N+]([O-])=O)NC(=O)CC1=CC=CS1 FBZDCMZXVFLUJS-LRTDYKAYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical class ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- CMKKEASDKHKEAE-XTBNCEIVSA-N (4-nitrophenyl)methyl (6r)-7-amino-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrochloride Chemical compound Cl.S([C@@H]1C(C(N11)=O)N)CC(O)=C1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 CMKKEASDKHKEAE-XTBNCEIVSA-N 0.000 description 3
- JKRDOIMPDULYGS-CTYRZGFYSA-N (4-nitrophenyl)methyl (6r)-7-amino-3-methylidene-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate;hydrochloride Chemical compound Cl.S([C@@H]1C(C(N11)=O)N)CC(=C)C1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JKRDOIMPDULYGS-CTYRZGFYSA-N 0.000 description 3
- OQSAFIZCBAZPMY-PUOGSPQQSA-N (6r)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class S1CC(Cl)=C(C(O)=O)N2C(=O)C(N)[C@H]21 OQSAFIZCBAZPMY-PUOGSPQQSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 238000002814 agar dilution Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- BYPHSRGQSFWOOC-XCWJXAQQSA-N benzhydryl (6r)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1C(C(N11)=O)N)CC(Cl)=C1C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 BYPHSRGQSFWOOC-XCWJXAQQSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
- 229940106164 cephalexin Drugs 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000002333 glycines Chemical class 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000005949 ozonolysis reaction Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 description 2
- QUSLYJRJAKKYQP-HTMVYDOJSA-N (4-nitrophenyl)methyl (6r,7r)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrochloride Chemical compound Cl.S([C@@H]1[C@@H](C(N11)=O)N)CC(Cl)=C1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 QUSLYJRJAKKYQP-HTMVYDOJSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- AJYXPNIENRLELY-UHFFFAOYSA-N 2-thiophen-2-ylacetyl chloride Chemical compound ClC(=O)CC1=CC=CS1 AJYXPNIENRLELY-UHFFFAOYSA-N 0.000 description 2
- NWWJFMCCTZLKNT-UHFFFAOYSA-N 3,4-dihydro-2h-thiazine Chemical group C1CC=CSN1 NWWJFMCCTZLKNT-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- 241000606768 Haemophilus influenzae Species 0.000 description 1
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- BJHSJJXGGGHTRK-XCWJXAQQSA-N benzhydryl (6r)-7-amino-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1C(C(N11)=O)N)CC(O)=C1C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 BJHSJJXGGGHTRK-XCWJXAQQSA-N 0.000 description 1
- KHEQVNAUUSSCRP-SAQPSMIMSA-N benzhydryl (6r)-7-amino-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrochloride Chemical compound Cl.S([C@@H]1C(C(N11)=O)N)CC(O)=C1C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 KHEQVNAUUSSCRP-SAQPSMIMSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- UEIHHVGIYYSXAY-UHFFFAOYSA-N carbon dioxide;tetrachloromethane Chemical compound O=C=O.ClC(Cl)(Cl)Cl UEIHHVGIYYSXAY-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical group 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
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- 229940117955 isoamyl acetate Drugs 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 238000012009 microbiological test Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000000033 nuclear magnetic resonance titration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 239000012048 reactive intermediate Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VWAWMPXOFHGGMY-UOQXYWCXSA-M sodium 2-[[(Z)-4-methoxy-4-oxobut-2-en-2-yl]amino]-2-phenylacetate Chemical compound [Na+].COC(=O)\C=C(\C)NC(C([O-])=O)C1=CC=CC=C1 VWAWMPXOFHGGMY-UOQXYWCXSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
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Description
Foreliggende oppfinnelse angår fremstilling av nye terapeutisk virksomme 3-klor-7-a-aminoacylcefalosporinforbindelser med formelen: The present invention relates to the production of new therapeutically effective 3-chloro-7-a-aminoacylcephalosporin compounds with the formula:
hvor R er fenyl, 3- eller 4-hydroksyfenyl eller 4-klorfenyl, samt farmasøytisk akseptable, ikke-toksiske salter derav. where R is phenyl, 3- or 4-hydroxyphenyl or 4-chlorophenyl, as well as pharmaceutically acceptable, non-toxic salts thereof.
Det er kjent flere 7-a-aminoacylcefalosporin-antibiotika Several 7-α-aminoacylcephalosporin antibiotics are known
med forskjellige substituenter i 3-stillingen i molekylet. Som eksempler kan nevnes det velkjente antibiotikum cefa-leksin, 7-(D-a-fenylglycylamino)-3-metyl-3-cefem-4-karboksylsyre som er beskrevet i US patent nr. 3.507.861. with different substituents in the 3-position in the molecule. Examples include the well-known antibiotic cephalexin, 7-(D-α-phenylglycylamino)-3-methyl-3-cephem-4-carboxylic acid, which is described in US patent no. 3,507,861.
Klor-cefalosporinforbindelsene som tilveiebringes ved foreliggende oppfinnelse er strukturelt enestående forbindelser i cefalosporingruppen ved at kloratomet er direkte knyttet til karbonatomet i 3-stillingen i dihydrotiazinringen. The chloro-cephalosporin compounds provided by the present invention are structurally unique compounds in the cephalosporin group in that the chlorine atom is directly linked to the carbon atom in the 3-position of the dihydrothiazine ring.
Forbindelsene med formel I fremstilles ifølge foreliggende oppfinnelse ved at en 3-klor-3-cefem-ester med formelen: hvor er benzyl, p-metoksybenzyl, p-nitrobenzyl, difenylmetyl, 2,2,2-trikloretyl, trimetylsilyl eller t-butyl, omsettes med et acyleringsmiddel med formelen: hvor R har den ovenfor angitte betydning, og er t-butyl-oksybarbonyl, benzyloksykarbonyl, p- nitrobenzyloksykarbonyl, trikloretoksykarbonyl eller en tritylgruppe, eller enaminer dannet med metylacetoacetat og acetylaceton, eller et reaktivt derivat derav, hvoretter de karboksylsyrebeskyttende og aminobeskyttende grupper fjernes, og, om ønsket, omdannelse av en således oppnådd forbindelse til et farmasøytisk akseptabelt, ikke-toksisk salt derav. The compounds of formula I are prepared according to the present invention by a 3-chloro-3-cephem ester of the formula: where is benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, trimethylsilyl or t-butyl , is reacted with an acylating agent of the formula: where R has the above meaning, and is t-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl or a trityl group, or enamines formed with methyl acetoacetate and acetylacetone, or a reactive derivative thereof, after which removing the carboxylic acid protecting and amino protecting groups, and, if desired, converting a compound thus obtained into a pharmaceutically acceptable, non-toxic salt thereof.
De estergrupper som er angitt for R^ i formel II er alle kjente estergrupper av den type som vanligvis anvendes i forbindelse med cefalosporiner for å beskytte C^-karboksylgruppen i cefalosporinmolekylet når man utfører reaksjoner som innbefatter andre reaktive posisjoner i molekylet. Fremstillingen av estere med formel II utføres ved de fremgangsmåter som er angitt i det etterfølgende. The ester groups indicated for R^ in formula II are all known ester groups of the type usually used in connection with cephalosporins to protect the C^-carboxyl group in the cephalosporin molecule when carrying out reactions involving other reactive positions in the molecule. The preparation of esters of formula II is carried out by the methods indicated below.
Med begrepet "farmasøytisk akseptable, ikke-toksiske salter" forstås både saltene av C^-karboksylsyrefunksjonen og syreaddisjonssalter av a-aminogruppen i 7-glycylamino-sidekjeden. Farmasøytisk akseptable salter som innbefatter C^-karboksylsyrefunksjonen innbefatter salter som. dannes med uorganiske baser såsom natrium-, kalium- og kalsiumsalter, og disse kan fremstilles med natriumbikarbonat, kaliumkarbonat, kalsiumhydroksyd eller natriumhydroksyd. Farmasøytisk akseptable aminsalter kan også fremstilles med organiske aminer By the term "pharmaceutically acceptable, non-toxic salts" are meant both the salts of the C 1 -carboxylic acid function and acid addition salts of the α-amino group in the 7-glycylamino side chain. Pharmaceutically acceptable salts containing the C 1 -carboxylic acid function include salts which. are formed with inorganic bases such as sodium, potassium and calcium salts, and these can be prepared with sodium bicarbonate, potassium carbonate, calcium hydroxide or sodium hydroxide. Pharmaceutically acceptable amine salts can also be prepared with organic amines
.såsom dicykloheksylamin, benzylamin, 2-aminoetanol, dietanol-amin eller diisopropylamin. Syreaddisjonssalter av a-aminogruppen innbefatter salter som dannes med mineralsyrer såsom .such as dicyclohexylamine, benzylamine, 2-aminoethanol, diethanolamine or diisopropylamine. Acid addition salts of the α-amino group include salts formed with mineral acids such as
hydroklorider, hydrobromider og sulfater, samt salter som dannes med organiske sulfonsyrer såsom p-toluensulfonat. hydrochlorides, hydrobromides and sulphates, as well as salts formed with organic sulphonic acids such as p-toluenesulphonate.
Forbindelsene med formel I kan eksistere i zwitterioneform som oppstår via intramolekylær saltdannelse, når R^ er om-dannet til hydrogen. The compounds of formula I can exist in zwitterionic form which occurs via intramolecular salt formation, when R 1 is converted to hydrogen.
På grunn av at man har et asymmetrisk karbonatom i a-amino-acylgruppen, kan 3-klor-cefalosporiner med formel I innbe-fatte D-, L- og DL-former. D-formen er den foretrukne isomere form. Due to having an asymmetric carbon atom in the α-amino-acyl group, 3-chloro-cephalosporins of formula I can include D, L and DL forms. The D form is the preferred isomeric form.
Forbindelser med formel I eller farmasøytisk akseptable, ikke-toksiske salter av slike forbindelser, er verdifulle antibiotika som kan brukes for bekjempelse av infeksjoner hos varm-blodige pattedyr som forårsakes av gram-positive og gram-negative mikroorganismer. De er effektive når de tilføres parenteralt, subkutant eller intramuskulært, så vel som oralt. Forbindelsene med formel I er oralt akseptable og mer sterkt-virkende enn eksisterende oralt akseptable cefalosporiner, dvs. cefalexin og cefradin. Compounds of formula I or pharmaceutically acceptable, non-toxic salts of such compounds are valuable antibiotics that can be used to combat infections in warm-blooded mammals caused by gram-positive and gram-negative microorganisms. They are effective when administered parenterally, subcutaneously, or intramuscularly, as well as orally. The compounds of formula I are orally acceptable and more potent than existing orally acceptable cephalosporins, i.e. cephalexin and cephradine.
I norsk søknad 792681 omhandles forbindelser som er nyttige som mellomprodukter for fremstilling av forbindelser med formel I; disse mellomprodukter har formelen: Norwegian application 792681 deals with compounds that are useful as intermediates for the production of compounds of formula I; these intermediates have the formula:
hvor R1 er hydrogen, benzyl, p_-metoksybenzyl, p_-nitrobenzyl, difenylmetyl, 2,2,2-trikloretyl eller t-butyl; og R~ er hydrogen, t-butyloksykarbonyl, benzyloksykarbony 1, p_-nitrobenzyloksykarbonyl, trikloretoksykarbonyl eller trityl, eller enaminer dannet med metylacetoacetat og acetylaceton; forut-satt at R.| og R2 ikke begge er hydrogen. where R 1 is hydrogen, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl or t-butyl; and R~ is hydrogen, t-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl or trityl, or enamines formed with methyl acetoacetate and acetylacetone; provided that R.| and R 2 are not both hydrogen.
Forbindelsene med formel I har et bredt anti-bakterielt spektrum slik det er illustrert ved in vitro-spekteret for 7-(D-fenylgiycylamino)-3-klor-3-cefem-4-karboksylsyre (cefaclor) som vist i etterfølgende tabeller. The compounds of formula I have a broad antibacterial spectrum as illustrated by the in vitro spectrum of 7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor) as shown in subsequent tables.
Tabell I angir minimumsinhiberende konsentrasjoner (MIC) i mikrogram pr. milliliter (yg/ml) som ble oppnådd med denne forbindelse vad en standard agarfortynningsprøve. Table I indicates minimum inhibitory concentrations (MIC) in micrograms per milliliters (µg/ml) obtained with this compound was a standard agar dilution sample.
Tabell II nedenfor angir diameteren i millimeter på vekst-inhiberingssonen for den angitte mikroorganisme ved en standard agarplateprøve, og som ble oppnådd med 7-(D-fenyl-giycylamino) -3-klor-3-cefem-4-karboksylsyre. Table II below indicates the diameter in millimeters of the growth inhibition zone of the indicated microorganism in a standard agar plate sample, and which was obtained with 7-(D-phenyl-glycylamino)-3-chloro-3-cephem-4-carboxylic acid.
Tabell III viser MIC-verdier som ble oppnådd med 7-(D-fenyl-glycylamino)-3-klor-3-cefem-4-karboksylsyre overfor en rekke gram-positive og gram-negative mikroorganismer ved en standard agarfortynningsprøve. Table III shows MIC values obtained with 7-(D-phenyl-glycylamino)-3-chloro-3-cephem-4-carboxylic acid against a variety of gram-positive and gram-negative microorganisms in a standard agar dilution test.
Ved en standard agarfortynningsprøve viste 7-(D-fenyl-glycylamino)-3-klor-3-cefem-4-karboksylsyre aktivitet overfor Hemophilus influenzae med MIC-verdier på fra 1-4 mg/ml for In a standard agar dilution test, 7-(D-phenyl-glycylamino)-3-chloro-3-cephem-4-carboxylic acid showed activity against Hemophilus influenzae with MIC values ranging from 1-4 mg/ml for
en rekke forskjellige stammer. a number of different strains.
Tabell IV viser den orale absorbsjonen av 7-(D-fenylglycyl-amino)-3-klor-3-cefem-4-karboksylsyre ved blod- og urin-innhold som ble oppnådd hos mus. I denne prøve anvendte man Mc-Allister Swiss mus som veide 11-13 g, og de ble fastet over natten og så oralt tilført 20 mg/kg av 7-(D-fenylglycyl-amino)-3-klor-3-cefem-4-karboksylsyre. Blod- og urinprøver ble tatt på de angitte tidspunkter, og konsentrasjonen av antibiotikumet i hver prøve ble bestemt ved en mikrobiologisk prøve hvor man brukte Sarcina lutea i en pH 6,0 agar i en standard agarplateprøve. Table IV shows the oral absorption of 7-(D-phenylglycyl-amino)-3-chloro-3-cephem-4-carboxylic acid at blood and urine levels obtained in mice. In this test, Mc-Allister Swiss mice weighing 11-13 g were used, and they were fasted overnight and then orally administered 20 mg/kg of 7-(D-phenylglycyl-amino)-3-chloro-3-cephem- 4-carboxylic acid. Blood and urine samples were taken at the indicated times, and the concentration of the antibiotic in each sample was determined by a microbiological test using Sarcina lutea in a pH 6.0 agar in a standard agar plate sample.
Den effektive dose (EDj-q) for 7-(D-f enylglycylamino) -3-klor-3-cefem-4-karboksylsyre som er illustrerende for den effektive dose for forbindelser med formel I er 0,74 mg/kg x 2 oralt og 0,48 mg/kg x 2 subkutant overfor Streptococcus pyogenes, og 5,5 mg/kg x 2 oralt overfor Escherichia coli og 17,6 mg/kg x 2 oralt overfor Diplococcus pneumoniae slik det ble bestemt i mus. The effective dose (EDj-q) for 7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid which is illustrative of the effective dose for compounds of formula I is 0.74 mg/kg x 2 orally and 0.48 mg/kg x 2 subcutaneously against Streptococcus pyogenes, and 5.5 mg/kg x 2 orally against Escherichia coli and 17.6 mg/kg x 2 orally against Diplococcus pneumoniae as determined in mice.
Tabell V nedenfor angir minimumsinhiberende konsentrasjoner (MIC) overfor en rekke representative gram-negative bakte-rier for 3-klor-3-cefem-forbindelser med formel I. Table V below indicates minimum inhibitory concentrations (MIC) against a number of representative gram-negative bacteria for 3-chloro-3-cephem compounds of formula I.
De inhiberende konsentrasjoner ble bestemt ved gradient-platemetoden slik den i alt vesentlig er beskrevet av Brijson og Szybalski, Science 116, 45 (1952). I tabell V refererer R<1> seg til strukturformelen. The inhibitory concentrations were determined by the gradient plate method as essentially described by Brijson and Szybalski, Science 116, 45 (1952). In Table V, R<1> refers to the structural formula.
I den etterfølgende tabell VI er det angitt aktivitet for 3-klor-3-cefem-forbindelser overfor kliniske isolater av penicillin-resistente staphylococci. Aktiviteten er angitt som minimumsinhiberende konsentrasjoner for prøve-forbindelsen. Denne konsentrasjon ble bestemt ved gradient-platemetoden. In the subsequent Table VI, the activity of 3-chloro-3-cephem compounds against clinical isolates of penicillin-resistant staphylococci is indicated. The activity is indicated as minimum inhibitory concentrations for the test compound. This concentration was determined by the gradient plate method.
I de nedenstående tabeller VII og VIII er det foretatt forsøk med forbindelser fremstilt ifølge oppfinnelsen, nemlig 7-(D-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre (cefaclor) og 7-[D-(p-hydroksyfenyl)glycylamino]-3-klor-3-cefem-4-karboksylsyre (p-hydroksycefaclor) samt den tidligere kjente forbindelsen 7-(D-fenylglycylamino)-3-metyl-3-cefem-4-karboksylsyre (cefalexin); og disse forsøk bekrefter de fordelaktige egenskaper som innehas av de ifølge oppfinnelsen fremstilte forbindelser sammenlignet med den kjente forbindelsen. Forbindelser med formel I fremstilles ved N-acylering av benzyl-, p-metoksybenzy1-, p-nitrobenzyl-, difenylmety1-, 2,2,2-trikloretyl-, trimetylsilyl- eller t-butylesteren av 7-amino-3-klor-3-cefem-4-karboksylsyre med et fenylsubstitu-ert glycin med formelen: In the tables VII and VIII below, tests have been carried out with compounds produced according to the invention, namely 7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid (cefaclor) and 7-[D-(p-hydroxyphenyl) )glycylamino]-3-chloro-3-cephem-4-carboxylic acid (p-hydroxycefaclor) as well as the previously known compound 7-(D-phenylglycylamino)-3-methyl-3-cephem-4-carboxylic acid (cephalexin); and these tests confirm the advantageous properties possessed by the compounds produced according to the invention compared to the known compound. Compounds of formula I are prepared by N-acylation of the benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, trimethylsilyl or t-butyl ester of 7-amino-3-chloro- 3-cephem-4-carboxylic acid with a phenyl-substituted glycine of the formula:
eller et derivat derav, hvor R og R2 har samme betydning som angitt i forbindelse med formel I og III. Aktiverte derivater av karboksylgruppen i det substituerte glycin kan være syre-halogenider såsom syreklorider, de aktiverte estere såsom de som dannes med pentaklorfenol, azidet eller et blandet anhydrid dannet med glycinet og metylklorformiat og iso-butylklorformiat. Videre kan amino-beskyttet glycin brukes direkte i acyleringen av den ønskede 3-klor-kjerneesteren ved å anvende et kondenseringsmiddel, f.eks. N-etoksykarbo-nyl-2-etoksy-1,2-dihydrokinolin (EEDQ). Således kan f.eks. p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat omsettes med N-(t-butyloksykarbonyl)-D-fenyl-glycin i et tørt, inert oppløsningsmiddel, f.eks. tetrahydrofuran, hvorved man får dannet p-nitrobenzyl-7-(D-fenylglycylamino)-3-klor-3-cefem-4-karboksylat. or a derivative thereof, where R and R2 have the same meaning as indicated in connection with formulas I and III. Activated derivatives of the carboxyl group in the substituted glycine may be acid halides such as acid chlorides, the activated esters such as those formed with pentachlorophenol, the azide or a mixed anhydride formed with the glycine and methyl chloroformate and iso-butyl chloroformate. Furthermore, amino-protected glycine can be used directly in the acylation of the desired 3-chloro core ester by using a condensing agent, e.g. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Thus, e.g. p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate is reacted with N-(t-butyloxycarbonyl)-D-phenyl-glycine in a dry, inert solvent, e.g. tetrahydrofuran, whereby p-nitrobenzyl-7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylate is formed.
Vanligvis kan enhver kjent amidkoplende fremgangsmåte brukes for acylering av 7-amino-3-klor-3-cefem-4-karboksyl- In general, any known amide coupling method can be used for the acylation of 7-amino-3-chloro-3-cephem-4-carboxyl-
syre- esterne. Når det aktiverte derivat er et syrehalogenid, kan acyleringen utføres i nærvær av en hydrogenhalogenid-akseptor såsom natriumbikarbonat, pyridin, natriumbisulfitt eller et alkylenoksyd såsom propylenoksyd. Når man bruker et blandet anhydrid ved acyleringen, kan det blandede anhydrid dannes ved hjelp av N-etoksykarbonyl-2-etoksy-1,2-dihydro-kinolin (EEDQ). Acyleringen kan også utføres i nærvær av et kondensasjonsmiddel såsom N,N'-dicykloheksylkarbodiimid. the acid esters. When the activated derivative is an acid halide, the acylation can be carried out in the presence of a hydrogen halide acceptor such as sodium bicarbonate, pyridine, sodium bisulfite or an alkylene oxide such as propylene oxide. When using a mixed anhydride in the acylation, the mixed anhydride can be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline (EEDQ). The acylation can also be carried out in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide.
Illustrerende eksempler på substituerte glyciner som kan brukes ved fremstillingen av forbindelser med formel I er pentaklorfenyl-D-fenyl-N-(t-butyloksykarbonyl)glycinat, N-(t-butoksykarbonyl)-D-fenylglycin, eller N-(1-karbometoksy-2- propenyl)-D-fenylglycin. Illustrative examples of substituted glycines which can be used in the preparation of compounds of formula I are pentachlorophenyl-D-phenyl-N-(t-butyloxycarbonyl)glycinate, N-(t-butoxycarbonyl)-D-phenylglycine, or N-(1-carbomethoxy -2-propenyl)-D-phenylglycine.
Acyleringen utføres fortrinnsvis i et inert oppløsningsmiddel, f.eks. i aceton, acetonitril, dimetylformamid eller metylenklorid, forbrinnsvis ved temperaturer mellom -20 og 20°C. The acylation is preferably carried out in an inert solvent, e.g. in acetone, acetonitrile, dimethylformamide or methylene chloride, combustible at temperatures between -20 and 20°C.
Illustrerende eksempler på 7-amino-3-klor-3-cefem-4-karbok-sylsyreestere som kan brukes som utgangsforbindelser for fremstilling av forbindelser med formel I, er p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat eller difenylmetyl-7-amino-3-klor-3-cefem-4-karboksylat. Illustrative examples of 7-amino-3-chloro-3-cephem-4-carboxylic acid esters which can be used as starting compounds for the preparation of compounds of formula I are p-nitrobenzyl-7-amino-3-chloro-3-cephem- 4-carboxylate or diphenylmethyl-7-amino-3-chloro-3-cephem-4-carboxylate.
7-amino-3-klor-3-cefem-4-karboksylsyre og estere derav kan fremstilles på følgende måte. En 7-acylamino-cefalosporan-syre eller en ester av denne omdannes til en 7-acylamino-3-eksometylencefam-4-karboksylsyre eller ester. En ester av 3- eksometylencefam-forbindelsen kan så oksyderes med ozon for dannelse av et intermediært ozonid idet 3-eksometylengruppen omdannes, og dette ozonid vil ved dekomponering gi 7-acylamino-3-hydroksy-3-cefem-4-karboksylsyren. 3-hydroksy-3-cefem-esteren kan så kloreres hvorved man får det tilsvarende 3-klor-3-cefem. 7-acylgruppen i 3-klor-cefemet kan så fjernes ved en velkjent sidekjedespaltningsreaksjon ved å anvende fosforpentaklorid i pyridin, hvorved man oppnår iminokloridderivatet i sidekjeden, og dette kan omsettes med en alkohol såsom metanol, hvorved man får iminoeteren, og denne kan igjen lett hydrolyseres slik at man får tilveiebragt 7-amino-3-klor-3-cefem-4-karboksylsyreesteren. 7-amino-3-chloro-3-cephem-4-carboxylic acid and esters thereof can be prepared in the following way. A 7-acylamino-cephalosporanic acid or an ester thereof is converted to a 7-acylamino-3-exomethylene cepham-4-carboxylic acid or ester. An ester of the 3-exomethylene cepham compound can then be oxidized with ozone to form an intermediate ozonide as the 3-exomethylene group is converted, and this ozonide will give 7-acylamino-3-hydroxy-3-cephem-4-carboxylic acid upon decomposition. The 3-hydroxy-3-cephem ester can then be chlorinated, whereby the corresponding 3-chloro-3-cephem is obtained. The 7-acyl group in the 3-chloro-cephem can then be removed by a well-known side chain cleavage reaction by using phosphorus pentachloride in pyridine, whereby one obtains the imino chloride derivative in the side chain, and this can be reacted with an alcohol such as methanol, whereby one obtains the iminoether, and this again can easily is hydrolysed so that the 7-amino-3-chloro-3-cephem-4-carboxylic acid ester is obtained.
Således kan f.eks. en 7-acylaminocefalosporansyre såsom 7-fenoksyacetamidocefalosporansyre omsettes med en svovel-holdig nukleofil forbindelse ved hjelp av kjente fremgangsmåter, hvorved man får en nukleofil forskyvning av acetoksy-gruppen i cefalosporansyren og man får tilveiebragt en 7-acylamino-3-tio-substituert-metyl-3-cefem-4-karboksylsyre. Denne forbindelse kan så reduseres med zink/maursyre i nærvær av dimetylformamid (DMF) eller med Raney-nikkel i nærvær av hydrogen, hvorved man får en 7-acylamino-3-eksometylencefam-4-karboksylsyre. Således kan f.eks. 7-fenoksyacet-amido-3-acetoksymetyl-3-cefem-4-karboksylsyre omsettes med kaliumetylxantat, hvorved man får 7-fenoksyacetamido-3-etoksytionokarbonyltiometyl-3-cefem-4-karboksylsyre. En reduksjon av sistnevnte forbindelse med zink og maursyre i nærvær av DMF gir 7-fenoksyacetamido-3-eksometylencefem-4-karboksylsyre. Etter den reduktive forskyvningsreaksjon som er beskrevet ovenfor, blir den fremstilte 3-eksometylencefam-4-karboksylsyre forestret, f.eks. med p-nitrobenzylbromid, p-metoksybenzylbromid, difenyldiazometan eller 2,2,2-tri-kloretylklorformiat eller andre esterdannende forbindelser, hvoretter 3-eksometylen-cefamesteren blir omsatt med ozon for dannelsen av 3-hydroksy-3-cefem-esteren. Ozonolysereaksjonen av en 3-eksometylencefamester utføres i et inert oppløsnings-middel ved temperaturer mellom -80 og 0°C, fortrinnsvis mellom -80 og -50°C for dannelse av et intermediært ozonid. Ozonidet blir så dekomponert in situ i kulden, hvorved man får den tilsvarende 3-hydroksy-3-cefem-ester, noe som er illustrert i det etterfølgende reaksjonsskjerna. Thus, e.g. a 7-acylaminocephalosporanic acid such as 7-phenoxyacetamidocephalosporanic acid is reacted with a sulphur-containing nucleophilic compound using known methods, whereby a nucleophilic displacement of the acetoxy group in the cephalosporanic acid is obtained and a 7-acylamino-3-thio-substituted-methyl is obtained -3-cephem-4-carboxylic acid. This compound can then be reduced with zinc/formic acid in the presence of dimethylformamide (DMF) or with Raney nickel in the presence of hydrogen, whereby a 7-acylamino-3-exomethylene cepham-4-carboxylic acid is obtained. Thus, e.g. 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid is reacted with potassium ethyl xanthate, whereby 7-phenoxyacetamido-3-ethoxythionocarbonylthiomethyl-3-cephem-4-carboxylic acid is obtained. A reduction of the latter compound with zinc and formic acid in the presence of DMF gives 7-phenoxyacetamido-3-exomethylene-cene-4-carboxylic acid. After the reductive displacement reaction described above, the 3-exomethylene cepham-4-carboxylic acid produced is esterified, e.g. with p-nitrobenzyl bromide, p-methoxybenzyl bromide, diphenyldiazomethane or 2,2,2-trichloroethyl chloroformate or other ester-forming compounds, after which the 3-exomethylene cephem ester is reacted with ozone to form the 3-hydroxy-3-cephem ester. The ozonolysis reaction of a 3-exomethylene encephamester is carried out in an inert solvent at temperatures between -80 and 0°C, preferably between -80 and -50°C to form an intermediate ozonide. The ozonide is then decomposed in situ in the cold, whereby the corresponding 3-hydroxy-3-cephem ester is obtained, which is illustrated in the subsequent reaction core.
I den ovennevnte formel er R" lik resten av en acylamino-gruppe, f.eks. kan R" være benzyl, fenoksymetyl, metyl, 2-tienylmetyl eller 2-furylmetyl, og R1 er som definert ovenfor. In the above formula, R" is equal to the remainder of an acylamino group, for example R" can be benzyl, phenoxymethyl, methyl, 2-thienylmethyl or 2-furylmethyl, and R1 is as defined above.
Ozonolysen av en 3-etoksymetylencefamester utføres ved å boble ozon inn i en oppløsning av esteren i et inert oppløs-ningsmiddel inntil ozoniddannelsen er fullstendig. Inerte oppløsningsmidler som kan brukes her er slike hvor 3-ekso-metylencef amesteren er delvis oppløselig og som ikke reagerer med ozonet under de beskrevne betingelser. Man vil vanligvis oppnå tilfredsstillende resultater med oppløsningsmidler som metanol, etanol, etylacetat, metylacetat, iso-amylacetat og metylenklorid. The ozonolysis of a 3-ethoxymethylene encephamester is carried out by bubbling ozone into a solution of the ester in an inert solvent until ozonide formation is complete. Inert solvents that can be used here are those in which the 3-exo-methylene cep amester is partially soluble and which does not react with the ozone under the described conditions. Satisfactory results will usually be obtained with solvents such as methanol, ethanol, ethyl acetate, methyl acetate, iso-amyl acetate and methylene chloride.
Ozongassen fremstilles ved hjelp av en ozongenerator av den type som vanligvis brukes ved syntetisk og analytisk kjemisk arbeid. Slike generatorer fremstiller ozon ved virkning av en elektrisk utladning i oksygen. Ozonet utvikles i en strøm av oksygen som deretter føres direkte inn i reaksjonskaret. Prosentvis innhold av ozon i oksygenstrømmen kan variere etter ønske, f.eks. ved å variere hastigheten på det oksygen som strømmer gjennom generatoren så vel som ved å variere inten-siteten på den elektriske utladningen. The ozone gas is produced using an ozone generator of the type usually used in synthetic and analytical chemical work. Such generators produce ozone by the action of an electrical discharge in oxygen. The ozone is developed in a stream of oxygen which is then fed directly into the reaction vessel. The percentage content of ozone in the oxygen stream can vary as desired, e.g. by varying the speed of the oxygen flowing through the generator as well as by varying the intensity of the electrical discharge.
Konsentrasjonen av den nevnte 3-eksometylencefamesteren i The concentration of the aforementioned 3-exomethylene encephamester i
det inerte oppløsningsmiddel er ikke kritisk, men det er foretrukket å bruke et tilstrekkelig volum av oppløsningsmidlet til at man får dannet en fullstendig oppløsning. the inert solvent is not critical, but it is preferred to use a sufficient volume of the solvent to form a complete solution.
Når ozoniddannelsen er fullstendig, blir et eventuelt overskudd av ozon i reaksjonsblandingen fjernet fra denne ved gjennombobling av nitrogen, oksygen eller en annen inert gass såsom argon. Etter at man har fjernet et overskudd av ozonet, blir ozonidet dekomponert ved å tilsette et reduk-sjonsmiddel valgt fra gruppen bestående av natriumbisulfitt, svoveldioksyd og trimetylfosfitt, hvorved man får 3-hydroksy-3-cefem-4-karboksylsyreesteren. Dekomponeringen utføres ved å tilsette et overskudd av det dekomponerende reagens og så omrøre reaksjonsblandingen inntil den er negativ i kalium-jodidstivelsesprøven. Et foretrukket middel for dekomponering av ozonidet er gassformet svoveldioksyd. When the ozonide formation is complete, any excess of ozone in the reaction mixture is removed from it by bubbling through nitrogen, oxygen or another inert gas such as argon. After removing an excess of the ozone, the ozonide is decomposed by adding a reducing agent selected from the group consisting of sodium bisulfite, sulfur dioxide and trimethylphosphite, whereby the 3-hydroxy-3-cephem-4-carboxylic acid ester is obtained. The decomposition is carried out by adding an excess of the decomposing reagent and then stirring the reaction mixture until it is negative in the potassium iodide starch test. A preferred agent for decomposing the ozonide is gaseous sulfur dioxide.
3-hydroksy-3-cefem-esterne utvinnes fra reaksjonsblandingen ved avdampning av de flyktige oppløsningsmidler, og man oppnår på denne måten en rest ut fra hvilket reaksjonsproduktet utkrystalliseres. The 3-hydroxy-3-cephem esters are recovered from the reaction mixture by evaporation of the volatile solvents, and in this way a residue is obtained from which the reaction product is crystallized.
7-acylamino-3-hydroksy-3-cefem-4-karboksylsyreestere fremstilt på den måten blir deretter klorert, hvorved man får den ønskede 7-acylamino-3-klor-3-cefem-karboksylsyreester. 7-acylamino-3-hydroxy-3-cephem-4-carboxylic acid esters prepared in that way are then chlorinated, whereby the desired 7-acylamino-3-chloro-3-cephem-carboxylic acid ester is obtained.
3-klor-3-cefemester-utgangsmaterialene kan fremstilles ved å omsette en 7-acylamino-3-hydroksy-3-cefemester eller en 3-l 3 1~ _ O -P^ty, _V -; ^ -v^ c 4- ^ v- i PlMP \ Tn^rl i^n The 3-chloro-3-cephemester starting materials can be prepared by reacting a 7-acylamino-3-hydroxy-3-cephemester or a 3-l 3 1~ _ O -P^ty, _V -; ^ -v^ c 4- ^ v- i PlMP \ Tn^rl i^n
reaktiv klorforbindelse som med nevnte DMF danner klor-dimetyliminiumklorid slik det er angitt ved følgende formel reactive chlorine compound which with said DMF forms chlorodimethyliminium chloride as indicated by the following formula
Det reaktive iminiumklorid med ovennevnte formel dannes in situ og er et meget reaktivt klorerings-mellomprodukt. Klorforbindelser som danner ovennevnte iminiumklorider innbefatter vanlig brukte kloreringsmidler som fosgen (karbo-nylklorid), oksalylklorid, tionylklorid og fosforklorider, f.eks. fosfortriklorid og fosforoksyklorid (fosforylklorid). Fosforpentaklorid kan brukes ved fremstillingen av 3-klor-3-cefem-forbindelser, men denne reagens reagerer samtidig med 7-acylamino-sidekjeden i utgangsmaterialet for dannelse av iminokloridet, det reaktive mellomproduktet i den velkjente cefalosporinsidekjedespaltningsreaksjonen. Det er følgelig foretrukket å bruke et av de andre angitte kloreringsmidler. The reactive iminium chloride with the above formula is formed in situ and is a highly reactive chlorination intermediate. Chlorine compounds which form the above iminium chlorides include commonly used chlorinating agents such as phosgene (carbonyl chloride), oxalyl chloride, thionyl chloride and phosphorus chlorides, e.g. phosphorus trichloride and phosphorus oxychloride (phosphoryl chloride). Phosphorus pentachloride can be used in the preparation of 3-chloro-3-cephem compounds, but this reagent reacts simultaneously with the 7-acylamino side chain in the starting material to form the imino chloride, the reactive intermediate in the well-known cephalosporin side chain cleavage reaction. It is therefore preferred to use one of the other specified chlorinating agents.
Kloreringen kan utføres ved å tilsette kloreringsreagensen til en oppløsning av 3-hydroksy-3-cefemesteren i tørr DMF ved temperaturer på 5-15°C, hvoretter man lar reaksjonsblandingen stå ved romtemperatur i 4-8 timer eller lenger. Reaksjonen er i begynnelsen eksoterm og reaksjonskaret bør derfor i begynnelsen avkjøles i et is-vannbad og så holdes på ca. The chlorination can be carried out by adding the chlorination reagent to a solution of the 3-hydroxy-3-cephemester in dry DMF at temperatures of 5-15°C, after which the reaction mixture is allowed to stand at room temperature for 4-8 hours or longer. The reaction is initially exothermic and the reaction vessel should therefore initially be cooled in an ice-water bath and then kept at approx.
25°C under resten av reaksjonen. Nevnte DMF blir fortrinnsvis tørket før det skal brukes ved hjelp av en molekylsil. Skjønt reaksjonen kan utføres i DMF som oppløsningsmiddel, kan man også anvende et samoppløsningsmiddel som kan anvendes sammen med nevnte DMF. Et slikt kooppløsningsmiddel er f.eks. tetrahydrofuran, dioksan, metylenklorid, dimetylacetamid eller dimetylsulfoksyd som kan brukes sammen med DMF. 25°C during the rest of the reaction. Said DMF is preferably dried before use using a molecular sieve. Although the reaction can be carried out in DMF as solvent, a co-solvent can also be used which can be used together with said DMF. Such a co-solvent is e.g. tetrahydrofuran, dioxane, methylene chloride, dimethylacetamide or dimethylsulfoxide which can be used together with DMF.
De ønskede 3-klor-3-cefem-estere kan utvinnes fra reaksjonsblandingen ved å helle denne over i en vann-etylacetat-blanding og skille ut den organiske fase som inneholder produktet. Den organiske fase kan vaskes, tørkes og så fordampes, hvorved man får 3-klor-3-cefemesteren som et •amorft residuum. Forbindelsen kan oppnås, i krystallinsk form ved behandling av resten med eter eller n-heksan. The desired 3-chloro-3-cephem esters can be recovered from the reaction mixture by pouring it into a water-ethyl acetate mixture and separating the organic phase containing the product. The organic phase can be washed, dried and then evaporated, whereby the 3-chloro-3-cephemester is obtained as an •amorphous residue. The compound can be obtained, in crystalline form, by treating the residue with ether or n-hexane.
Etter fremstillingen av de angitte 7-acylamino-3-klor-3-cefem-4-karboksylsyreestere slik det er beskrevet ovenfor, kan de respektive 7-amino-3-klor-3-cefem-4-karboksylsyre-esterne fremstilles ved å utføre den velkjente N-deacylerin-gen av 7-acylamino-sidekjeden. Således kan 7-acylamino-3-klor-cefalosporinesteren omsettes med fosforpentaklorid i metylenklorid i nærvær av pyridin, hvorved man får dannet iminoklorid-mellomproduktet. Dette kan så omsettes med et alkoholisk oppløsningsmiddel som metanol eller isobutanol, hvorved man får den tilsvarende iminoeter. Denne kan så hydrolyseres, hvorved man får 7-amino-3-klor-3-cefem-4-karboksylsyreesteren som et hydrokloridsalt. After the preparation of the stated 7-acylamino-3-chloro-3-cephem-4-carboxylic acid esters as described above, the respective 7-amino-3-chloro-3-cephem-4-carboxylic acid esters can be prepared by carrying out the well-known N-deacylerin gene of the 7-acylamino side chain. Thus, the 7-acylamino-3-chloro-cephalosporin ester can be reacted with phosphorus pentachloride in methylene chloride in the presence of pyridine, whereby the imino chloride intermediate is formed. This can then be reacted with an alcoholic solvent such as methanol or isobutanol, whereby the corresponding iminoether is obtained. This can then be hydrolysed, whereby the 7-amino-3-chloro-3-cephem-4-carboxylic acid ester is obtained as a hydrochloride salt.
I en spesifikk utførelse av fremstillingen av utgangsforbindelser og forbindelser med formel I blir 7-fenoksyacetamidocefalosporansyre omsatt med tiourea for fremstilling av isotiouroniumsaltet ved en forskyvning av acetoksy-gruppen i 3-stillingen i cefalosporansyre-dihydrotiazinringen. Isotiouroniumsaltet blir så omsatt med sink og et overskudd av 90% maursyre i nærvær av dimetylformamid ved temperaturer på ca. 25°C, hvorved man får fremstilt 7-fenoksy-acetamido-3-eksometylencefam-4-karboksylsyren. Denne syren kan så forestres med p-nitrobenzylbromid i nærvær av hydrogen-halogenidakseptor, hvorved man får 3-eksometylencefam-4-karboksylsyre-p-nitrobenzylesteren. Denne esteren kan så ozoniseres i metylenklorid ved temperaturer på ca. -70°C, og ozonolyseblandingen blir behandlet med svoveldioksyd for dekomponering av det intermediære ozonid, noe som gir p-nitrobenzyl-7-fenoksyacetamido-3-hydroksy-3-cefem-4-karboksylat. 3-hydroksyesteren blir så omsatt med fosfortriklorid i tørr DMF, noe som gir p-nitrobenzyl-7-fenoksy-acetamido-3-klor-3-cefem-4-karboksylat. 3-klor-esteren blir så omsatt i metylenklorid med fosforpentaklorid i nærvær av pyridin, noe som in situ gir iminokloridmellomproduktet som så omsettes med metanol for fremstilling av det tilsvarende iminoetermellomprodukt. Ved tilsetning av vann til reaksjonsblandingen vil iminoeteren dekomponere til p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylatet. 7-amino-3-klor-3-cefem-4-karboksylsyreesteren kan så acyleres slik det tidligere er beskrevet, med et amino-beskyttet D-fenyl-glycinderivat, hvorved man får et N-beskyttet derivat av 7-(.-D-f enylglycylamino )-3- In a specific embodiment of the preparation of starting compounds and compounds of formula I, 7-phenoxyacetamidocephalosporanic acid is reacted with thiourea to produce the isothiouronium salt by a displacement of the acetoxy group in the 3-position of the cephalosporanic acid dihydrothiazine ring. The isothiouronium salt is then reacted with zinc and an excess of 90% formic acid in the presence of dimethylformamide at temperatures of approx. 25°C, whereby the 7-phenoxy-acetamido-3-exomethylene cepham-4-carboxylic acid is produced. This acid can then be esterified with p-nitrobenzyl bromide in the presence of a hydrogen-halide acceptor, whereby the 3-exomethylene encepham-4-carboxylic acid p-nitrobenzyl ester is obtained. This ester can then be ozonized in methylene chloride at temperatures of approx. -70°C, and the ozonolysis mixture is treated with sulfur dioxide to decompose the intermediate ozonide, yielding p-nitrobenzyl-7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate. The 3-hydroxy ester is then reacted with phosphorus trichloride in dry DMF, which gives p-nitrobenzyl-7-phenoxy-acetamido-3-chloro-3-cephem-4-carboxylate. The 3-chloroester is then reacted in methylene chloride with phosphorus pentachloride in the presence of pyridine, which in situ gives the imino chloride intermediate which is then reacted with methanol to produce the corresponding imino ether intermediate. When water is added to the reaction mixture, the iminoether will decompose to p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate. The 7-amino-3-chloro-3-cephem-4-carboxylic acid ester can then be acylated as previously described, with an amino-protected D-phenyl-glycine derivative, thereby obtaining an N-protected derivative of 7-(.-D-f enylglycylamino )-3-
klor-3-c efem-4-karboksylsyre-p-nitrobenzyl.es t- chloro-3-cephem-4-carboxylic acid-p-nitrobenzyl.es t-
eren. Etter fjerning av den a-amino-beskyttende gruppe og C4~karboksylestergruppen, oppnår man 7-(D-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre. Det er underforstått fra den foregående beskrivelse av fremstillingen av utgangsforbindelser, at en rekke kjente 7-acylamino-cefalosporan-syrer kan anvendes for fremstilling av de her beskrevne 7-amino-3-klor-3-cefem-4-karboksylsyrer. is a. After removal of the α-amino protecting group and the C4~carboxylic ester group, 7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid is obtained. It is understood from the preceding description of the preparation of starting compounds that a number of known 7-acylamino-cephalosporanic acids can be used for the preparation of the 7-amino-3-chloro-3-cephem-4-carboxylic acids described here.
7-(D-ct-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre er en foretrukken forbindelse fordi den er av stor kommersiell verdi• 7-(D-ct-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid is a preferred compound because it is of great commercial value•
De følgende eksempler illustrerer fremstilling av utgangs-inaterialer og sluttforbindelser. The following examples illustrate the production of starting materials and final connections.
Eksempel 1 Example 1
p-nitrobenzyl-7-amino-3-metylencefam-4-karboksylat-hydro-klorid. p-nitrobenzyl-7-amino-3-methylene cepham-4-carboxylate hydrochloride.
En oppløsning av 965 mg (2 mmol) p-nitrobenzyl-7-fenoksy-acetamido-3-metylencefam-4-karboksylat i 10 ml metylenklorid ble tilsatt 175 mg tørr pyridin og 460 mg fosforpentaklorid og blandingen ble omrørt ved romtemperatur i 6 timer. A solution of 965 mg (2 mmol) of p-nitrobenzyl-7-phenoxy-acetamido-3-methylene cepham-4-carboxylate in 10 ml of methylene chloride was added to 175 mg of dry pyridine and 460 mg of phosphorus pentachloride and the mixture was stirred at room temperature for 6 hours.
1 ml isobutanol ble tilsatt blandingen som så ble lagret ved 1 ml of isobutanol was added to the mixture which was then stored at
0°C over natten. Reaksjonsproduktet, p-nitrobenzyl-7-amino-3- metylencefam-4-karboksylat-hydroklorid som svar dannet som et krystallinsk bunnfall ble frafiltrert og ga 430 mg 0°C overnight. The reaction product, p-nitrobenzyl-7-amino-3-methylene cepham-4-carboxylate hydrochloride in response formed as a crystalline precipitate was filtered off to give 430 mg
(58% utbytte). (58% yield).
Elementæranalyse for C^^H-^gN^O^SCl Elemental analysis for C^^H-^gN^O^SCl
Teoretisk: C 46,69, H 4,18, N 10,89 Theoretical: C 46.69, H 4.18, N 10.89
Funnet: C 46,40, H 4,20, N 10,62 Found: C 46.40, H 4.20, N 10.62
I.R. (Nujol) I.R. (Nujol)
Karbonylabsorpsjon ved 5,65 (.-3-laktam) og 5,75 (ester) ym. NMR (DMSO dg)-signaler ved 6,35 (2d, 2H, C2~ H2), 4,98 (d, 1H, Carbonyl absorption at 5.65 (.-3-lactam) and 5.75 (ester) ym. NMR (DMSO dg) signals at 6.35 (2d, 2H, C2~ H2), 4.98 (d, 1H,
Cg-H), 4,7-4,4(m, 6H, C4~H, ester CH2, C4~CH2 og C?-H), og 2,4-1,6 (m, 4H, aromatisk H) tau. Cg-H), 4.7-4.4(m, 6H, C4~H, ester CH2, C4~CH2 and C?-H), and 2.4-1.6 (m, 4H, aromatic H) rope.
Eksempel 2 Example 2
p-nitrobenzyl-7-amino-3-hydroksy-3-cefem-4-karboksylat-hydroklorid. p-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride.
En oppløsning av 4 g p-nitrobenzyl-7-amino-3-metylen-cefam-4- karboksylat-hydroklorid i 620 ml metanol ble avkjølt i et tørris-acetonbad, og ozon ble boblet gjennom den kalde opp-løsningen i ca. 20 minutter. Reaksjonsblandingen ble renset for gjenværende ozon ved at man førte, nitrogen gjennom opp-løsningen, hvoretter man tilsatte 10 g natriumbisulfitt. A solution of 4 g of p-nitrobenzyl-7-amino-3-methylene-cepham-4-carboxylate hydrochloride in 620 ml of methanol was cooled in a dry ice-acetone bath, and ozone was bubbled through the cold solution for approx. 20 minutes. The reaction mixture was purified from residual ozone by passing nitrogen through the solution, after which 10 g of sodium bisulphite was added.
Reaksjonsblandingen ble omrørt i 1 time ved isbadtemperatur og blandingen ga på dette tidspunkt en negativ kaliumjodid-stivelsesprøve. The reaction mixture was stirred for 1 hour at ice bath temperature and the mixture gave a negative potassium iodide starch test at this time.
Blandingen ble fordampet i vakuum hvorved man fikk reaksjonsproduktet som en amorf gul rest. Dette ble utkrystallisert i, aceton, og ga 3,4 g p-nitrobenzyl-7-amino-3-hydroksy-3-cefem-4-karboksylat-hydroklorid som et krystallinsk acetonsolvat. The mixture was evaporated in vacuo, whereby the reaction product was obtained as an amorphous yellow residue. This was crystallized in acetone to give 3.4 g of p-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride as a crystalline acetone solvate.
I.R. (Nujol) I.R. (Nujol)
Karbonylabsorpsjonsbånd ved 5,60 (3-laktam) og 6,04' Carbonyl absorption bands at 5.60 (3-lactam) and 6.04'
(esterkarbonylhydrogen bundet til 3-hydroksy) ym. N.M.R. (DMSO db,)-signaler ved 7,92 (s, 3H, 0,5 mol aceton), (ester carbonyl hydrogen bonded to 3-hydroxy) etc. N.M.R. (DMSO db,) signals at 7.92 (s, 3H, 0.5 mol acetone),
6,22 (2d, 2H, C2-H2), 5,07 (d, 1H, CgH), 4,8-4,5 (m, 3H, ester CH^ og C7H) , 2,4-1,6 (m, aromatisk II) Lau. 6.22 (2d, 2H, C2-H2), 5.07 (d, 1H, CgH), 4.8-4.5 (m, 3H, ester CH^ and C7H), 2.4-1.6 (m, aromatic II) Lau.
Eksempel 3 Example 3
p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-hydroksy-3-cefem-4-karboksylat p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate
En oppløsning av 1,55 g p-nitrobenzyl-7-amino-3-hydroksy-3-cefem-4-karboksylat-hydroklorid i 30 ml aceton inneholdende 364 mg (0,5 ml, 3,6 mmol) trietylamin, ble tilsatt 962 mg urea. Under omrøring ved romtemperatur ble det tilsatt dråpevis en oppløsning av 730 mg (4,4 mmol) av 2-tiofenacetyl-klorid i 20 ml aceton. Etter 2,5 timer ble reaksjonsblandingen filtrert og fordampet. Resten ble oppløst i etylacetat, og oppløsningen ble vasket suksessivt med vann, en 5% oppløsning av natriumbikarbonat, 5% saltsyre og en mettet oppløsning av natriumklorid. Den vaskede oppløsning ble tør-ket og konsentrert ved fordampning i vakuum, og dette ga 1,2 g reaksjonsprodukt som krystallinsk rest. Produktet ble omkrystallisert fra etylacetat og ga rent p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-hydroksy-3-cefem-4-karboksylat med følgende spektrale egenskaper. A solution of 1.55 g of p-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 30 ml of acetone containing 364 mg (0.5 ml, 3.6 mmol) of triethylamine was added 962 mg urea. While stirring at room temperature, a solution of 730 mg (4.4 mmol) of 2-thiopheneacetyl chloride in 20 ml of acetone was added dropwise. After 2.5 hours, the reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate, and the solution was washed successively with water, a 5% solution of sodium bicarbonate, 5% hydrochloric acid and a saturated solution of sodium chloride. The washed solution was dried and concentrated by evaporation in vacuo, and this gave 1.2 g of reaction product as a crystalline residue. The product was recrystallized from ethyl acetate to give pure p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate with the following spectral properties.
I.R. (Nujol) I.R. (Nujol)
Absorpsjonstopper ved 3,0 (amid NH), 5,68 (a-laktamkarbonyl) og 6,1 (amid og esterhydrogen bundet til Absorption peaks at 3.0 (amide NH), 5.68 (α-lactam carbonyl) and 6.1 (amide and ester hydrogen bonded to
3 OH) ym. 3 OH) etc.
N.M.R. (CDC13 dg): N.M.R. (CDC13 d):
Signaler ved 6,54 (2d, 2H, C2H2), 6,16 (s, 2H, side-kjede CH2), 4,90 (d, 1H, CgH), 4,60 (d, 2H, ester CH2), 4,43 (q, 1H, C7H), 3,1-1,6 (m, 7H, aromatisk H) og 1,30 (d, 1H, amid NH) tau. Signals at 6.54 (2d, 2H, C2H2), 6.16 (s, 2H, side-chain CH2), 4.90 (d, 1H, CgH), 4.60 (d, 2H, ester CH2), 4.43 (q, 1H, C7H), 3.1-1.6 (m, 7H, aromatic H) and 1.30 (d, 1H, amide NH) tau.
Eksempel 4 Example 4
Difenylmetyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat Diphenylmethyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate
a) En oppløsning av 34 g(100 mmol) 7-[2-(2-tienyl)-acetamido]-3-metylencefam-4-karboksylsyre i 500 ml metylenklorid ble a) A solution of 34 g (100 mmol) of 7-[2-(2-thienyl)-acetamido]-3-methylenecepham-4-carboxylic acid in 500 ml of methylene chloride was
tilsatt 21,4 g (110 mmol) difenyldiazometan, og den resul-terende blanding ble omrørt i 2 timer ved romtemperatur. Oppløsningsmidlet ble fordampet under redusert trykk, og resten ble oppløst i etylacetat. Etylacetatoppløsningen ble vasket med en 5% oppløsning av natriumbikarbonat, deretter med vann og så tørket over magnesiumsulfat. Den tørre oppløsning ble konsentrert til et lite volum. Ved henstand ble det utfelt som et krystallinsk fast stoff 40 g difenylmetyl-7-[2-(2-tienyl)acetamido]-3-metylencefam-4-karboksylat med smeltepunkt ca. 132-133°C. added 21.4 g (110 mmol) of diphenyldiazomethane, and the resulting mixture was stirred for 2 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a 5% solution of sodium bicarbonate, then with water and then dried over magnesium sulfate. The dry solution was concentrated to a small volume. On standing, 40 g of diphenylmethyl-7-[2-(2-thienyl)acetamido]-3-methylene cepham-4-carboxylate with a melting point of approx. 132-133°C.
IR (kloroform): IR (chloroform):
Absorpsjonstopper ved 2,9 (amid N-H), 5,65, 5,75 og 5,93 (|3-laktam, ester og amidkarbonylgrupper henholdsvis) og 6,62 (amid II) ym. Absorption peaks at 2.9 (amide N-H), 5.65, 5.75 and 5.93 (|3-lactam, ester and amide carbonyl groups respectively) and 6.62 (amide II) ym.
NMR (CDC13): NMR (CDCl 3 ):
Signaler ved 6,72 (ABq, 2H, C2~H2), 6,21 (s, 2H, a-CH2), 4,83-4,65 (m, 4H, C4~H, Cg-H og C3~CH2), 4,39 (q, 1H, C7-H), 3,4-2,65 (m, 15H, C?-NH, ester CH og aromatisk H) tau. Signals at 6.72 (ABq, 2H, C2~H2), 6.21 (s, 2H, a-CH2), 4.83-4.65 (m, 4H, C4~H, Cg-H and C3~ CH2), 4.39 (q, 1H, C7-H), 3.4-2.65 (m, 15H, C?-NH, ester CH and aromatic H) tau.
b) En oppløsning av 8,1 g (16 mmol) av ovennevnte ester i b) A solution of 8.1 g (16 mmol) of the above-mentioned ester i
80 ml metylenklorid ble tilsatt 1,57 g (1,6 ml, 19,6 mmol) 80 ml of methylene chloride was added to 1.57 g (1.6 ml, 19.6 mmol)
tørr pyridin og 3,8 g (18,1 mmol) fosforpentaklorid. Reak-sjonsblandingen ble omrørt i 2 timer ved romtemperatur og deretter avkjølt i et is-vannbad. Den kalde blandingen ble behandlet med 8 ml isobutanol under omrøring. Omrør-ingen ble fortsatt i 2 timer og det dannet seg i løpet av denne tiden som et krystallinsk bunnfall 3 g difenylmetyl-7-amino-3-metylencefam-4-karboksylat-hydroklorid. Dette produktet ble frafiltrert og vasket med metylenklorid og vakuumtørket. dry pyridine and 3.8 g (18.1 mmol) phosphorus pentachloride. The reaction mixture was stirred for 2 hours at room temperature and then cooled in an ice-water bath. The cold mixture was treated with 8 ml of isobutanol with stirring. Stirring was continued for 2 hours and during this time 3 g of diphenylmethyl-7-amino-3-methylene cepham-4-carboxylate hydrochloride formed as a crystalline precipitate. This product was filtered off and washed with methylene chloride and vacuum dried.
Elementæranalyse (prosent) for <C>21<H>21N203SC1: Teoretisk: C 60,50, H 5,08, N 6,72, Cl 8,50 Funnet: C 60,70, H 5,02, N 6,71, Cl 8,80 Elemental analysis (percent) for <C>21<H>21N203SC1: Theoretical: C 60.50, H 5.08, N 6.72, Cl 8.50 Found: C 60.70, H 5.02, N 6, 71, Cl 8.80
NMR (DMSO dg): NMR (DMSO dg):
Signaler ved 6,45 (ABq, 2H, C2~H2), 5,00 (d, 1H, Cg-H), 4,68 (d, 1H, C?-H), 4,60 (s, 2H, 3-CH2), 4,44 (s, 1H, C4-H), 3,10 (s, 1H, ester CH), og 2,61 (s, 10H, aromatisk H) tau. Signals at 6.45 (ABq, 2H, C2~H2), 5.00 (d, 1H, Cg-H), 4.68 (d, 1H, C?-H), 4.60 (s, 2H, 3-CH2), 4.44 (s, 1H, C4-H), 3.10 (s, 1H, ester CH), and 2.61 (s, 10H, aromatic H) tau.
c) 7-amino-3-eksometylencefamester-hydrokloridsaltet 2,1 g (5 mmol), ble oppløst i 200 ml metanol og oppløsningen ble c) The 7-amino-3-exomethylene encephamester hydrochloride salt 2.1 g (5 mmol), was dissolved in 200 ml of methanol and the solution was
avkjølt i et aceton-tørrisbad. Ozon ble boblet inn i den kalde oppløsningen i 7 minutter for dannelse av det intermediære ozonid. Ozonidet ble dekomponert ved å føre en strøm av svoveldioksydgass gjennom reaksjonsblandingen i 2 minutter. Deretter ble blandingen fordampet og resten cooled in an acetone-dry ice bath. Ozone was bubbled into the cold solution for 7 minutes to form the intermediate ozonide. The ozonide was decomposed by passing a stream of sulfur dioxide gas through the reaction mixture for 2 minutes. Then the mixture was evaporated and the residue
ble behandlet med dietyleter, noe som ga 1,6 g difenylmetyl-7-amino-3-hydroksy-3-cefem-4-karboksylat-hydroklorid som et krystallinsk fast stoff. was treated with diethyl ether to give 1.6 g of diphenylmethyl-7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride as a crystalline solid.
NMR (CDC13): NMR (CDCl 3 ):
Signaler ved 6,4 (ABq, 2H, C2~H2), 5,0-4,5 (m, 2H, Cg-H og C7~H), 3,2-2,4 (m, 11H, ester CH og aromatisk H) tau. Signals at 6.4 (ABq, 2H, C2~H2), 5.0-4.5 (m, 2H, Cg-H and C7~H), 3.2-2.4 (m, 11H, ester CH and aromatic H) rope.
IR (kloroform): IR (chloroform):
Karbonylabsorpsjonstopper ved 5,57 og 5,70 (3-laktam og esterkarbonyl henholdsvis) ym. Carbonyl absorption peaks at 5.57 and 5.70 (3-lactam and ester carbonyl respectively) ym.
UV (pH 7-buffer): UV (pH 7 buffer):
A max 275 my, e 7550. A max 275 my, e 7550.
Elektrometrisk titrering (60% vandig DMF): Electrometric titration (60% aqueous DMF):
Titrerbare grupper ved 4,5 og 6,5. Titratable groups at 4.5 and 6.5.
d) En oppløsning av 84 0 mg difenylmetyl-7-amino-3-hydroksy-3-cefem-4-karboksylat i 10 ml vann og 10 ml aceton ble d) A solution of 840 mg of diphenylmethyl-7-amino-3-hydroxy-3-cephem-4-carboxylate in 10 ml of water and 10 ml of acetone was
tilsatt 1 g natriumbisulfitt. Blandingen ble omrørt og dråpevis ble det tilsatt 800 mg tiofen-2-acetylklorid i added 1 g of sodium bisulphite. The mixture was stirred and 800 mg of thiophene-2-acetyl chloride was added dropwise
10 ml aceton. Blandingen ble omrørt ved romtemperatur i 10 ml of acetone. The mixture was stirred at room temperature i
4,5 time og ble så fordampet under redusert trykk. Resten ble oppløst i en blanding av etylacetat og en vandig 5% oppløsning av natriumbikarbonat. Etylacetatlaget ble utskilt, vasket med vann og tørket. Den tørrede oppløsning ble fordampet, og resten behandlet med eter, noe som ga 500 mg difenyl-metyl-7-[2-(2-tienyl)acetamido]-3-hydroksy-3-cefem-4-karboksylat. 4.5 hours and was then evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and an aqueous 5% solution of sodium bicarbonate. The ethyl acetate layer was separated, washed with water and dried. The dried solution was evaporated and the residue treated with ether to give 500 mg of diphenyl-methyl-7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate.
NMR (CDC13): NMR (CDCl 3 ):
Signaler ved 6,79 (s, 2H, C2"H2), 6,16 (s, 2H, a-CH2), 5,0 (d, 1H, Cg-H), 4,32 (q, 1H, C?-H), 3,05-2,46 (m, 15H, C^-NH, ester CH og aromatisk H) tau. Signals at 6.79 (s, 2H, C2"H2), 6.16 (s, 2H, a-CH2), 5.0 (d, 1H, Cg-H), 4.32 (q, 1H, C ?-H), 3.05-2.46 (m, 15H, C^-NH, ester CH and aromatic H) tau.
IR (kloroform): IR (chloroform):
Absorpsjonstopper ved 2,9 (amid NH), 5,6, 5,73 og 5,95 (3-laktam, ester og amidkarbonyl respektivt) og 6,65 (amin II) ym. e) En oppløsning av 4,2 g difenylmetyl-7-[2-(2-tienyl)-acet-amido] -3-hydroksy-3-cefem-4-karboksylat i 44 ml tørr dimetylformamid ble tilsatt 865 mg fosfortriklorid. Blandingen ble omrørt i 1,5 timer ved romtemperatur og ble helt over i en blanding av etylacetat og 5% vandig saltsyre. Etylacetatlaget ble fordampet, vasket med 5% saltsyre, vann og tørket. Den tørkede oppløsning ble konsentrert i vakuum, og man fikk utkrystallisert et produkt: 3-kloresteren ble frafiltrert, vasket med kald etylacetat og tørket, hvorved man fikk 2,2 g. Absorption peaks at 2.9 (amide NH), 5.6, 5.73 and 5.95 (3-lactam, ester and amide carbonyl respectively) and 6.65 (amine II) ym. e) To a solution of 4.2 g of diphenylmethyl-7-[2-(2-thienyl)-acet-amido]-3-hydroxy-3-cephem-4-carboxylate in 44 ml of dry dimethylformamide was added 865 mg of phosphorus trichloride. The mixture was stirred for 1.5 hours at room temperature and poured into a mixture of ethyl acetate and 5% aqueous hydrochloric acid. The ethyl acetate layer was evaporated, washed with 5% hydrochloric acid, water and dried. The dried solution was concentrated in vacuo, and a product crystallized out: the 3-chloroester was filtered off, washed with cold ethyl acetate and dried, whereby 2.2 g were obtained.
Elementæranalyse (%) for C2gH21<N>2<0>4<S>2<Cl>: Elemental analysis (%) for C2gH21<N>2<0>4<S>2<Cl>:
Teoretisk: C 59,48, H 4,03, N 5,34, Cl 6,75 Funnet: C 59,77, H 4,25, N 5,40, Cl 6,91 Theoretical: C 59.48, H 4.03, N 5.34, Cl 6.75 Found: C 59.77, H 4.25, N 5.40, Cl 6.91
NMR (CDC13) : NMR (CDCl 3 ) :
Signaler ved 6,49 (ABq, 2H, C2~H2), 6,22 (s, 2H, a-CH2), 5,08 (d, 1H, Cg-H), 4,19 (q, 1H, C?-H), 3,13-2,5 '(m, 15H, C7~NH, ester CH og aromatisk H) tau. Signals at 6.49 (ABq, 2H, C2~H2), 6.22 (s, 2H, a-CH2), 5.08 (d, 1H, Cg-H), 4.19 (q, 1H, C ?-H), 3.13-2.5 '(m, 15H, C7~NH, ester CH and aromatic H) tau.
IR (CHC13) : IR (CHC13) :
Absorpsjonstopper ved 2,9 (amid NH), 5,55, 5,72 oy Absorption peaks at 2.9 (amide NH), 5.55, 5.72 oy
5,90 (3-laktam, ester og amidkarbonylgrupper) og 6,60 (amid II) ym. 5.90 (3-lactam, ester and amide carbonyl groups) and 6.60 (amide II) ym.
UV (dioksan): UV (dioxane):
X max 275 my, e = 8700. X max 275 my, e = 8700.
Eksempel 5 Example 5
p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat (via tionylklorid). p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate (via thionyl chloride).
En oppløsning av 1,9 g (4 mmol) p-nitrobenzyl-7-[2-(2-tienyl)-acetamido]-3-hydroksy-3-cefem-4-karboksylat i 10 ml DMF (tør-ket over en molekylsil) ble tilsatt 950 mg (0,58 ml, 8 mmol) A solution of 1.9 g (4 mmol) of p-nitrobenzyl-7-[2-(2-thienyl)-acetamido]-3-hydroxy-3-cephem-4-carboxylate in 10 ml of DMF (dried over a molecular sieve) was added 950 mg (0.58 ml, 8 mmol)
av nylig destillert tionylklorid. Blandingen ble omrørt ved romtemperatur i 6,5 timer og deretter helt over i 100 ml etylacetat. Blandingen ble ekstrahert tre ganger med 30 ml por-sjoner av 5% saltsyre og med en mettet oppløsning av natriumklorid. Den vaskede etylacetatoppløsning ble filtrert og fordampet til tørrhet i vakuum. Resten ble behandlet med eter, hvorved man fikk 1,2 g p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat som et brunt krystallinsk fast stoff, smeltepunkt ca. 164-166°C. of freshly distilled thionyl chloride. The mixture was stirred at room temperature for 6.5 hours and then poured into 100 ml of ethyl acetate. The mixture was extracted three times with 30 ml portions of 5% hydrochloric acid and with a saturated solution of sodium chloride. The washed ethyl acetate solution was filtered and evaporated to dryness in vacuo. The residue was treated with ether, whereby 1.2 g of p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate was obtained as a brown crystalline solid, melting point approx. . 164-166°C.
Elementæranalyse (%) for C__H,,No0,SoCl: Elemental analysis (%) for C__H,,No0,SoCl:
20 16 3 6 2 20 16 3 6 2
Teoretisk: C 48,63, H 3,27, N 8,51, Cl 7,18 Theoretical: C 48.63, H 3.27, N 8.51, Cl 7.18
Funnet: C 48,47, H 3,29, N 8,78, Cl 6,96 Found: C 48.47, H 3.29, N 8.78, Cl 6.96
IR (kloroform) IR (chloroform)
viste absorpsjonsbånd ved 2,9 (amid NH), 5,59 (&-laktamkarbonyl), 5,75 (esterkarbonyl) og 5,92 <y>m (amidkarbonyl) . showed absorption bands at 2.9 (amide NH), 5.59 (β-lactam carbonyl), 5.75 (ester carbonyl) and 5.92 μm (amide carbonyl).
UV-absorpsjonsspektrum (acetonitril) UV absorption spectrum (acetonitrile)
viste maksima ved A max 235 my, e = 12.100 og showed maxima at A max 235 my, e = 12,100 and
A max 268 my, e = 15.800. A max 268 my, e = 15,800.
Massespektrumet av produktet viste et molekylært ion ved The mass spectrum of the product showed a molecular ion at
4 93 m/e. 4 93 m/e.
NMR (CDC13) NMR (CDCl 3 )
viste signaler ved 6,39 (ABq, 2H, C2~H2), 6,17 (s, 2H, showed signals at 6.39 (ABq, 2H, C2~H2), 6.17 (s, 2H,
a CH2), 4,99 (d, 1H, Cg-H), 4,64 (s, 2H, ester CH2), a CH2), 4.99 (d, 1H, Cg-H), 4.64 (s, 2H, ester CH2),
4,19 (q, 1H, C?-H), 3,45 (d, 1H, Cy-NH), 3,1-1,67 (m, 7H, aromatisk H) tau. 4.19 (q, 1H, C?-H), 3.45 (d, 1H, Cy-NH), 3.1-1.67 (m, 7H, aromatic H) tau.
Eksempel 6 Example 6
p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat (via fosfortriklorid). p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate (via phosphorus trichloride).
En avkjølt oppløsning av 439 mg (0,93 mmol) p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-hydroksy-3-cefem-4-karboksylat i 4,4 ml DMF ble langsomt tilsatt 85 mg (0,05 ml, 0,63 mmol) fosfortriklorid. Reaksjonsblandingen ble hensatt i 4 timer A cooled solution of 439 mg (0.93 mmol) p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml DMF was slowly added 85 mg (0.05 ml, 0.63 mmol) phosphorus trichloride. The reaction mixture was allowed to stand for 4 hours
ved romtemperatur, deretter ble reaksjonsblandingen opparbei-det på den måten som er angitt i eksempel 4, og man fikk ialt 374 mg p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat. NMR-spektrumet av produktet var i overens-stemmelse med det forventede produkt og tilsvarte det man fant for forbindelsen fra eksempel 5. at room temperature, then the reaction mixture was worked up in the manner indicated in example 4, and a total of 374 mg of p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem- 4-carboxylate. The NMR spectrum of the product was in agreement with the expected product and corresponded to that found for the compound from Example 5.
Eksempel 7Example 7
p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat (via oksalylklorid). p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate (via oxalyl chloride).
En oppløsning av 439 mg (0,93 mmol) p-nitrobenzyl-7-[2-(2-tie-nyl )acetamido]-3-hydroksy-3-cefem-4-karboksylat i 4,4 ml DMF avkjølt i et isbad, ble dråpevis tilsatt 118 mg (0,07 ml, 0,93 mmol) oksalylklorid. Reaksjonsblandingen ble hensatt ved romtemperatur i 4 timer og så helt over i en blanding av vandig 5% saltsyre og etylacetat. Det organiske lag ble utskilt og vasket først med 5% saltsyre, så med vann og en mettet oppløsning av natriumklorid. Det vaskede lag ble tørket og fordampet til tørrhet, hvorved man fikk reaksjonsproduktet, p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat som et amorft faststoff. Produktet ble oppnådd i krystallinsk form ved behandling av den amorfe rest med eter. Utbytte 360 mg. Det infrarøde spektrum og NMR-spektret for det krystallinske produkt var i overensstem-melse med et spektrum av autentisk materiale. A solution of 439 mg (0.93 mmol) of p-nitrobenzyl-7-[2-(2-thien-nyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml of DMF cooled in a ice bath, 118 mg (0.07 ml, 0.93 mmol) of oxalyl chloride was added dropwise. The reaction mixture was left at room temperature for 4 hours and then poured into a mixture of aqueous 5% hydrochloric acid and ethyl acetate. The organic layer was separated and washed first with 5% hydrochloric acid, then with water and a saturated solution of sodium chloride. The washed layer was dried and evaporated to dryness to give the reaction product, p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate as an amorphous solid. The product was obtained in crystalline form by treating the amorphous residue with ether. Yield 360 mg. The infrared spectrum and the NMR spectrum of the crystalline product were consistent with a spectrum of authentic material.
Eksempel 8 Example 8
p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat-hydroklorid. p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride.
En oppløsning av 500 mg p-nitrobenzyl-7-[2-(2-tienyl)acetamido]-3-klor-3-cefem-4-karboksylat i 6 ml metylenklorid ble til- A solution of 500 mg of p-nitrobenzyl-7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate in 6 ml of methylene chloride was added
satt 95 mg tørr pyridin og 237 mg fosforpentaklorid. Reaksjonsblandingen ble omrørt ved romtemperatur i 1,5 timer, og deretter avkjølt i et isbad til ca. 5°C, hvoretter man tilsatte 0,6 ml isobutylalkohol. Under fortsatt avkjøling og omrøring, fikk man utkrystallisert reaksjonsproduktet, p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat-hydroklorid, fra reaksjonsblandingen. Produktet ble frafiltert, vasket med kald metylenklorid og tørket, hvorved man fikk 200 mg krystallinsk produkt som under dekomponering smeltet ved ca. 168°C. added 95 mg of dry pyridine and 237 mg of phosphorus pentachloride. The reaction mixture was stirred at room temperature for 1.5 hours, and then cooled in an ice bath to approx. 5°C, after which 0.6 ml of isobutyl alcohol was added. During continued cooling and stirring, the reaction product, p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride, was crystallized from the reaction mixture. The product was filtered off, washed with cold methylene chloride and dried, whereby 200 mg of crystalline product was obtained which, during decomposition, melted at approx. 168°C.
Prosent elementær sammensetning for C,.H,_C1N_0_S.HC1: Percent elemental composition for C,.H,_C1N_0_S.HC1:
3 14 13 3 5 3 14 13 3 5
Teoretisk: C 41,39, H 3,20, N 10,34, Cl 17,45 Theoretical: C 41.39, H 3.20, N 10.34, Cl 17.45
Funnet: C 41,14, H 3,31, N 10,44, Cl 17,29 Found: C 41.14, H 3.31, N 10.44, Cl 17.29
IR (Nujol):IR (Nujol):
viste absorpsjonsbånd ved 5,55 (3-laktamkarbonyl) og showed absorption bands at 5.55 (3-lactam carbonyl) and
ved 5,78 (esterkarbonyl) ym. at 5.78 (ester carbonyl) ym.
UV (pH 7-buffer): UV (pH 7 buffer):
viste absorpsjonsmaksimum X max 268 my (e = 13.800) showed absorption maximum X max 268 my (e = 13,800)
NMR (DMSO dg): NMR (DMSO dg):
Signaler ved 5,97 (s, 2H, C2"H2), 4,8-4,5 (m, 4H, Signals at 5.97 (s, 2H, C2"H2), 4.8-4.5 (m, 4H,
C,-H og ester CH_) og 2,35-1,6 (q, 4H, aromatisk H) C,-H and ester CH_) and 2.35-1.6 (q, 4H, aromatic H)
tau. rope.
Eksempel 9 Example 9
DifenyImetyl-7-amino-3-klor-3-cefem-4-karboksylat. Diphenylmethyl 7-amino-3-chloro-3-cephem-4-carboxylate.
En oppløsning av 525 mg difenylmetyl-7-[2-(2-tienyl)-acetamido]-3-klor-3-cefem-4-karboksylat i 20 ml metylenklorid ble tilsatt 0,1 ml tørr pyridin og 237 mg fosforpentaklorid. Reaksjonsblandingen ble omrørt i 2 timer ved romtemperatur og så av-kjølt i en is-vann-blanding. Den kalde blandingen ble tilsatt 0,6 ml isobutanol og etter 30 minutter ble blandingen fordampet. Resten ble oppløst i etylacetat, og oppløsningen ble vasket med en 5% natriumbikarbonatoppløsning og så med vann og deretter tørket. Den tørkede oppløsning ble fordampet til .tørrhet og resten ble behandlet med eter og man fikk 190 mg av 3-klor-kjerneesteren, difenylmetyl-7-amino-3-klor-3-cefem-4-karboksylat. To a solution of 525 mg of diphenylmethyl-7-[2-(2-thienyl)-acetamido]-3-chloro-3-cephem-4-carboxylate in 20 ml of methylene chloride was added 0.1 ml of dry pyridine and 237 mg of phosphorus pentachloride. The reaction mixture was stirred for 2 hours at room temperature and then cooled in an ice-water mixture. To the cold mixture was added 0.6 ml of isobutanol and after 30 minutes the mixture was evaporated. The residue was dissolved in ethyl acetate, and the solution was washed with a 5% sodium bicarbonate solution and then with water and then dried. The dried solution was evaporated to dryness and the residue was treated with ether to give 190 mg of the 3-chloro-nuclear ester, diphenylmethyl-7-amino-3-chloro-3-cephem-4-carboxylate.
IR (mølle): IR (mill):
absorpsjonstopper ved 5,7 og 5,9 (3-laktam og esterkarbonyl) ym. absorption peaks at 5.7 and 5.9 (3-lactam and ester carbonyl) etc.
NMR (CDC13): NMR (CDCl 3 ):
Signaler ved 6,35 (ABq, 2H, C2~H2), 4,78 (2d, 2H, Cg-H og C?-H), 3,05 (s, 1H, ester CH) og 2,65 (s, 10H, aromatisk H) . Signals at 6.35 (ABq, 2H, C2~H2), 4.78 (2d, 2H, Cg-H and C?-H), 3.05 (s, 1H, ester CH) and 2.65 (s , 10H, aromatic H) .
Eksempel 1 0 Example 1 0
7-(D-a-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre 7-(D-a-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid
En suspensjon av 280 mg (1,2 mmol) 7-amino-3-klor-3-cefem-4-karboksylsyre i 14 ml acetonitril ble under omrøring ved A suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem-4-carboxylic acid in 14 ml of acetonitrile was stirred at
romtemperatur tilsatt 0,5 ml N,0-bis-(trimetylsilyl)acetamid, hvorved man oppnådde et oppløselig disilylmetylderivat. Opp-løsningen ble avkjølt til 0°C og langsomt tilsatt en oppløs-ning av et blandet anhydrid som ble dannet ved å omsette 408 mg (1,5 mmol) metyl-3-a-karboksybenzylaminokrotonat-natriumsalt og 161 mg (1,7 mmol) metylklorformiat i nærvær av 2 dråper dimetylbenzylamin i 7 ml acetonitril. Blandingen ble omrørt ved isbadtemperatur i 2 timer, 1 ml metanol ble tilsatt og blandingen filtrert for å fjerne uløselige urenheter. 2 ml vann ble tilsatt filtratet, og pH ble justert til 1,5, for å fjerne enaminblokkeringen, og deretter til pH 4,5 med trietylamin. Etter omrøring i ytterligere 1 time ved isbadtemperatur, fikk man utfelt reaksjonsproduktet 7-(D-a-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre (zwitterion) fra reaksjonsblandingen som et krystallinsk fast stoff. Produktet ble filtrert, vasket med acetonitril og tørket i vakuum, og man fikk totalt 200 mg. room temperature added 0.5 ml of N,0-bis-(trimethylsilyl)acetamide, whereby a soluble disilylmethyl derivative was obtained. The solution was cooled to 0°C and slowly added a solution of a mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl 3-α-carboxybenzylaminocrotonate sodium salt and 161 mg (1.7 mmol) of methyl chloroformate in the presence of 2 drops of dimethylbenzylamine in 7 ml of acetonitrile. The mixture was stirred at ice bath temperature for 2 hours, 1 ml of methanol was added and the mixture was filtered to remove insoluble impurities. 2 ml of water was added to the filtrate, and the pH was adjusted to 1.5, to remove the enamine block, and then to pH 4.5 with triethylamine. After stirring for a further 1 hour at ice bath temperature, the reaction product 7-(D-α-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid (zwitterion) was precipitated from the reaction mixture as a crystalline solid. The product was filtered, washed with acetonitrile and dried in vacuum, and a total of 200 mg was obtained.
Produktet hadde følgende fysikalske karakteristika: Elementæranalyse for C15H14N304SC1.0,5H20: Teoretisk: C 47,80, H 4,01, N 11,15, Cl 9,40 Funnet: C 47,55, H 4,12, N 10,98, Cl 9,21 The product had the following physical characteristics: Elemental analysis for C15H14N304SC1.0.5H20: Theoretical: C 47.80, H 4.01, N 11.15, Cl 9.40 Found: C 47.55, H 4.12, N 10, 98, Cl 9,21
IR-spektrum IR spectrum
absorpsjonstopper ved 2,9 (amid NH), 5,70 (3-laktamkarbonyl), 5,95 (amidkarbonyl) og 6,28 (karboksylat) absorption peaks at 2.9 (amide NH), 5.70 (3-lactam carbonyl), 5.95 (amide carbonyl) and 6.28 (carboxylate)
■pm. ■p.m.
NMR-spektrum (D20/DC1): NMR spectrum (D20/DC1):
signaler ved 6,5-6,7 (ABq, 2H, C2"H2), 4,84 (d, 1H, Cb ,-H), 4,26 (d, 1H, C_/-H) og 2,44 (s, 5H, aromatisk signals at 6.5-6.7 (ABq, 2H, C2"H2), 4.84 (d, 1H, Cb ,-H), 4.26 (d, 1H, C_/-H) and 2.44 (p, 5H, aromatic
H) tau. H) rope.
UV-spektrum (pH 7-buffer): UV spectrum (pH 7 buffer):
X max 265 my (e = 6.800). X max 265 my (e = 6,800).
Eksempel 11 Example 11
En oppløsning av 500 mg (1,85 mmol) metyl-3-a-karboksybenzyl-aminokrotonat-natriumsalt (dannet med fenylglycin og metylacetoacetat) i 20 ml acetonitril ble tilsatt 4 dråper dimetylbenzylamin, og oppløsningen ble avkjølt i en tørris-karbon-tetrakloridblanding under omrøring. Den kalde oppløsningen ble langsomt tilsatt 184 mg (1,95 mmol) metylklorformiat for dannelse av et blandet anhydrid. Etter 20 minutter ble en foravkjølt oppløsning av 750 mg(1,85 mmol) p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat og 188 mg (1,85 mmol) trietylamin i 40 ml aceton tilsatt. Tilsetningen skjedde i løpet av 3 minutter, og deretter ble reaksjonsblandingen om-rørt i kulden i 30 minutter og så ved romtemperatur i 2 timer. Blandingen ble filtrert for å fjerne uløselige urenheter og så fordampet i vakuum. Resten ble oppløst i en blanding av etylacetat og vann, og oppløsningens pH ble justert til 7. Det organiske laget ble utskilt og vasket med vann. Etter tørking over magnesiumsulfat ble det organiske lag konsentrert i vakuum til et lite volum. Ved tilsetning av n-heksan til konsentratet fikk man utfelt 620 mg p-nitrobenzyl-7-[N-(1-karbometoksy-2-propenyl)-D-a-fenylglycylamino]-3-klor-3-cefem-4-karboksylat fra reaksjonsblandingen. To a solution of 500 mg (1.85 mmol) of methyl 3-α-carboxybenzyl-aminocrotonate sodium salt (formed with phenylglycine and methyl acetoacetate) in 20 mL of acetonitrile was added 4 drops of dimethylbenzylamine, and the solution was cooled in a dry ice-carbon tetrachloride mixture while stirring. To the cold solution was slowly added 184 mg (1.95 mmol) of methyl chloroformate to form a mixed anhydride. After 20 minutes, a pre-cooled solution of 750 mg (1.85 mmol) of p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate and 188 mg (1.85 mmol) of triethylamine in 40 ml of acetone was added . The addition took place over 3 minutes, and then the reaction mixture was stirred in the cold for 30 minutes and then at room temperature for 2 hours. The mixture was filtered to remove insoluble impurities and then evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water, and the pH of the solution was adjusted to 7. The organic layer was separated and washed with water. After drying over magnesium sulfate, the organic layer was concentrated in vacuo to a small volume. By adding n-hexane to the concentrate, 620 mg of p-nitrobenzyl-7-[N-(1-carbomethoxy-2-propenyl)-D-a-phenylglycylamino]-3-chloro-3-cephem-4-carboxylate were precipitated from the reaction mixture .
Produktet ga følgende elementæranalyse og hadde følgende kjernemagnetiske resonansspektrum: The product gave the following elemental analysis and had the following nuclear magnetic resonance spectrum:
Elementæranalyse for C„-,H„^N .0oSCl: Elemental analysis for C„-,H„^N .0oSCl:
J 27 26 4 8 J 27 26 4 8
Teoretisk: C 53,87, H 4,35, N 9,31 Theoretical: C 53.87, H 4.35, N 9.31
Funnet: C 54,05, H 4,13, N 9,36 Found: C 54.05, H 4.13, N 9.36
NMR (DMSO d,): NMR (DMSO d, ):
b b
Signaler ved 8,20 (s, 3H, enamin CH3), 6,60 (ABq, 2H, C2-H2), 6,45 (s, 3H, ester CH"3) , 5,48 (s, 1H, enamin-vinyl H), 4,90-4,1 (m, 5H, Cg-H, C?-H, a-CH og ester CH2) og 3,10-1,5 (m, 9H, aromatisk H) tau. Signals at 8.20 (s, 3H, enamine CH3), 6.60 (ABq, 2H, C2-H2), 6.45 (s, 3H, ester CH"3), 5.48 (s, 1H, enamine -vinyl H), 4.90-4.1 (m, 5H, Cg-H, C?-H, a-CH and ester CH2) and 3.10-1.5 (m, 9H, aromatic H) tau .
Produktet, 540 mg (0,9 mmol), ble oppløst i 40 ml acetonitril inneholdende 20 ml vann, og oppløsningen ble først avkjølt i en is-vannblanding og så umiddelbart surgjort til pH 1,5 The product, 540 mg (0.9 mmol), was dissolved in 40 mL of acetonitrile containing 20 mL of water, and the solution was first cooled in an ice-water mixture and then immediately acidified to pH 1.5
og deretter justert til pH 2,5. Blandingen ble fordampet og resten ble oppløst i 40 ml tetrahydrofuran og 80 ml metanol. and then adjusted to pH 2.5. The mixture was evaporated and the residue was dissolved in 40 ml of tetrahydrofuran and 80 ml of methanol.
Oppløsningen ble så tilsatt 540 mg 5% palladium-på-karbon (forredusert i 20 ml etanol) i løpet av 45 minutter under et hydrogentrykk på 3,5 kg/cm 2 ved romtemperatur), og oppløsningen ble hydrogenert ved romtemperatur i 2,5 timer under et hydrogentrykk pa 3,5 kg/cm 2. Katalysatoren ble frafiltrert og vasket på filteret med metanol, THF og med vann. Filtratet og vaskeoppløsningen ble slått sammen og fordampet til tørr-het i vakuum. Resten ble oppløst i vann-etylacetat og opp-løsningens pH ble justert til 4,5. Den vandige fase ble utskilt, vasket med etylacetat og så fordampet til et lite volum på ca. 2 ml. Ved avkjøling fikk man utfelt 65 mg av produktet, dvs.: 7-(D-a-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre som et krystallinsk fast stoff. To the solution was then added 540 mg of 5% palladium-on-carbon (pre-reduced in 20 ml of ethanol) over 45 minutes under a hydrogen pressure of 3.5 kg/cm 2 at room temperature), and the solution was hydrogenated at room temperature for 2.5 hours under a hydrogen pressure of 3.5 kg/cm 2 . The catalyst was filtered off and washed on the filter with methanol, THF and with water. The filtrate and washing solution were combined and evaporated to dryness in vacuo. The residue was dissolved in water-ethyl acetate and the pH of the solution was adjusted to 4.5. The aqueous phase was separated, washed with ethyl acetate and then evaporated to a small volume of approx. 2 ml. Upon cooling, 65 mg of the product was precipitated, i.e.: 7-(D-α-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid as a crystalline solid.
Eksempel 12 Example 12
En suspensjon av 3,0 g (8,1 mmol) p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat i 200 ml tetrahydrofuran (tørket med en molekylsil) ble tilsatt 2,1 g (8,3 mmol) N-(t-butyloksykarbonyl)-D-a-fenylglycin og 2,0 g (8,3 mmol) N-etoksy-karbonyl-2-etoksy-l,2-dihydrokinolin (EEDQ). Reaksjonsblandingen ble omrørt over natten ved romtemperatur, og opp-løsningsmidlet ble fjernet under redusert trykk. Resten ble oppløst i en blanding av etylacetat og vann, og den organiske fase ble utskilt. Den ble avkjølt og suksessivt vasket med kald 5% vandig oppløsning av natriumbikarbonat, en kald opp-løsning av 5% saltsyre og så med vann. Den vaskede oppløs-ning ble tørket over magnesiumsulfat, filtrert og konsentrert ved fordampning under redusert trykk til et volum på To a suspension of 3.0 g (8.1 mmol) of p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate in 200 ml of tetrahydrofuran (dried with a molecular sieve) was added 2.1 g (8 .3 mmol) N-(t-butyloxycarbonyl)-D-α-phenylglycine and 2.0 g (8.3 mmol) N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The reaction mixture was stirred overnight at room temperature and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water, and the organic phase was separated. It was cooled and successively washed with cold 5% aqueous solution of sodium bicarbonate, a cold solution of 5% hydrochloric acid and then with water. The washed solution was dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure to a volume of
ca. 50 ml. Fra dette konsentrat fikk man som et krystallinsk produkt 3,7 g (63% utbytte) av reaksjonsproduktet, nemlig p-nitrobenzyl-7-[D-2-(t-butyloksykarbamido)-2-fenylacetamido]-3-klor-3-cefem-4-karboksylat. Et nytt utbytte av produktet på ca. 2 g ble oppnådd ved ytterligere konsentrasjon av det filtrat som ble oppnådd etter frafiltrering av første utbytte. about. 50 ml. From this concentrate, 3.7 g (63% yield) of the reaction product was obtained as a crystalline product, namely p-nitrobenzyl-7-[D-2-(t-butyloxycarbamido)-2-phenylacetamido]-3-chloro-3- cephem-4-carboxylate. A new yield of the product of approx. 2 g was obtained by further concentration of the filtrate obtained after filtering off the first yield.
Elementæranalyse beregnet for C0_,H„_C1N .0oS Elemental analysis calculated for C0_,H„_C1N .0oS
z / z / 4 o z / z / 4 o
Teoretisk: C 53,78, H 4,51, N 9,29 Theoretical: C 53.78, H 4.51, N 9.29
Funnet: C 52,66, H 4,36, N 8,88 Found: C 52.66, H 4.36, N 8.88
UV (acetonitril) viste et maksimum ved 268 ym (e = 17.100). UV (acetonitrile) showed a maximum at 268 µm (e = 17,100).
IR: De følgende betydningsfulle absorpsjonstopper ble obser-vert i det infrarøde spektrum av produktet. Amid NH absorpsjonstopp ved 3,05 ym og karbonylabsorpsjonstopper ved 5,59, 5,75 og 6,0 ym. IR: The following significant absorption peaks were observed in the infrared spectrum of the product. Amide NH absorption peak at 3.05 um and carbonyl absorption peaks at 5.59, 5.75 and 6.0 um.
NMR (CDC13): NMR (CDCl 3 ):
Signaler ved 8,60 (s, 9H, t-BOC), 6,45 (ABq, 2H, Signals at 8.60 (s, 9H, t-BOC), 6.45 (ABq, 2H,
C2-H2), 5,03 (d, 1H, Cg-H), 4,67 (s, 3H, a CH og ester CH2), 4,12 (m, 3H, C7~H og amid NH), og 2,72-1,74 (m, 10H, aromatisk H og amid NH) tau. C2-H2), 5.03 (d, 1H, Cg-H), 4.67 (s, 3H, a CH and ester CH2), 4.12 (m, 3H, C7~H and amide NH), and 2.72-1.74 (m, 10H, aromatic H and amide NH) tau.
En oppløsning av 3,0 g (5,0 mmol) av produktet i 15 ml tørr tetrahydrofuran (tørket med en molekylsil) og 185 ml metanol ble tilsatt 3 g forredusert 5% palladium-på-karbon. Katalysatoren var forredusert i etanol i 30 minutter ved romtemperatur under et hydrogentrykk på 3,5 kg/cm . Etter at den for-reduserte katalysatoren var tilsatt ble produktet hydrogenert ved romtemperatur i 1 time under et hydrogentrykk på 3,5 kg/cm 2. Katalysatoren ble frafiltrert og vasket på filteret med tetra-hydrof uran og metanol. Filtratet og vaskeoppløsningen ble slått sammen og fordampet under redusert trykk. Resten ble oppløst i etylacetat og vann ble så tilsatt. pH på blandingen ble justert til 7 ved å tilsette IN natriumhydroksyd. Den vandige fase ble utskilt, vasket med etylacetat og så overlagt etylacetat og tilbaketitrert til pH 2,5 med IN saltsyre. Den organiske fase ble utskilt fra den vandige fase og vasket med vann og tørket over magnesiumsulfat. A solution of 3.0 g (5.0 mmol) of the product in 15 ml of dry tetrahydrofuran (dried with a molecular sieve) and 185 ml of methanol was added to 3 g of pre-reduced 5% palladium-on-carbon. The catalyst was pre-reduced in ethanol for 30 minutes at room temperature under a hydrogen pressure of 3.5 kg/cm . After the pre-reduced catalyst had been added, the product was hydrogenated at room temperature for 1 hour under a hydrogen pressure of 3.5 kg/cm 2 . The catalyst was filtered off and washed on the filter with tetrahydrofuran and methanol. The filtrate and washing solution were combined and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water was then added. The pH of the mixture was adjusted to 7 by adding 1N sodium hydroxide. The aqueous phase was separated, washed with ethyl acetate and then overlaid with ethyl acetate and back titrated to pH 2.5 with 1N hydrochloric acid. The organic phase was separated from the aqueous phase and washed with water and dried over magnesium sulfate.
Den tørre organiske fase ble fordampet under redusert trykk til tørrhet, hvorved man fikk reaksjonsproduktet 7-[D-2-(t-butyloksykarbamido)-2-fenylacetamido]-3-klor-3-cefem-4-karboksylsyre som en tørr fast rest. Produktet ble utkrystallisert fra 70 ml eter inneholdende 20 ml petroleter og man fikk 1,75 g (75%) krystallinsk produkt. The dry organic phase was evaporated under reduced pressure to dryness, whereby the reaction product 7-[D-2-(t-butyloxycarbamido)-2-phenylacetamido]-3-chloro-3-cephem-4-carboxylic acid was obtained as a dry solid residue . The product was crystallized from 70 ml of ether containing 20 ml of petroleum ether and 1.75 g (75%) of crystalline product was obtained.
Elementæranalyse beregnet for CoriH__ClN^.O,S: Elemental analysis calculated for CoriH__ClN^.O,S:
Zv ZZ ob Zv ZZ ob
Teoretisk: C 51,34, H 4,74, N 8,98, Cl 7,58 Theoretical: C 51.34, H 4.74, N 8.98, Cl 7.58
Funnet: C 51,02, H 4,96, N 8,75, Cl 7,30 Found: C 51.02, H 4.96, N 8.75, Cl 7.30
UV (acetonitril): UV (acetonitrile):
maksimum ved 2 68 ym (e = 74 00) . maximum at 2 68 ym (e = 74 00) .
NMR (CDC1 ): NMR (CDC1 ):
c c
Signaler ved 8,55 (s, 9H, 5-BOC), 6,48 (ABq, 2H, C2-H2), 5,0 (d, 1H, Cg-H), 4,63 (d, 1H, a-CH), 4,25 (q, 1H, Cy-H), 3,90 (d, 1H, amid NH), og 2,59 (s, 5H, aromatisk H) tau. Signals at 8.55 (s, 9H, 5-BOC), 6.48 (ABq, 2H, C2-H2), 5.0 (d, 1H, Cg-H), 4.63 (d, 1H, a -CH), 4.25 (q, 1H, Cy-H), 3.90 (d, 1H, amide NH), and 2.59 (s, 5H, aromatic H) tau.
En oppløsning av 420 mg (2,2 mmol) p-toluensulfonsyre i 5 ml acetonitril ble tilsatt 468 mg (1 mmol) av det krystallinske hydrogenolyseproduktet. Oppløsningen ble hensatt ved romtemperatur i ca. 16 timer og så fortynnet med 0,5 ml vann. Oppløsningens pH ble justert til 4,8, og man fikk utfelt A solution of 420 mg (2.2 mmol) of p-toluenesulfonic acid in 5 ml of acetonitrile was added to 468 mg (1 mmol) of the crystalline hydrogenolysis product. The solution was left at room temperature for approx. 16 hours and then diluted with 0.5 ml of water. The pH of the solution was adjusted to 4.8, and a precipitate was obtained
320 mg (87%) av det krystallinske avblokkerte produkt, nemlig 7-(D-fenylglycylamino)-3-klor-3-cefem-4-karboksylsyre. Produktet ble oppsamlet ved filtrering og tørket. 320 mg (87%) of the crystalline deblocked product, namely 7-(D-phenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid. The product was collected by filtration and dried.
Elementæranalyse beregnet for C,rH, .C1N.0.S.0,5 H„0 Elemental analysis calculated for C,rH, .C1N.0.S.0.5 H„0
2 ^ 15 14 3 4 2 Teoretisk: C 47,80, H 4,01, N 11,15, Cl 9,40 Funnet: C 48,04, H 3,82, N 11,18, Cl 9,70 2 ^ 15 14 3 4 2 Theoretical: C 47.80, H 4.01, N 11.15, Cl 9.40 Found: C 48.04, H 3.82, N 11.18, Cl 9.70
Eksempel 13 Example 13
7-(D-3-hydroksyfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre. 7-(D-3-hydroxyphenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid.
N-(t-butyloksykarbonyl)-D-3-hydroksyfenylglycin, 2,9 g (11 mmol), ble omsatt med 3,7 g (10 mmol) p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat og 2,6 g (10,5 mmol) av kop-lingsreagensen EEDQ. Reaksjonen ble utført og produktet isolert ved å anvende den fremgangsmåte som er beskrevet i forbindelse med acyleringsmetoden fra eksempel 12. Produktet ble oppnådd som et amorft fast stoff etter behandling med eter, og man fikk 2,8 g (46%). N-(t-butyloxycarbonyl)-D-3-hydroxyphenylglycine, 2.9 g (11 mmol), was reacted with 3.7 g (10 mmol) of p-nitrobenzyl-7-amino-3-chloro-3-cephem- 4-carboxylate and 2.6 g (10.5 mmol) of the coupling reagent EEDQ. The reaction was carried out and the product isolated by using the method described in connection with the acylation method from Example 12. The product was obtained as an amorphous solid after treatment with ether, and 2.8 g (46%) were obtained.
Elementæranalyse beregnet for C^H^ClN^OgS Elemental analysis calculated for C^H^ClN^OgS
Teoretisk: C 52,39, H 4,40, N 9,05 Theoretical: C 52.39, H 4.40, N 9.05
Funnet: C 52,16, H 4,59, N 8,79 Found: C 52.16, H 4.59, N 8.79
Ultrafiolett absorpsjonsspektrum (acetonitril): Ultraviolet absorption spectrum (acetonitrile):
maksimum ved 270 ym (e = 17.200). maximum at 270 ym (e = 17,200).
Kjernemagnetisk resonansspektrum (CDCl^): Nuclear magnetic resonance spectrum (CDCl^):
Signaler ved 8,59 (s, 9H, t-BOC), 6,50 (ABq, 2H, C2~H2), 5,06 (d, 1H, Cg-H), 4,66 (s, 1H, a-CH), 4,09 (m, 2H, C7-H), 3,34-1,70 (m, 9Y, aromatisk H og amid NH) tau. Signals at 8.59 (s, 9H, t-BOC), 6.50 (ABq, 2H, C2~H2), 5.06 (d, 1H, Cg-H), 4.66 (s, 1H, a -CH), 4.09 (m, 2H, C7-H), 3.34-1.70 (m, 9Y, aromatic H and amide NH) tau.
Produktet, p-nitrobenzyl-7-[D-2-(t-butyloksykarbamido)-2-(3-hydroksy)fenylacetamido]-3-klor-3-cefem-4-karboksylat, 3,5 g (5,6 mmol) ble hydrogenert i etanol i nærvær av forredusert 5% palladium-på-karbon og etterfulgt av den deforestrings-fremgangsmåte som er beskrevet i eksempel 12. Produktet, 7-[D-2-(t-butyloksykarbamido)-2-(3-hydroksy)fenylacetamido]-3-klor-3-cefem-4-karboksylsyre ble oppnådd i krystallinsk form ved en behandling av det amorfe råproduktet med en opp-løsning av heksan i dietyleter. Utbytte: 1,5 g (55%). The product, p-nitrobenzyl-7-[D-2-(t-butyloxycarbamido)-2-(3-hydroxy)phenylacetamido]-3-chloro-3-cephem-4-carboxylate, 3.5 g (5.6 mmol ) was hydrogenated in ethanol in the presence of prereduced 5% palladium-on-carbon and followed by the deesterification procedure described in Example 12. The product, 7-[D-2-(t-butyloxycarbamido)-2-(3- hydroxy)phenylacetamido]-3-chloro-3-cephem-4-carboxylic acid was obtained in crystalline form by treating the amorphous crude product with a solution of hexane in diethyl ether. Yield: 1.5 g (55%).
Ultrafiolett absorpsjonsspektrum (acetonitril) : Ultraviolet absorption spectrum (acetonitrile) :
maksimum ved 272 ym (e = 8,280). maximum at 272 ym (e = 8.280).
Elektrometrisk titrering (66% vandig DMF): Electrometric titration (66% aqueous DMF):
pKa ved 4,5. pKa at 4.5.
Det ovennevnte produkt, 1,3 g (2,7 mmol), ble reagert med The above product, 1.3 g (2.7 mmol), was reacted with
1,1 g (5,9 mmol) p-toluensulfonsyre i 28 ml acetonitril for å fjerne den t-butyloksykarbonyl-beskyttende gruppe. Frem-gangsmåten ble gjennomført slik det er beskrevet i eksempel 12. 1.1 g (5.9 mmol) of p-toluenesulfonic acid in 28 ml of acetonitrile to remove the t-butyloxycarbonyl protecting group. The procedure was carried out as described in example 12.
Produktet, 7-(D-3-hydroksyfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre, ble utkrystallisert fra reaksjonsblandingen, ble frafiltrert og så vakuumtørket. Utbytte 700 mg (64%). The product, 7-(D-3-hydroxyphenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid, was crystallized from the reaction mixture, filtered off and then vacuum dried. Yield 700 mg (64%).
Elementæranalyse beregnet for C^H-^CIN-jOj-S . 1^0 Elemental analysis calculated for C^H-^CIN-jOj-S . 1^0
Teoretisk: C 44,83, H 4,01, N 10,46 Theoretical: C 44.83, H 4.01, N 10.46
Funnet: C 45,12, H 4,06, N 10,31 Found: C 45.12, H 4.06, N 10.31
Ultrafiolett absorpsjonsspektrum (pH 6-buffer): Ultraviolet absorption spectrum (pH 6 buffer):
maksimum ved 268 ym (e = 9750). maximum at 268 ym (e = 9750).
Kjernemagnetisk resonansspektrum (D20/DC1): Nuclear magnetic resonance spectrum (D20/DC1):
Signaler ved 6,31 (ABq, 2H, C2~H2), 4,81 (d, 1H, Cg-H), 4,52 (s, 1H, ct-CH) , 4,26 (d, 1H, C?-H) og 3,1-2,5 (m, 4H, aromatisk H) tau. Signals at 6.31 (ABq, 2H, C2~H2), 4.81 (d, 1H, Cg-H), 4.52 (s, 1H, ct-CH) , 4.26 (d, 1H, C ?-H) and 3.1-2.5 (m, 4H, aromatic H) tau.
Eksempel 14 Example 14
7-(D-4-klorfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre. 7-(D-4-chlorophenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid.
Ved å anvende de fremgangsmåter som er beskrevet i eksempel 12, ble 850 mg (2,3 mmol) p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat acylert med 700 mg (2,5 mmol) N-t-butyloksykarbonyl-D-4-klorfenylglycin og 567 mg (2,3 mmol) EEDQ, hvorved man fikk 1,2 p-nitrobenzyl-7-[D-2-(t-butyloksykarb-amido) -2-(4-klorfenylacetamido)]-3-klor-3-cefem-4-karboksylat. Using the procedures described in Example 12, 850 mg (2.3 mmol) of p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate was acylated with 700 mg (2.5 mmol) N-t-butyloxycarbonyl-D-4-chlorophenylglycine and 567 mg (2.3 mmol) EEDQ, whereby 1,2 p-nitrobenzyl-7-[D-2-(t-butyloxycarb-amido)-2-(4- chlorophenylacetamido)]-3-chloro-3-cephem-4-carboxylate.
Produktet, 1,2 g (1,9 mmol) ble hydrogenert ved romtemperatur i nærvær av forredusert 5% palladium-på-karbon for å fjerne p-nitrobenzylestergruppen, og man fikk 450 mg 7-[D-2-(t-butyl-oksykarbamido) -2-(4-klorfenylacetamido)]-3-klor-3-cefem-4-karboksylsyre som et krystallinsk produkt. Produktet ble oppnådd i krystallinsk form ved behandling av den amorfe rest med dietyleter. The product, 1.2 g (1.9 mmol) was hydrogenated at room temperature in the presence of pre-reduced 5% palladium-on-carbon to remove the p-nitrobenzyl ester group to give 450 mg of 7-[D-2-(t-butyl -oxycarbamido)-2-(4-chlorophenylacetamido)]-3-chloro-3-cephem-4-carboxylic acid as a crystalline product. The product was obtained in crystalline form by treating the amorphous residue with diethyl ether.
Elementæranalyse beregnet for C^H^C^N^OgS Elemental analysis calculated for C^H^C^N^OgS
Teoretisk: C 47,82, H 4,21, N 8,36, Cl 14,11 Theoretical: C 47.82, H 4.21, N 8.36, Cl 14.11
Funnet: C 47,75, H 4,43, N 8,11, Cl 14,15 Elektrometrisk titrering (66% vandig DMF): pKa ved 4,4, tilsynelatende molekylvekt = 508, beregnet molekylvekt = 502. Found: C 47.75, H 4.43, N 8.11, Cl 14.15 Electrometric titration (66% aqueous DMF): pKa at 4.4, apparent molecular weight = 508, calculated molecular weight = 502.
Deforestringsproduktet, 450 mg (0,9 mmol) ble omsatt med p-toluensulfonsyre i acetonitril ved å anvende den fremgangsmåte som er beskrevet i tidligere eksempler for å fjerne den t-butyloksykarbonyl-beskyttende gruppe, og man fikk fremstilt 160 mg (44%) krystallinsk 7-(D-4-klorfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre i zwitterioneformen. The de-esterification product, 450 mg (0.9 mmol) was reacted with p-toluenesulfonic acid in acetonitrile using the procedure described in previous examples to remove the t-butyloxycarbonyl protecting group, yielding 160 mg (44%) crystalline 7-(D-4-chlorophenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid in the zwitterionic form.
Elementæranalyse beregnet for C15N13C12N304S.1H20 Elemental analysis calculated for C15N13C12N304S.1H20
Teoretisk: C 42,86, H 3,59, N 9,99, Cl 16,87 Theoretical: C 42.86, H 3.59, N 9.99, Cl 16.87
Funnet: C 43,07, H 3,63, N 9,69, Cl 16,75 Ultrafiolett absorpsjonsspektrum (pH 6-buffer): maksima ved 265 ym (e = 8100) og 2,25 ym (e = 13900). Elektrometrisk titrering (66% vandig DMF): pKa = 4,15 og 6,8, tilsynelatende molekylvekt er 407, beregnet molekylvekt 403. Found: C 43.07, H 3.63, N 9.69, Cl 16.75 Ultraviolet absorption spectrum (pH 6 buffer): maxima at 265 ym (e = 8100) and 2.25 ym (e = 13900). Electrometric titration (66% aqueous DMF): pKa = 4.15 and 6.8, apparent molecular weight is 407, calculated molecular weight 403.
Eksempel 1 5 Example 1 5
7-(D-4-hydroksyfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre. 7-(D-4-hydroxyphenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid.
N-(t-butyloksykarbonyl)-D-4-hydroksyfenylglycin, 2,9 g (11 mmol), ble omsatt med 3,7 g (10 mmol) p-nitrobenzyl-7-amino-3-klor-3-cefem-4-karboksylat og 2,6 g (10,5 mmol) av koplings-reagensen EEDQ i tørr tetrahydrofuran. Reaksjonen ble utført og produktet isolert slik som det er beskrevet i eksempel 12. Produktet på 3,7 g (60 % utbytte) ble oppnådd i krystallinsk form fra kald dietyleter. N-(t-butyloxycarbonyl)-D-4-hydroxyphenylglycine, 2.9 g (11 mmol), was reacted with 3.7 g (10 mmol) of p-nitrobenzyl-7-amino-3-chloro-3-cephem- 4-carboxylate and 2.6 g (10.5 mmol) of the coupling reagent EEDQ in dry tetrahydrofuran. The reaction was carried out and the product isolated as described in Example 12. The product of 3.7 g (60% yield) was obtained in crystalline form from cold diethyl ether.
Produktet, p-nitrobenzyl-7-[D-2-(t-butyloksykarbamido)-2-(4-hydroksy)fenylacetamido]-3-klor-3-cefem-4-karboksylat ga følgende prosentvise elementæranalyse og kjernemagnetiske The product, p-nitrobenzyl-7-[D-2-(t-butyloxycarbamido)-2-(4-hydroxy)phenylacetamido]-3-chloro-3-cephem-4-carboxylate gave the following percent elemental analysis and nuclear magnetic
resonansspektrum. resonance spectrum.
Elementæranalyse beregnet for <C>27<H>27N4OgSCl Elemental analysis calculated for <C>27<H>27N4OgSCl
Teoretisk: C 52,39, H 4,40, N 9,05 Theoretical: C 52.39, H 4.40, N 9.05
Funnet: C 52,12, H 4,26, N 8,91 Found: C 52.12, H 4.26, N 8.91
Kjernemagnetisk resonansspektrum (DMSO db,)Nuclear magnetic resonance spectrum (DMSO db,)
viste signaler ved: 8,62 (s, 9H, t-BOC-CH3), 6,16 (ABq, 2H, C2-H2), 4,81 (d, 1H, Cg-H), 4,75 (d, 1H, a-CH), 4,53 (s, 2H, ester-CH2), 4,18 (q, 1H, C?-H), 7,04 og 2,0 (2q, 8H, aromatisk H), 0,76 (d, 1H, C7~NH) og 0,58 (s, 1H, p-OH) tau. showed signals at: 8.62 (s, 9H, t-BOC-CH3), 6.16 (ABq, 2H, C2-H2), 4.81 (d, 1H, Cg-H), 4.75 (d , 1H, α-CH), 4.53 (s, 2H, ester-CH2), 4.18 (q, 1H, C?-H), 7.04 and 2.0 (2q, 8H, aromatic H) , 0.76 (d, 1H, C7~NH) and 0.58 (s, 1H, p-OH) tau.
Produktet på 2,2 g (3,5 mmol) ble hydrogenert i etanol i nærvær av forredusert 5% palladium-på-karbonkatalysator for fjerning av p-nitrobenzylgruppen. Det deforestrede produkt, 7-[D-2-(t-butyloksykarbamido)-2-(4-hydroksy)fenylacetamido]-3-klor-3-cefem-4-karboksylsyre, ble oppnådd i krystallinsk form fra en blanding av dietyleter og heksan. 1 g av produktet ble oppnådd og dette tilsvarer 59% utbytte: The product of 2.2 g (3.5 mmol) was hydrogenated in ethanol in the presence of pre-reduced 5% palladium-on-carbon catalyst to remove the p-nitrobenzyl group. The deesterified product, 7-[D-2-(t-butyloxycarbamido)-2-(4-hydroxy)phenylacetamido]-3-chloro-3-cephem-4-carboxylic acid, was obtained in crystalline form from a mixture of diethyl ether and hexane. 1 g of the product was obtained and this corresponds to a 59% yield:
Elementæranalyse beregnet for C2qH22C1N307S Elemental analysis calculated for C2qH22C1N307S
Teoretisk: C 49,64, H 4,58, N 8,08 Theoretical: C 49.64, H 4.58, N 8.08
Funnet: C 48,92, H 4,40, N 8,24 Found: C 48.92, H 4.40, N 8.24
Kjernemagnetisk resonansspektrum (DMSO dg) Nuclear magnetic resonance spectrum (DMSO dg)
viser signaler ved 8,61 (s, 9H, t-B0C-CH3), 6,26 (ABq, 2H, C2H2), 4,89 (d, 1H, Cg-H), 4,78 (d, 1H, a-CH), shows signals at 8.61 (s, 9H, t-B0C-CH3), 6.26 (ABq, 2H, C2H2), 4.89 (d, 1H, Cg-H), 4.78 (d, 1H, a-CH),
4,28 (q, 1H, C?-H), 3,06 (q, 4H, aromatisk-H) og 1,20 (d, 1H, C?-NH) tau. 4.28 (q, 1H, C?-H), 3.06 (q, 4H, aromatic-H) and 1.20 (d, 1H, C?-NH) tau.
Nevnte t-BOC-beskyttende gruppe ble fjernet fra deforestrings-produktet ved at dette i acetonitril ble omsatt med p-toluensulfonsyre. Fra 1 g produkt oppnådde man 330 mg (40%) av sluttproduktet, dvs. 7-(D-4-hydroksyfenylglycylamino)-3-klor-3-cefem-4-karboksylsyre med følgende elementæranalyse, kjernemagnetisk resonansspektrum og titreringsverdier. Said t-BOC protecting group was removed from the deesterification product by reacting this in acetonitrile with p-toluenesulfonic acid. From 1 g of product, 330 mg (40%) of the final product was obtained, i.e. 7-(D-4-hydroxyphenylglycylamino)-3-chloro-3-cephem-4-carboxylic acid with the following elemental analysis, nuclear magnetic resonance spectrum and titration values.
Elementæranalyse beregnet for C^j-H-^ClN^Oj-S . 1^0 Elemental analysis calculated for C^j-H-^ClN^Oj-S . 1^0
Teoretisk: C 44,83, H 4,01, N 10,46 Theoretical: C 44.83, H 4.01, N 10.46
Funnet: C 44,92, H 3,45, N 10,63 Elektrometrisk titrering i 66% vandig DMF ga Found: C 44.92, H 3.45, N 10.63 Electrometric titration in 66% aqueous DMF gave
pKa-verdier på 4,2, 7,7 og 12,4. Tilsynelatende pKa values of 4.2, 7.7 and 12.4. Apparently
molekylvekt var 384, den beregnede molekylvekt var 383,8. Kjernemagnetisk spektrum (D2O/DCI) molecular weight was 384, the calculated molecular weight was 383.8. Nuclear magnetic spectrum (D2O/DCI)
viste signaler ved: 6,32 (ABq, 2H, C2~H2), 4,84 (d, 1H, Cg-H), 4,27 (d, 1H, C?-H), og 2,79 (q, 4H, aromatisk H) tau. showed signals at: 6.32 (ABq, 2H, C2~H2), 4.84 (d, 1H, Cg-H), 4.27 (d, 1H, C?-H), and 2.79 (q , 4H, aromatic H) tau.
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AT342197B (en) * | 1975-02-20 | 1978-03-28 | Ciba Geigy Ag | NEW PROCESS FOR PRODUCING 3-CEPHEM CONNECTIONS |
CH619233A5 (en) * | 1975-07-31 | 1980-09-15 | Ciba Geigy Ag | |
CH622802A5 (en) * | 1975-08-20 | 1981-04-30 | Ciba Geigy Ag | |
IE45158B1 (en) * | 1976-08-16 | 1982-06-30 | Lilly Co Eli | 3-chloro-cephem synthesis |
DE3508258A1 (en) * | 1985-03-08 | 1986-09-18 | Bayer Ag, 5090 Leverkusen | SS LACTAMANTIBIOTICS, METHOD FOR THE PRODUCTION AND THEIR USE AS AND IN MEDICINAL PRODUCTS |
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ES2010075A6 (en) * | 1989-01-10 | 1989-10-16 | Antibioticos Sa | Process for the preparation of 3-chloro-cefem compounds. |
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IT1255458B (en) * | 1992-05-11 | 1995-11-02 | Col Marco Da | PROCEDURE FOR THE PREPARATION OF HALOGENATED BETA-LACTAMIC DERIVATIVES |
ES2079327B1 (en) | 1994-12-13 | 1996-08-01 | Lilly Sa | PHARMACEUTICAL FORMULATIONS OF CEFACLOR. |
CN101805357B (en) * | 2010-04-28 | 2012-01-11 | 陶灵刚 | Cefaclor compound and novel preparation method thereof |
CN103588790A (en) * | 2013-11-29 | 2014-02-19 | 中国科学院长春应用化学研究所 | Preparation method of 7-amino-3-chloro-3-cephem-4-carboxylic acid-p-nitrobenzyl ester |
CN106632400A (en) * | 2016-12-16 | 2017-05-10 | 石家庄柏奇化工有限公司 | Method for preparing 7-ACCA by removing 4-nitrobenzyl through catalytic hydrogenation of Pd-C |
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AR206201A1 (en) * | 1972-06-29 | 1976-07-07 | Ciba Geigy Ag | PROCEDURE FOR OBTAINING ACID COMPOUNDS 7BETA-AMINO-3-CEFEM-3-01-4-CARBOXILICO0-SUBSTITUIDOS |
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- 1974-02-22 HU HUEI528A patent/HU166849B/hu unknown
- 1974-02-22 SE SE7402413A patent/SE411212B/en not_active IP Right Cessation
- 1974-02-22 DK DK095274A patent/DK153157C/en not_active IP Right Cessation
- 1974-02-22 FI FI525/74A patent/FI63035C/en active
- 1974-02-22 ZM ZM35/74A patent/ZM3574A1/en unknown
- 1974-02-22 BR BR1384/74A patent/BR7401384D0/en unknown
- 1974-02-22 IE IE00356/74A patent/IE39046B1/en unknown
- 1974-02-22 DD DD176751A patent/DD110278A5/xx unknown
- 1974-02-22 AR AR252493A patent/AR199510A1/en active
- 1974-02-23 PL PL1974169035A patent/PL88702B1/pl unknown
- 1974-02-23 RO RO7477796A patent/RO64663A/en unknown
- 1974-02-23 JP JP49021870A patent/JPS6139313B2/ja not_active Expired
- 1974-02-23 EG EG52/74A patent/EG11104A/en active
- 1974-02-23 OA OA55128A patent/OA04809A/en unknown
- 1974-02-25 CS CS741376A patent/CS187409B2/en unknown
- 1974-02-25 CH CH265374A patent/CH593988A5/xx not_active IP Right Cessation
-
1979
- 1979-08-16 NO NO792681A patent/NO148377C/en unknown
-
1980
- 1980-02-27 KE KE3027A patent/KE3027A/en unknown
- 1980-04-17 HK HK200/80A patent/HK20080A/en unknown
-
1981
- 1981-02-20 JP JP2533081A patent/JPS56138192A/en active Granted
- 1981-02-20 JP JP2532881A patent/JPS56138190A/en active Granted
- 1981-02-20 JP JP2532981A patent/JPS56138191A/en active Granted
- 1981-12-30 MY MY24/81A patent/MY8100024A/en unknown
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