DE1445619B - Process for the preparation of 7 amino cephalosporan acid esters - Google Patents
Process for the preparation of 7 amino cephalosporan acid estersInfo
- Publication number
- DE1445619B DE1445619B DE1445619B DE 1445619 B DE1445619 B DE 1445619B DE 1445619 B DE1445619 B DE 1445619B
- Authority
- DE
- Germany
- Prior art keywords
- ester
- acid
- cephalosporin
- amino
- aqueous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002148 esters Chemical class 0.000 title claims description 15
- 239000002253 acid Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- 150000001780 cephalosporins Chemical class 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229960000583 Acetic Acid Drugs 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- -1 tert-butyloxy Chemical group 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7-ACA Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- FEMOMIGRRWSMCU-UHFFFAOYSA-N Ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- PDOIGRRPKSYVKH-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O PDOIGRRPKSYVKH-UHFFFAOYSA-N 0.000 claims description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-Nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 2
- JKTYGPATCNUWKN-UHFFFAOYSA-N 4-nitrobenzyl alcohol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1 JKTYGPATCNUWKN-UHFFFAOYSA-N 0.000 claims description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N Diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 claims description 2
- CUXSAAMWQXNZQW-UHFFFAOYSA-N acetic acid;butan-1-ol Chemical compound CC(O)=O.CCCCO CUXSAAMWQXNZQW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 claims description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N Dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 2
- 150000004702 methyl esters Chemical class 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 2
- NOTFZGFABLVTIG-UHFFFAOYSA-N 2-cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 claims 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 1
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N Cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 claims 1
- RAABOESOVLLHRU-UHFFFAOYSA-N Diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N Picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims 1
- 208000000260 Warts Diseases 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000001506 calcium phosphate Substances 0.000 claims 1
- 229910000389 calcium phosphate Inorganic materials 0.000 claims 1
- 235000011010 calcium phosphates Nutrition 0.000 claims 1
- NHZZUJIRMHDTKR-UHFFFAOYSA-N carbonic acid;toluene Chemical compound OC(O)=O.CC1=CC=CC=C1 NHZZUJIRMHDTKR-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims 1
- 229910000071 diazene Inorganic materials 0.000 claims 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000001962 electrophoresis Methods 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 239000000155 melt Substances 0.000 claims 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims 1
- 229910052753 mercury Inorganic materials 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 201000010153 skin papilloma Diseases 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- UKNAYQWNMMGCNX-UHFFFAOYSA-N sodium;[hydroxy(phenyl)methyl]-oxido-oxophosphanium Chemical compound [Na+].[O-][P+](=O)C(O)C1=CC=CC=C1 UKNAYQWNMMGCNX-UHFFFAOYSA-N 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000004809 thin layer chromatography Methods 0.000 claims 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 1
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 1
- 238000002211 ultraviolet spectrum Methods 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 239000000284 extract Substances 0.000 description 22
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 5
- HOKIDJSKDBPKTQ-GLXFQSAKSA-M cephalosporin C(1-) Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H]([NH3+])C([O-])=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-M 0.000 description 5
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- WYPXLRODNLXDQJ-UHFFFAOYSA-N 6-aminopiperidin-2-one Chemical compound NC1CCCC(=O)N1 WYPXLRODNLXDQJ-UHFFFAOYSA-N 0.000 description 1
- MSHFRERJPWKJFX-UHFFFAOYSA-N Anisyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- XWIFUHDKWWEJQU-UHFFFAOYSA-N COC(C1=CC=CC=C1)(C1=CC=CC=C1)O Chemical compound COC(C1=CC=CC=C1)(C1=CC=CC=C1)O XWIFUHDKWWEJQU-UHFFFAOYSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N Nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N Nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 240000002799 Prunus avium Species 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- CRGRWBQSZSQVIE-UHFFFAOYSA-N diazomethylbenzene Chemical compound [N-]=[N+]=CC1=CC=CC=C1 CRGRWBQSZSQVIE-UHFFFAOYSA-N 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 235000009808 lpulo Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 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 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Description
1 21 2
Gegenstand der Erfindung ist ein Verfahren zur 19,3 mg Extrakt Nr. 2 (chloroformlöslicher Nieder-;:The invention relates to a process for 19.3 mg extract no. 2 (chloroform-soluble lower ;:
Herstellung von 7-Amino-cephalosporansäureestern, · schlag), der nach Dünnschichtchromatogramm (Ta-?Production of 7-amino-cephalosporanic acid esters, · Schlag), which according to thin-layer chromatogram (Ta-?
das dadurch gekennzeichnet ist, daß man Diester des belle 1) und IR-Spektrum (Banden bei 5,61, 5,75 undwhich is characterized in that one diester des Belle 1) and IR spectrum (bands at 5.61, 5.75 and
Cephalosporin C mit niedermolekularen Alkylalko- 5,93 ηιμ) neben wenig Ausgangsmaterial Nebenpro-Cephalosporin C with low molecular weight alkyl alcohol 5.93 ηιμ) in addition to little starting material side pro-
holen, p-Nitrophenol, 2,4-Dinitrophenol, 2,3,6-Tri- 5 dukte enthält.get, p-nitrophenol, 2,4-dinitrophenol, 2,3,6-tri-5 contains.
nitrophenol, Benzylalkohol, p-Nitrobenzylalkohol, 4,3 mg Extrakt Nr. 3 (aus Anteil Puffer pH 3,3),nitrophenol, benzyl alcohol, p-nitrobenzyl alcohol, 4.3 mg extract No. 3 (from the proportion of buffer pH 3.3),
p-Methoxybenzylalkohol, Benzhydrol oder p,p-Di- nach Dünnschichtchromatogramm (Tabelle 1) wenigp-Methoxybenzyl alcohol, benzhydrol or p, p-di- according to thin-layer chromatogram (Table 1) little
methoxybenzhydrol mit freier Aminogruppe in Ben- Ausgangsmaterial enthaltend,containing methoxybenzhydrol with free amino group in Ben- starting material,
zol, Nitromethan, Dioxan oder chlorierten Kohlen- 26,8 mg (44% Ausbeute, auf Cephalosporin bezo-zol, nitromethane, dioxane or chlorinated carbon 26.8 mg (44% yield, based on cephalosporin
wasserstoffen in einer Konzentration von etwa 0,2 io gene Gesamtausbeute: 25,4%) 7-Amino-cephalospo-hydrogen in a concentration of about 0.2 ion overall yield: 25.4%) 7-amino-cephalospo-
bis 1% bei Zimmertemperatur, gegebenenfalls in ransäurebenzylester in Extrakt Nr. 4 (aus 2% Phos-j!up to 1% at room temperature, if necessary in rans acid benzyl ester in extract no. 4 (from 2% Phos-j!
Gegenwart von Essigsäure oder wäßriger Essigsäure, ' phorsäure-Anteil). IR-Spektrum in Methylenchlo-!Presence of acetic acid or aqueous acetic acid, 'phosphoric acid component). IR spectrum in methylene-!
gewünschtenfalls zusammen mit Pyridin, einige Tage rid: Banden bei 5,62 und 5,75 ηιμ. Nach Dünnschicht-!if desired together with pyridine, rid for a few days: bands at 5.62 and 5.75 ηιμ. After thin-film!
stehen läßt und den 7-Amino-cephalosporansäure- chromatogramm (Tabelle) einheitlich,lets stand and the 7-amino-cephalosporanic acid chromatogram (table) uniformly,
ester isoliert. . 15 Das Produkt kann in Eisessig in Gegenwart von jester isolated. . 15 The product can be dissolved in glacial acetic acid in the presence of j
Die Ester können durch Hydrolyse oder Hydro- Palladiumkohle (10 % Pd) zur 7-Amino-cephalospo-j|The esters can be converted to 7-amino-cephalospo-j |
genolyse in die freie 7-Amino-cephalosporansäure ransäure hydriert werden. ||genolysis can be hydrogenated into the free 7-amino-cephalosporanic acid. ||
übergeführt werden. In dieser Beziehung besonders Der als Ausgangsstoff verwendete Cephalosporin!!be transferred. In this regard, especially the cephalosporin used as a starting material!
günstig ist der Benzhydrylester, der mittels Trifluor- C-dibenzylester kann wie folgt hergestellt werden: t The benzhydryl ester is favorable, which can be prepared by means of trifluoro-C-dibenzyl ester as follows: t
essigsäure und Anisol gespalten werden kann, auch der 20 9,43 g Cephalosporin C (20 mMol) werden in 250 ml!acetic acid and anisole can be split, even the 20 9.43 g cephalosporin C (20 mmol) are in 250 ml!
p-Methoxybenzylester kann so hydrolysiert werden; 1 n-Natriumbicarbonat gelöst, mit 3,62 ml tertt-Bu-p-Methoxybenzyl ester can be hydrolyzed in this way; 1 n-sodium bicarbonate dissolved, with 3.62 ml tertt-Bu-
sehr geeignet sind ferner der p-Nitrobenzol- und tyloxycarbonylazid (26 mMol), gelöst in 150 ml Di-p-nitrobenzene and tyloxycarbonylazide (26 mmol), dissolved in 150 ml of di-
Benzylester, die mittels katalytisch erregten Wasser- oxan, versetzt und 5 Stunden bei 40° gerührt. Die an-Benzyl ester, which is added by means of catalytically excited water oxane, and the mixture is stirred at 40 ° for 5 hours. The other
stoffs gespalten werden. schließend im Vakuum bei 0,5 mm Hg und 30° aufbe split into the fabric. closing in a vacuum at 0.5 mm Hg and 30 °
Die als Ausgangsmaterial verwendeten Diester 25 etwa 150 ml eingeengte Lösung verdünnt man mit des Cephalosporins C werden beispielsweise herge- 200 ml Wasser und extrahiert mehrere Male mitstellt, indem man die freie Aminogruppe des Cephalo- Essigester. Die mit Kochsalz gesättigte, wäßrige; sporins C durch eine Aminoschutzgruppe, z. B. eine Phase wird darauf bei pH 2,0 in der Kälte er-; Acylgruppe, wie Trifluoracetyl, Tosyl, Carbobenzoxy schöpfend mit Essigester ausgezogen. Trocknen des!| oder vor allem tert.-Butyloxycarbonyl, Trityl oder 30 mit gesättigter Kochsalzlösung gewaschenen Extrakt o-Nitrophenylsulfenyl, blockiert, dann die Carboxyl- tes über Natriumsulfat und Eindampfen im Vakuum!! gruppen verestert und die Aminoschutzgruppe ab- ergibt 10,7 g amorphes, farbloses N-tert.-Butyloxy-l spaltet. carbonyl-cephalosporin C (91,6% Ausbeute). ρThe diester 25 used as starting material, about 150 ml of concentrated solution, is diluted with of the cephalosporin C are produced, for example, 200 ml of water and extracted several times, by removing the free amino group of the cephalo ethyl acetate. The aqueous, saturated with table salt; sporins C by an amino protecting group, e.g. B. a phase is then generated at pH 2.0 in the cold; Acyl group such as trifluoroacetyl, tosyl, carbobenzoxy scooped out with ethyl acetate. Drying the! | or especially tert-butyloxycarbonyl, trityl or extract washed with saturated sodium chloride solution o-Nitrophenylsulfenyl, blocked, then the carboxylates over sodium sulphate and evaporation in vacuo !! groups esterified and the amino protective group gives off 10.7 g of amorphous, colorless N-tert-butyloxy-l splits. carbonyl-cephalosporin C (91.6% yield). ρ
Als Nebenprodukt wird bei der Aminolyse ε-Ami- Rf-Wert im Papierchromatogramm im System IjIAs a by-product of the aminolysis, the ε-Ami-Rf value in the paper chromatogram in the system IjI
noadipinsäurelactam-monoester gebildet. Dieser läßt 35 [n-Butanol—Essigsäure (10:1) gesättigt mit Wasser]:!1 noadipic acid lactam monoester formed. This leaves 35 [n-butanol-acetic acid (10: 1) saturated with water] :! 1
sich als neutrale Substanz von dem gewünschten ba- 0,80; im System 2 (wassergesättigtes n-Butanol + 1%Eprove to be a neutral substance of the desired ba- 0.80; in system 2 (water-saturated n-butanol + 1% E
sischen Reaktionsprodukt leicht trennen, z. B. durch Eisessig): 0,51. Bioautographischer Nachweis mit;1 Easily separate sischen reaction product, z. B. by glacial acetic acid): 0.51. Bioautographic evidence with; 1
Extraktion mit sauren Lösungsmitteln, Chromato- Staph. aureus. ■Extraction with acidic solvents, chromato- staph. aureus. ■
graphie oder Gegenstromverteilung. Zu einer Lösung von 3,2 g (6,15 mMol) N-tert.-!graphy or countercurrent distribution. To a solution of 3.2 g (6.15 mmol) of N-tert.-!
In den nachfolgenden Beispielen sind die Tempera- 40 Butyloxycarbonyl-cephalosporin C in 64 ml abs.;In the following examples the temperatures are 40 butyloxycarbonyl-cephalosporin C in 64 ml abs .;
türen in Celsiusgraden angegeben. Äthylenglykoldimethyläther läßt man im Verlaufe vonDoors indicated in degrees Celsius. Ethylene glycol dimethyl ether is left in the course of
. . 5 Minuten 185 ml ätherische Phenyldiazomethanlö-,. . 5 minutes 185 ml of essential phenyldiazomethane solution,
Beispiel 1 sung) enthaltend 16 mMol Reagens, zutropfen und!;Example 1 solution) containing 16 mmol of reagent, add dropwise and !;
100 mg Cephalospirin C-dibenzylester werden in rührt 40 Minuten bei 25° im Dunkeln. Hierauf wirdji100 mg of cephalospirin C-dibenzyl ester are stirred for 40 minutes at 25 ° in the dark. Then ji
20 ml reinstem Methylenchlorid gelöst und im Dun- 45 überschüssiges Reagens durch Zugabe von 2 ml Eis-Dissolve 20 ml of the purest methylene chloride and remove excess reagent by adding 2 ml of ice
keln bei 22° stehengelassen. Die dabei ablaufende intra- essig zerstört, wobei man 30 Minuten im Dunkelnangle left at 22 °. The intravinegar which runs off is destroyed, taking 30 minutes in the dark
molekulare Reaktion läßt sich bequem im IR-Spek- weiterrührt. Die Reaktionslösung wird im Vakuumj;Molecular reaction can easily be stirred further in the IR spectrum. The reaction solution is in vacuo;
trum (1-mm-Zelle) verfolgen: eingedampft, der Rückstand in 120 ml Methylenchlo-ijTrack trum (1 mm cell): evaporated, the residue in 120 ml of methylene-ij
Die Amidbande des Ausgangsmaterials bei 5,93 ηιμ rid aufgenommen, zweimal mit 60 ml eiskalter n-Na-'The amide band of the starting material at 5.93 ηιμ rid added, twice with 60 ml of ice-cold n-Na- '
wird im Laufe mehrerer Tage stetig schwächer, wäh- 50 triumbicarbonatlösung und dann zweimal mit 50 ml!becomes steadily weaker over the course of several days, with 50 trium bicarbonate solution and then twice with 50 ml!
rend sich daneben bei 6,00 ΐημ eine neue Bande wach- 10 %iger Natriumchloridlösung gewaschen. Die wäß-!A new band of waxy 10% sodium chloride solution was washed next to it at 6.00 ΐημ. The water!
sender Intensität ausbildet (Lactambande des Spalt- rigen Phasen werden der Reihe nach zweimal mitsender intensity develops (lactam bands of the split phase are sequentially with twice
Produktes o-Carbobenzoxy-o-amino-valerolactam). 40 ml Methylenchlorid nachextrahiert. Die mit Na-;Product o-carbobenzoxy-o-amino-valerolactam). 40 ml of methylene chloride extracted. The one with Na-;
Nach 20 Tagendampft man im Vakuum ein, nimmt triumsulfat getrockneten und im Vakuum eingedampf-1 After 20 days is concentrated by evaporation in a vacuum, taken triumsulfat and dried in vacuo eingedampf- 1
in Chloroform—Äther (1:3) auf und schüttelt nach- 55 ten Methylenchloridlösungen ergeben 6,17 g amorphen,in chloroform-ether (1: 3) and shaken after 55 th methylene chloride solutions give 6.17 g of amorphous,
einander mit 0,1-molarem Phosphatpuffer pH 3,3 und zum Teil öligen Rückstand, welcher an der zwanzig-each other with 0.1 molar phosphate buffer pH 3.3 and partly oily residue, which at the twenty-
2 % wäßriger Phosphorsäure aus. Dabei scheidet sich fachen Gewichtsmenge Silicagel (entaktiviert mit2% aqueous phosphoric acid. In the process, times the amount by weight of silica gel separates out (deactivated with
ein Niederschlag ab, der in Chloroform gelöst wird. 5 Gewichtsprozent Wasser) chromatographiert wird.a precipitate forms which is dissolved in chloroform. 5 weight percent water) is chromatographed.
Die beiden wäßrigen Auszüge extrahiert man bei Mit Methylenchlorid-Aceton-Gemisch (95:5) lassenThe two aqueous extracts are extracted with a methylene chloride-acetone mixture (95: 5)
pH 8,5 separat mit Essigester. Die über Magnesium- 60 sich 2,73 g (Ausbeute 63 %) N-tert.-Butyloxycarbonyl-pH 8.5 separately with ethyl acetate. The over magnesium 60 2.73 g (yield 63%) of N-tert-butyloxycarbonyl-
sulfat getrockneten organischen Phasen geben beim cephalosporin C-dibenzylester eluieren, welcher ausSulphate-dried organic phases give the cephalosporin C-dibenzyl ester elute, which from
Eindampfen folgende Rückstände: Aceton—Äther—Petroläther (Kp. 50 bis 70°) umkri-Evaporation of the following residues: acetone — ether — petroleum ether (b.p. 50 to 70 °).
25,9 mg Extrakt Nr. 1 [Chloroform—Äther (1:3)- stallisiert wird. F. 88,5 bis 91°.25.9 mg extract no. 1 [chloroform-ether (1: 3) - is installed. F. 88.5 to 91 °.
Anteil], der nach IR-Spektrum (Banden bei 5,75 und IR-Absorptionsspektrum in Nujol: Banden unterProportion], according to the IR spectrum (bands at 5.75 and IR absorption spectrum in Nujol: bands below
6,00 ιτιμ in Methylenchlorid) aus o-Carbobenzoxy- 65 anderem bei 2,98 μ, 5,61 μ, 5,78 μ (mit Schulter bei6.00 ιτιμ in methylene chloride) from o-carbobenzoxy 65 others at 2.98 μ, 5.61 μ, 5.78 μ (with shoulder at
(5-amino-valerolactam besteht. Im Dünnschichtchro- 5,70 μ), 5,91 μ, 6,05 μ, 6,57 μ, 6,83 μ, 7,24 μ, 7,69 μ;1 (Consists of 5-amino-valerolactam. Im thin-layer chromium 5.70 μ), 5.91 μ, 6.05 μ, 6.57 μ, 6.83 μ, 7.24 μ, 7.69 μ ; 1
matogramm keine Flecke mit Jodstärke und Nin- 8,02 μ, 8,17 μ, 8,55 μ, 8,99 μ, 9,32 μ, 9,53 μ, 9,75 μ,!matogram no spots with iodine starch and nin- 8.02 μ, 8.17 μ, 8.55 μ, 8.99 μ, 9.32 μ, 9.53 μ, 9.75 μ ,!
hydrin-Collidin. 10,37 μ, 11,0 μ, 11,53 μ, 13,37 μ und 14,40 μ. UV.-Ab-ihydrin-collidine. 10.37 µ, 11.0 µ, 11.53 µ, 13.37 µ and 14.40 µ. UV.-Ab-i
Sorptionsspektrum in Feinsprit: Xmax 265 ηιμ (ε = 8200).Sorption spectrum in fine spirits: X max 265 ηιμ (ε = 8200).
Rf-Wert im Dünnschichtchrömatogramm auf Silicagel (System Benzol—Aceton 8:2): 0,46.Rf value in the thin-layer chromatogram on silica gel (benzene-acetone system 8: 2): 0.46.
Reaktion nach R e i η d e 1 und Hoppe (Ber., 87, S. 1103 [1954]): gelb mit violettem Hof.Reaction according to R e i η d e 1 and Hoppe (Ber., 87, P. 1103 [1954]): yellow with a purple halo.
Reaktion mit Jod-Stärke-Essigsäure (R. Thomas, Nature, 191, S. 1161 [1961]; P. H. A. S η e a t h und Z. F. Collins, Biochem. J., 79, S. 512 [1961]): positiv. ίοReaction with iodine-starch-acetic acid (R. Thomas, Nature, 191, p. 1161 [1961]; P. H. A. S η e a t h and Z. F. Collins, Biochem. J., 79, p. 512 [1961]): positive. ίο
140 mg N - tert. - Butyloxycarbonyl - cephalosporin C-dibenzylester (0,2 mMol) werden mit 2 ml Trifluoressigsäure 5 Minuten bei 25° stehengelassen. Man entfernt hierauf die Trifluoressigsäure im Vakuum. Der ölige Rückstand wird in 20 ml Methylenchlorid aufgenommen, zweimal mit 10 ml eiskalter n-Natriumcarbonatlösung, dann zweimal mit 10 ml 10 °/oiger Natriumchloridlösung gewaschen. Die wäßrigen Phasen werden noch zweimal mit 5 ml Methylenchlorid nachextrahiert. Aus den mit Natriumsulfat getrockneten Methylenchloridlösungen erhält man beim Eindampfen im Vakuum 120 mg (Ausbeute quantitativ) Cephalosporin C-dibenzylester, welcher im Dünnschichtchromatogramm folgende Rf-Werte aufweist:140 mg N - tert. - Butyloxycarbonyl - cephalosporin C-dibenzyl ester (0.2 mmol) are left with 2 ml of trifluoroacetic acid at 25 ° for 5 minutes. The trifluoroacetic acid is then removed in vacuo. The oily residue is taken up in 20 ml of methylene chloride, washed twice with 10 ml of ice-cold n-sodium carbonate solution, then washed twice with 10 ml of 10 ° / o sodium chloride solution. The aqueous phases are extracted twice more with 5 ml of methylene chloride. The methylene chloride solutions dried with sodium sulfate give 120 mg (quantitative yield) of cephalosporin C-dibenzyl ester on evaporation in vacuo, which has the following Rf values in the thin-layer chromatogram:
Systen RfSysten Rf
Dioxan—Wasser 0,77Dioxane-water 0.77
Benzol—Aceton (1:1) 0,29Benzene-acetone (1: 1) 0.29
Chloroform—Methanol (9:1) 0,56Chloroform-methanol (9: 1) 0.56
tert.-Benzylalkohol—i-Propanol—tert-benzyl alcohol — i-propanol—
Wasser (100:40:55) 0,62Water (100: 40: 55) 0.62
n-Butanol—Essigsäure—Wassern-butanol — acetic acid — water
(100:100: gesättigt) 0,57;(100: 100: saturated) 0.57;
Reaktion mit Jod-Stärke-Essigsäure ... positiv Reaktion nach R e i η d e 1 undReaction with iodine-starch-acetic acid ... positive reaction according to R e i η d e 1 and
Hoppe gelbHop yellow
Reaktion mit Ninhydrin-Collidin kirschrotReaction with ninhydrin collidine, cherry red
Rf-Werte im Dünnschichtchrömatogramm an SilicagelRf values in the thin-layer chromatogram on silica gel
Ausgangsmaterial Extrakt Nr. 2Starting material extract no.2
Extrakt Nr. 3Extract No. 3
Extrakt Nr. 4Extract No. 4
Systemsystem
n-Butanol—Essigsäure 10:1 gesättigt mit Wasser n-butanol-acetic acid 10: 1 saturated with water
System
Benzol—Aceton 6:4system
Benzene-acetone 6: 4
Indikatorindicator
Ninhydrin-Collidin
IndikatorNinhydrin collidine
indicator
Jodstärke Iodine starch
0,600.60
0,160.16
rotviolettred-violet
positiv (0,61)
0,80 bis 0,95positive (0.61)
0.80 to 0.95
0,0 bis 0,220.0 to 0.22
fleischfarbenflesh colored
positivpositive
0,610.61
(0,47)(0.47)
0,360.36
0,15
0,00.15
0.0
rotviolett
positivred-violet
positive
0,670.67
0,620.62
dunkelgelb positivdark yellow positive
Das Reagens wird nach R. T h ο m a s, Nature, 191, S. 1161 (1961), hergestellt Schwache Flecke sind durch Klammern angedeutet.The reagent is prepared according to R. T hο m a s, Nature, 191, p. 1161 (1961). Weak spots are indicated by brackets.
2,61 g Cephalosporin C-dibenzylester werden in 520 ml Methylenchlorid gelöst, mit 5,2 ml eines äquimolekularen Gemisches von Pyridin und Eisessig versetzt und 4 Tage im Dunkeln bei 22° stehengelassen. Die wie im Beispiel 1 durchgeführte Aufarbeitung ergibt folgende Extrakte: 2.61 g of cephalosporin C-dibenzyl ester are dissolved in 520 ml of methylene chloride, with 5.2 ml of one Equimolecular mixture of pyridine and glacial acetic acid and left to stand for 4 days in the dark at 22 °. The work-up carried out as in Example 1 gives the following extracts:
945 mg Extrakt Nr. 1 [Chloroform—Äther-(1: 3)-Anteil], bestehend aus o-Carbobenzoxy-o-amino-valerolactam. 945 mg extract No. 1 [chloroform-ether (1: 3) portion], consisting of o-carbobenzoxy-o-amino-valerolactam.
680 mg Extrakt Nr. 2 (chloroformlöslicher Niederschlag). 680 mg extract No. 2 (chloroform-soluble precipitate).
j 136 mg Extrakt Nr. 3 (aus Anteil Puffer pH 3,3), [bestehend aus Cephalosporin C-dibenzylester.
j 604 mg (38 °/0 der Theorie) einheitlichen 7-Amino- ;cephalosporansäure-benzylester in Extrakt Nr. 4 (2%
IPhosphorsäureanteil) auf Cephalosporin C bezogene !Ausbeute: 21,9%.j 136 mg extract no. 3 (from the portion of buffer pH 3.3), [consisting of cephalosporin C-dibenzyl ester.
j 604 mg (38 ° / 0 of theory) of 7-amino uniform; cephalosporanic acid benzyl ester in extract # 4 (2% IPhosphorsäureanteil) related to cephalosporin C. Yield:.! 21.9%.
Die Charakterisierung aller Produkte erfolgt wie im Beispiel 1 mittels IR-Absorptionsspektrum und Dünnschichtchrömatogramm (vgl. Tabelle).All products are characterized as in Example 1 by means of an IR absorption spectrum and a thin-layer chromatogram (see table).
100 mg Cephalosporin C-dibenzylester werden in 20 ml Methylenchlorid gelöst, mit 0,02 ml eines äquimolekularen Gemisches von Pyridin und Eisessig sowie mit 0,02 ml Wasser versetzt und I1I2 Tage im Dunkeln bei 22° stehengelassen. Aufarbeitung analog Beispiel 1 gibt folgende Extrakte:100 mg of cephalosporin C-dibenzyl ester are dissolved in 20 ml of methylene chloride with 0.02 ml of an equimolar mixture of pyridine and acetic acid and treated with 0.02 ml of water and allowed to stand for I 1 I 2 days in the dark at 22 °. Working up as in Example 1 gives the following extracts:
46,2 mg Extrakt Nr. 1 15,5 mg Extrakt Nr. 2 9,5 mg Extrakt Nr. 346.2 mg extract No. 1 15.5 mg extract No. 2 9.5 mg extract No. 3
32,1 mg Extrakt Nr. 432.1 mg extract No. 4
bestehend aus einheitlichem 7-Amino-cephalosporansäurebenzylester. Ausbeute: 53%, auf Cephalosporine bezogen: 30,5%.Consists of a uniform 7-amino-cephalosporanic acid benzyl ester. Yield: 53%, based on cephalosporins: 30.5%.
100 mg Cephalosporin C-dibenzylester, gelöst in 20 ml Methylenchlorid, versetzt man mit 0,02 ml 2 η-Essigsäure und läßt 7 V2 Tage bei 22° stehen. Aufarbeitung wie im Beispiel 1 liefert100 mg of cephalosporin C-dibenzyl ester, dissolved in 20 ml of methylene chloride, are mixed with 0.02 ml of 2η-acetic acid and left to stand for 7 V for 2 days at 22 °. Working up as in Example 1 delivers
42.8 mg Extrakt Nr. 1
20,0 mg Extrakt Nr. 2
15,2 mg Extrakt Nr. 3 und42.8 mg extract no.1
20.0 mg extract no.2
15.2 mg extract No. 3 and
30.9 mg (Ausbeute: 51%, auf Cephalosporin C30.9 mg (yield: 51%, based on cephalosporin C
bezogen: 29,4%) 7-Amino-cephalosporansäure-benzylester in Extrakt Nr. 4based on: 29.4%) 7-Amino-cephalosporanic acid benzyl ester in extract No. 4
6060
In gleicher Weise, wie im Beispiel 1 bis 4 beschrieben, werden Cephalosporin C-dimethylester, Cephalo-In the same way as described in Example 1 to 4, cephalosporin C-dimethyl ester, cephalo-
Claims (1)
und l°/oigem Phenylacetylchlorid in Aceton. Dashen with 1 molar pyridine in acetone-water (1: 1), split off with trifluoroacetic acid,
and L ° / o sodium phenylacetyl chloride in acetone. The
(ε = 8000).The UV spectrum shows a maximum at 263 πιμ B eis ρ ie 1 7
(ε = 8000).
Dann löst man das Material in Aceton, wodurch weiterer Dicyclohexylharnstoff (0,19 g) abgeschieden wird. Patentanspruch:
Eindampfen des Filtrats, Aufnehmen in Chloroform
und erschöpfendes Ausschütteln mit 0,5molarem Phos- Verfahren zur Herstellung von 7-Amino-cephalo-] phatpuffer pH 7,0 gibt nach Waschen (gesättigte 65 sporansäureestern, dadurch gekennzeich-l Kochsalzlösung), Trocknen (Natriumsulfat) und Ein- net, daß man Diester des Cephalosporins C mit dampfen der organischen Phase 0,92 g rohen tert.- niedermolekularen Alkylalkoholen, p-Nitrophe-i Butyloxycarbonyl-cephalosporin C-di-p-nitrophenyl- nol, 2,4-Dinitrophenol, 2,4,6-Trinitrophenol, Ben-6.47 g tert. - Butyloxycarbonyl - cephalosporin C, twice more with 10 ml of ethyl acetate each time and the three vinegar-4.24 g of p-nitrophenol and 8.56 g of dicyclohexylcarbo ester phases are dissolved twice with 5 ml of 3% aqueous diimide each time in 300 ml of acetonitrile and washed in riger dipotassium hydrogen phosphate solution. In the dark under a nitrogen atmosphere for 17 hours at Man discard the organic phases, combine the 22 ° left to stand. Then the precipitated aqueous solution is filtered off and dicyclohexylurea (4.38 g) is removed with about 4 ml of concentrated salts and evaporated to pH 3.5 in the acid. The vacuum after 15 hours of standing at 0 ". By triturating the deposited product three times, the product is filtered off, the water is washed with a little ice vapor residue with 100 ml of petroleum ether each time and dried. 3.90 g of excess dicyclohexylcarbodiimide is obtained (yield 92%) ) pure 7-amino-cephalosporanic acid (2.94 g) and filtered off from the insoluble product
The material was then dissolved in acetone, which deposited more dicyclohexylurea (0.19 g). Claim:
Evaporation of the filtrate, take up in chloroform
and exhaustive shaking with 0.5 molar Phos. Process for the production of 7-amino-cephalo-] phate buffer pH 7.0 gives after washing (saturated 65 sporic acid esters, characterized by saline solution), drying (sodium sulfate) and Einnet that one diester of cephalosporin C with vapors of the organic phase 0.92 g of crude tert-low molecular weight alkyl alcohols, p-nitrophe-i-butyloxycarbonyl-cephalosporin C-di-p-nitrophenyl nol, 2,4-dinitrophenol, 2,4,6 -Trinitrophenol, Ben-
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0135758A2 (en) | Derivatives of oligoglucosides | |
DE2331078C2 (en) | 3-Substituted 7β-amino-cepham-4-carboxylic acid compounds | |
US3799938A (en) | Certain 4-thia-2,6-diazabicyclo(3.2.0)heptane derivatives | |
DE1917874B2 (en) | 14-halo-daunomycins, processes for their preparation and their use for the preparation of adriamycin | |
DE1445619C (en) | Process for the preparation of 7 Amino cephalosporansuree stars | |
DE3026045A1 (en) | METHOD FOR PRODUCING ESTERS OF THE POLYEN MACROLIDS AND THEIR N-SUBSTITUTED DERIVATIVES | |
DE1445619B (en) | Process for the preparation of 7 amino cephalosporan acid esters | |
CH630333A5 (en) | METHOD FOR SPLIT OF benzyl OF carboxylic acids. | |
DE2303022C2 (en) | Process for the preparation of 3-carbamoyloxymethylcephalosporins | |
CH618961A5 (en) | ||
DE2706490A1 (en) | NEW CARBON ACID ESTERS | |
DE2128605A1 (en) | New cephalosporanic acid derivatives and processes for their preparation | |
DE2057381A1 (en) | 2-Substituted thiazolidine compounds | |
DE1445633A1 (en) | Process for the preparation of new amides | |
DE2938065C2 (en) | ||
AT246920B (en) | New process for the production of 7-aminocephalosporanic acid and its derivatives | |
DE2533273C2 (en) | Process for the production of penicillin derivatives | |
DE1445615C (en) | Process for the preparation of 7 aminocephalosporanic acid and desacetyl 7 aminocephalosporan aurelactone | |
AT247521B (en) | New process for the preparation of 7-aminocephalosporanic acid and its derivatives with free amino groups | |
DE3101427A1 (en) | "METHOD FOR PRODUCING COMPOUNDS CONTAINING CARBONIC ACID AMIDE, IN PARTICULAR PEPTIDES" | |
DE1445619A1 (en) | New process for the production of amino compounds | |
DE2145354C3 (en) | Thioesters and process for their preparation | |
DE1445615B (en) | Process for the preparation of 7-aminocephalosporanic acid and desacetyl-7-aminocephalosporanic acid lactone | |
DE2253924A1 (en) | PROCESS FOR T-BUTYLATION OF HYDROXY- OR THIOL-SUBSTITUTED AMINO ACIDS | |
DE2208631A1 (en) | Cephem compounds and processes for their preparation |