WO1997042177A1 - Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese - Google Patents
Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese Download PDFInfo
- Publication number
- WO1997042177A1 WO1997042177A1 PCT/EP1997/002221 EP9702221W WO9742177A1 WO 1997042177 A1 WO1997042177 A1 WO 1997042177A1 EP 9702221 W EP9702221 W EP 9702221W WO 9742177 A1 WO9742177 A1 WO 9742177A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chosen
- group
- process according
- formula
- ethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 21
- 150000007945 N-acyl ureas Chemical class 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000000543 intermediate Substances 0.000 title abstract description 16
- -1 chloro-carbonyl Chemical class 0.000 claims abstract description 28
- 238000009833 condensation Methods 0.000 claims abstract description 13
- 230000005494 condensation Effects 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 125000001174 sulfone group Chemical group 0.000 claims description 12
- 150000003141 primary amines Chemical group 0.000 claims description 10
- 229930182555 Penicillin Natural products 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 5
- 229960003022 amoxicillin Drugs 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 229940049954 penicillin Drugs 0.000 claims description 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims 1
- 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 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 229960003424 phenylacetic acid Drugs 0.000 claims 1
- 239000003279 phenylacetic acid Substances 0.000 claims 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000002132 β-lactam antibiotic Substances 0.000 abstract description 3
- 229940124586 β-lactam antibiotics Drugs 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 10
- 229960002292 piperacillin Drugs 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 8
- 229960000723 ampicillin Drugs 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229940086542 triethylamine Drugs 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 150000002960 penicillins Chemical class 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- SXVBQOZRZIUHKU-UHFFFAOYSA-N 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride Chemical compound CCN1CCN(C(Cl)=O)C(=O)C1=O SXVBQOZRZIUHKU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000005273 aeration Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 2
- 229960004682 cefoperazone Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 2
- 229960000198 mezlocillin Drugs 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- WVFSGNOCYSQSBQ-UHFFFAOYSA-N 1-(2-chloroacetyl)-4-ethylpiperazine-2,3-dione Chemical compound CCN1CCN(C(=O)CCl)C(=O)C1=O WVFSGNOCYSQSBQ-UHFFFAOYSA-N 0.000 description 1
- JYPVRQZNYMUVCU-UHFFFAOYSA-N 1-ethyl-4-(2,2,2-trichloroacetyl)piperazine-2,3-dione Chemical compound CCN1CCN(C(=O)C(Cl)(Cl)Cl)C(=O)C1=O JYPVRQZNYMUVCU-UHFFFAOYSA-N 0.000 description 1
- ZBEKOEYCWKIMGU-UHFFFAOYSA-N 1-ethylpiperazine-2,3-dione Chemical compound CCN1CCNC(=O)C1=O ZBEKOEYCWKIMGU-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- RIOMYFJVIQPQRJ-UHFFFAOYSA-N 4-acetyl-5,5,6-trichloro-1-ethylpiperazine-2,3-dione Chemical compound CCN1C(Cl)C(Cl)(Cl)N(C(C)=O)C(=O)C1=O RIOMYFJVIQPQRJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000008225 Klebsiella pneumonia Diseases 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- KGZAACIWFGYYHJ-UHFFFAOYSA-N carbonyl dichloride;trichloromethyl carbonochloridate Chemical compound ClC(Cl)=O.ClC(=O)OC(Cl)(Cl)Cl KGZAACIWFGYYHJ-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
- 150000002830 nitrogen compounds Chemical class 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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
Definitions
- the present invention regards a new low environmental impact and economically
- chloro-carbonyl derivatives to give acylureide derivatives, uses new intermediates of synthesis that are particularly advantageous in the industrial preparation of various classes of semisynthetic antibiotics
- N - C - N ureide bond having the formula y x Piperacillin, mezlocillin and azlocillin are semisynthetic penicillins, whilst cefoperazone is a widespread third-generation cephalospo ⁇ n
- aminopenicilhns or aminocephalospo ⁇ ns for example, from amoxycillin or ampicilhn, in the case of penicillins
- condensation with a suitable nitrogen heterocyclic derivative with the use of isocyanates or phosgene (COCI 2 ) as coupling agents
- Phosgene which is considered to be responsible for the majority of casualties due to gas in the First World War, is a gaseous
- diphosgene t ⁇ chloromethyl chloroformiate
- triphosgene b ⁇ s-(tr ⁇ chloromethyl)-
- the P ring is a saturated or unsaturated nitrogen heterocycle with 5 or 6 members, possibly containing in addition one or more hetero-atoms chosen from among N, O and S, and in which -L is the radical of a compound containing a primary amine group
- the said process comprises the condensation of a PN-H
- R ⁇ and R 2 which are the same or different from each other, are leaving groups, with the condition that said chlorocarbonyl derivative is different from
- R 2 ' is chosen from the group consisting of -CCI 3 , -O-CCI 3 , 2,4,6- t ⁇ chlorophenyl, 2,4,6-tnchlorobenzyl, -O-R 3 , where R 3 is a lower alkyl, and -CO-
- R1 0 where R 10 is chosen from the group consisting of -CCI 3 , -O-CCI3, 2,4,6- trichlorophenyl, 2,4,6-tnchlorobenzyl and -O-R 3 , R3 being defined as above
- Said intermediates are particularly useful in the synthesis of ureide derivatives of
- the process according to the present invention enables the condensation, in an effective and economic way, of nitrogen-containing heterocycles and compounds containing primary amme groups, by means of chlorocarbonyl derivatives which
- amino-cephalospo ⁇ ns such as ampicillin and amoxycillin, yielding piperazine antibiotics (e g , piperacillm), other acylureide penicillins (e g , azlociliin and mezlocillin) and cephalosporins (e g , cefoperazone)
- reaction conditions may
- the aforesaid condensation may be carried out in either protic or aprotic solvent at a temperature between 0 and 100°C for a period of time between 30 minutes and 20 hours, with a molar ratio between said PN-H heterocycle and said chlorocarbonyl derivative of between 1 2
- PN-H nitrogen-containing heterocycles where the P ring is a 5- or 6-member heterocycle, as mentioned previously, are chosen preferably from the
- R 4 is chosen in the group consisting of -H, -OH, saturated or unsaturated, linear or branched C ⁇ -C 4 alkyl, possibly substituted by sulphone or alkyl sulphone groups saturated or unsaturated C 3 -C 7 cyclo-alkyl, possibly replaced with
- Said 6-member nitrogen heterocycle is preferably 1 -ethyl-2,3-d ⁇ oxo-p ⁇ peraz ⁇ ne
- the coupling agent is a chlorocarbonyl derivative
- R ⁇ is chosen preferably from the group consisting of -Cl,
- R 3 is a lower alkyl, preferably methyl or ethyl
- R 2 may have one of the meanings of R 1 ⁇
- chlorocarbonyl derivative is different from phosgene diphosgene and triphosgene
- the said chlorocarbonyl derivative of formula (II) is preferably chosen from the
- chlorocarbonyl derivative is oxalyl chloride
- the aforesaid chlorocarbonyl derivatives may be prepared previously or generated in situ in the reaction environment, using conventional procedures
- CI 3 C-CO-CCI 3l is prepared from a solution of chlorine gas in acetone by catalysis of red or UV phosphorous
- CI 3 C-CO-CI and CI-CO-CO-CI are prepared by aeration of chlorine gas in acetic acid or in acetic anhydride in the
- CI-CO-O-CH 3 may be advantageously prepared by aeration of chlorine gas in methyl formate in the presence of a suitable catalyst
- chlorocarbonyl derivatives are used in approximately equimolar quantities with respect to the nitrogen-containing heterocycle and to the compound containing a primary amme group This represents an advantage over phosgene,
- chlorocarbonyl derivatives eliminate the problems of safety and toxicity associated with phosgene, both in the phase of preparation and in that of use, and enable the development of non-pollutant processes of synthesis
- the said compound containing a primary amine group, of the L-NH 2 formula may be, for example phenylglycme H 2 N-CH(Ph)-COOH or parahydroxyphenylglycme H 2 N-CH(C 6 H 4 -OH)-COOH
- this compound is phenylglycme or parahydroxyphenylglycme and said nitrogen-containing heterocycle is 1 -ethyl-2,3-
- the process according to the present invention leads to the obtaining of ⁇ -(4-ethyl-2,3-d ⁇ oxo-1-p ⁇ peraz ⁇ necarbonylam ⁇ ne)-phenylacet ⁇ c acid
- these phenylacetic acids may be subsequently condensed with the amine group of 6-APA (6-am ⁇ no-pen ⁇ c ⁇ llan ⁇ c acid) and of 7- ACA (7-am ⁇ no-cephalosporan ⁇ c acid) and their derivatives, obtaining second- and
- ampicillin and amoxycillin or in position 7 of an amino-cephalospo ⁇ n
- 1 -ethyl-2,3-d ⁇ oxo- ⁇ peraz ⁇ ne may be condensed with the amme group on
- piperazine penicillins such as piperacillm
- R 9 is chosen from the group consisting of -H, -CHs
- R 7 is chosen from the group consisting of -C 6 H 5 , -C 6 H 4 -OH and ,
- R 8 is chosen from the group consisting of H, methyl, ethyl and a quaternary
- condensation may take place in two stages in the first stage by activating the aforesaid nitrogen-containing heterocycles with chlorocarbonyl derivatives, and in
- R 2 ' is chosen from the group consisting of -CCI 3 , -O-CCI 3 , 2,4,6- t ⁇ chlorophenyl, 2,4,6-tnchlorobenzyl, -O-R 3 , where R 3 is a lower alkyl, preferably methyl or ethyl, and -CO-R 10 , where R 10 is chosen from the group consisting of -
- R 2 ' is preferably -CCI 3 , 2,4,6-t ⁇ chlorophenyl or 2,4,6-
- the following two stages of synthesis are provided (1 ) the said PN-H nitrogen-containing heterocycle is reacted with one of the aforesaid chlorocarbonyl derivatives (II) to give an activated intermediate (III), where R 2 is a good leaving group, preferably, the nitrogen heterocycle and the chlorocarbonyl derivative, in equimolar ratio, are reacted in an organic solvent,
- nitrogen-containing heterocycle may reacted first with a promotor, such as
- the L-NH 2 compound in an organic solvent, such as water acetone, hexane, THF, dioxane, acetonitrile, DMF, triethylamine, methanol, ethanol, diethyl ether, isopropyl ether, benzene, toluene, ethyl acetate, etc , and then reacting the activated intermediate in the solution so obtained at a temperature of between 0
- the said inorganic base is chosen preferably from the group consisting of hydroxides, bicarbonates, carbonates and acetates of alkaline and alkaline-earth metals, said
- organic base is chosen preferably from the group consisting of secondary and tertiary amines, such as diethyl amine, trimethyl amine, triethyl amine, t ⁇ butyl amme, pindine, N-methylpi ⁇ dine, and N-methylmorpholine
- secondary and tertiary amines such as diethyl amine, trimethyl amine, triethyl amine, t ⁇ butyl amme, pindine, N-methylpi ⁇ dine, and N-methylmorpholine
- reagents used in the range may vary according to the reagents used in the range preferaoly of between 2 and 10, and more preferably still of between 4 and 8
- Stage 1 preparation of trichloroacetyl 1-ethyl-2,3-dioxo-piperazine
- Stage 1 preparation of trichloro-acetyl 1-ethyl-2,3-dioxo-piperazine
- stage (1a) The residue obtained from stage (1a) was re-suspended in 50 ml of hexane, and
- gaseous HCI was bubbled through the solution for a period of 15 minutes, at a
- Stage 2 formation of the acylureide bond with phenylglycine or ampicillin
- the reaction mixture was kept under stirring for a period of 30 minutes, at a temperature of 0-5°C, keeping the pH at values of 7 5-8 0 by means of gradual addition of triethylamine, and then the temperature was raised to 5-10°C for an hour
- the residue obtained was re-suspended in 10 ml of H 2 O and washed twice with ethyl acetate
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU27755/97A AU2775597A (en) | 1996-05-03 | 1997-04-30 | Process for the preparation of ureide derivatives and new intermediates of synthesis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT96MI000873A IT1282955B1 (it) | 1996-05-03 | 1996-05-03 | Processo per la preparazione di derivati ureidici e intermedi di sintesi |
ITMI96A000873 | 1996-05-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997042177A1 true WO1997042177A1 (fr) | 1997-11-13 |
Family
ID=11374193
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/002221 WO1997042177A1 (fr) | 1996-05-03 | 1997-04-30 | Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese |
Country Status (4)
Country | Link |
---|---|
AR (1) | AR006997A1 (fr) |
AU (1) | AU2775597A (fr) |
IT (1) | IT1282955B1 (fr) |
WO (1) | WO1997042177A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2321153A1 (es) * | 2007-10-11 | 2009-06-02 | Astur Pharma S.A. | Intermedio para la sintesis de piperacilina. |
CN101857574A (zh) * | 2010-07-05 | 2010-10-13 | 山东鑫泉医药中间体有限公司 | 一种n-乙基-2,3-双氧哌嗪的合成方法 |
CN103360343A (zh) * | 2012-03-30 | 2013-10-23 | 凯惠药业(上海)有限公司 | 一种哌嗪酰胺类化合物的制备方法 |
CN104910178A (zh) * | 2015-05-22 | 2015-09-16 | 华北制药集团先泰药业有限公司 | 一种哌拉西林酸的制备方法 |
CN109438476A (zh) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | 哌拉西林酸的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0018546A2 (fr) * | 1979-04-25 | 1980-11-12 | BIOCHEMIE Gesellschaft m.b.H. | Procédé de production de chlorhydrates du chlorure de phénylglycyle |
BE892370A (fr) * | 1981-10-06 | 1982-07-01 | Kim Young Sul | Nouveau procede de preparation de derives de la penicilline et de la cephalosporine |
EP0249176A2 (fr) * | 1986-06-11 | 1987-12-16 | BASF Aktiengesellschaft | Procédé de préparation de dérivés de 2,3-dioxo-4-oxycarbonylpipérazine |
EP0317484A2 (fr) * | 1987-11-16 | 1989-05-24 | Gema S.A. | N,N'-Carboxyl-bis-(4-éthyl-2,3-dioxo)-pipérazine, procédé de préparation et son application |
-
1996
- 1996-05-03 IT IT96MI000873A patent/IT1282955B1/it active IP Right Grant
-
1997
- 1997-04-30 WO PCT/EP1997/002221 patent/WO1997042177A1/fr active Application Filing
- 1997-04-30 AU AU27755/97A patent/AU2775597A/en not_active Abandoned
- 1997-05-05 AR ARP970101846A patent/AR006997A1/es unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0018546A2 (fr) * | 1979-04-25 | 1980-11-12 | BIOCHEMIE Gesellschaft m.b.H. | Procédé de production de chlorhydrates du chlorure de phénylglycyle |
BE892370A (fr) * | 1981-10-06 | 1982-07-01 | Kim Young Sul | Nouveau procede de preparation de derives de la penicilline et de la cephalosporine |
EP0249176A2 (fr) * | 1986-06-11 | 1987-12-16 | BASF Aktiengesellschaft | Procédé de préparation de dérivés de 2,3-dioxo-4-oxycarbonylpipérazine |
EP0317484A2 (fr) * | 1987-11-16 | 1989-05-24 | Gema S.A. | N,N'-Carboxyl-bis-(4-éthyl-2,3-dioxo)-pipérazine, procédé de préparation et son application |
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS, vol. 104, no. 17, 28 April 1986, Columbus, Ohio, US; abstract no. 148590, YAO Q. ET AL.: "Synthetic studies of piperacillin" XP002037154 * |
SHENYANG YAOXUEYUAN XUEBAO, vol. 2, no. 2, 1985, CHINA, pages 128 - 130 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2321153A1 (es) * | 2007-10-11 | 2009-06-02 | Astur Pharma S.A. | Intermedio para la sintesis de piperacilina. |
CN101857574A (zh) * | 2010-07-05 | 2010-10-13 | 山东鑫泉医药中间体有限公司 | 一种n-乙基-2,3-双氧哌嗪的合成方法 |
CN103360343A (zh) * | 2012-03-30 | 2013-10-23 | 凯惠药业(上海)有限公司 | 一种哌嗪酰胺类化合物的制备方法 |
CN103360343B (zh) * | 2012-03-30 | 2017-04-19 | 凯惠药业(上海)有限公司 | 一种哌嗪酰胺类化合物的制备方法 |
CN104910178A (zh) * | 2015-05-22 | 2015-09-16 | 华北制药集团先泰药业有限公司 | 一种哌拉西林酸的制备方法 |
CN104910178B (zh) * | 2015-05-22 | 2017-06-13 | 华北制药集团先泰药业有限公司 | 一种哌拉西林酸的制备方法 |
CN109438476A (zh) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | 哌拉西林酸的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
ITMI960873A1 (it) | 1997-11-03 |
IT1282955B1 (it) | 1998-04-02 |
AR006997A1 (es) | 1999-10-13 |
AU2775597A (en) | 1997-11-26 |
ITMI960873A0 (fr) | 1996-05-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4358588A (en) | Process for preparing cephalosporanic acid compounds | |
EP1748049B1 (fr) | Procédé de préparation de Céfoxitine | |
US20040242557A1 (en) | Process for preparing cefdinir | |
HU202184B (en) | Process for producing terc-butyl-3-oxobutirate | |
EP0548338B1 (fr) | Procede d'elaboration d'intermediaires des cephalosporines | |
CA2326441C (fr) | Procede de purification d'un derive de cephalosporine | |
WO1997042177A1 (fr) | Procede de preparation de derives d'ureide et nouveaux intermediaires de synthese | |
US4791210A (en) | Process for the production of 5-methyltetrazole | |
FI109126B (fi) | Menetelmä kefepiimidihydrokloridihydraattiantibiootin valmistamiseksi | |
KR100458233B1 (ko) | 3-비닐-세펨화합물의 제조방법 | |
US3920640A (en) | Acylamino-cephem-carboxylic acids and process for preparing them | |
US5574155A (en) | Process for the synthesis of the disodium salt hemiheptahydrate of ceftriaxone | |
GB2257703A (en) | Acylation of 7 - amino-cephems | |
IL43913A (en) | Preparation of acid D] - 7) a - amino - a - p - hydroxyphenyl (- acetamido [- 3 -) 1, 2, 3 - triazole - 5 - ile (thymethyl - 3 - cephalic - 4 - carboxylitol salt | |
EP0581220A2 (fr) | Procédé pour la préparation d'intermédiaires de céphalosporine | |
RO109651B1 (ro) | Procedeu pentru preparea unui antibiotic cefepim dihidroclorura hidrat | |
US3925362A (en) | {60 -Alkylsulfobenzyl penicillins and production thereof | |
FI66387B (fi) | Foerfarande foer framstaellning av hydroxi-alfa-aminobensyl-penicillin | |
US20040132996A1 (en) | Method for preparation of ceftiofur and salts thereof | |
IE41557B1 (en) | Intermediates and production thereof for use in the preparation of 6-2-phenyl-2-(guanylureidoacetamido)- acetamido penicillanic acid | |
US6313289B1 (en) | Purification process | |
US4310460A (en) | Process for the production of 6-D-α-amino-p-hydroxyphenylacetamido penicillanic acid | |
WO2002072555A1 (fr) | Procede de preparation de certains caprolactames substitues | |
US6414140B2 (en) | Process for the production of 3-vinyl cephalosporins | |
US4301072A (en) | Process for preparing aminopenicillins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 97539508 Format of ref document f/p: F |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
122 | Ep: pct application non-entry in european phase |