DK156575B - Fremgangsmaade til fremstilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxylsyrederivater - Google Patents
Fremgangsmaade til fremstilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxylsyrederivater Download PDFInfo
- Publication number
- DK156575B DK156575B DK061976AA DK61976A DK156575B DK 156575 B DK156575 B DK 156575B DK 061976A A DK061976A A DK 061976AA DK 61976 A DK61976 A DK 61976A DK 156575 B DK156575 B DK 156575B
- Authority
- DK
- Denmark
- Prior art keywords
- oxo
- solution
- acetate
- cephem
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- ZUBXPSDFPQTKQN-ZCFIWIBFSA-N (6r)-3-hydroxy-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1CC(O)=CN2C(=O)C[C@H]21 ZUBXPSDFPQTKQN-ZCFIWIBFSA-N 0.000 title claims description 5
- URKCXUCFZYUXPA-LWOQYNTDSA-N (6r)-3,8-dioxo-5-thia-1-azabicyclo[4.2.0]octane-4-carboxylic acid Chemical class C1C(=O)C(C(=O)O)S[C@@H]2CC(=O)N21 URKCXUCFZYUXPA-LWOQYNTDSA-N 0.000 title claims description 3
- -1 phenylacetamido Chemical group 0.000 claims description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000005909 Kieselgur Substances 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 37
- 229940022663 acetate Drugs 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 8
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 7
- 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 description 7
- 239000006260 foam Substances 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical group OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- MSJBRVIZZHKNPL-BDPMCISCSA-N (4-nitrophenyl)methyl (6r)-3-hydroxy-8-oxo-7-[(2-phenoxyacetyl)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)COC1=CC=CC=C1 MSJBRVIZZHKNPL-BDPMCISCSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- FZEVMBJWXHDLDB-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical group S1CC=CN2C(=O)C[C@H]21 FZEVMBJWXHDLDB-ZCFIWIBFSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AJAYYHYWTPEASL-BDPMCISCSA-N (4-nitrophenyl)methyl (6r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)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=CC=C1 AJAYYHYWTPEASL-BDPMCISCSA-N 0.000 description 2
- OZXDVHCYEWWWLI-UHFFFAOYSA-N (4-nitrophenyl)methyl 4-bromo-2-[2-(cyclopropylmethoxycarbonylsulfanyl)-4-oxo-3-[(2-phenoxyacetyl)amino]azetidin-1-yl]-3-hydroxybut-2-enoate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1COC(=O)C(=C(CBr)O)N(C(C1NC(=O)COC=2C=CC=CC=2)=O)C1SC(=O)OCC1CC1 OZXDVHCYEWWWLI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 150000001782 cephems Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- QYIYFLOTGYLRGG-RPFQZYLTSA-N (6R)-7-[(2-amino-1-oxo-2-phenylethyl)amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]12)CC(Cl)=C(C(O)=O)N1C(=O)C2NC(=O)C(N)C1=CC=CC=C1 QYIYFLOTGYLRGG-RPFQZYLTSA-N 0.000 description 1
- QPGKPKMGLQZZSG-LWOQYNTDSA-N (6r)-3,8-dioxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid Chemical compound S1CC(=O)C(C(=O)O)N2C(=O)C[C@H]21 QPGKPKMGLQZZSG-LWOQYNTDSA-N 0.000 description 1
- MPLGPTNVGARJRP-FFFFSGIJSA-N (6r)-3-bromo-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@H]2SCC(Br)=C(N2C1=O)C(=O)O)NC(=O)CC1=CC=CS1 MPLGPTNVGARJRP-FFFFSGIJSA-N 0.000 description 1
- YTCUEIOOUOMPAT-RXMQYKEDSA-N (6r)-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical group OC(=O)C1=C(O)CS[C@@H]2CC(=O)N12 YTCUEIOOUOMPAT-RXMQYKEDSA-N 0.000 description 1
- SVOXDJIRULKZTA-SBXXRYSUSA-N (6r)-3-hydroxy-8-oxo-7-[(2-phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@H]2SCC(O)=C(N2C1=O)C(=O)O)NC(=O)COC1=CC=CC=C1 SVOXDJIRULKZTA-SBXXRYSUSA-N 0.000 description 1
- RASPLVISAYEZCJ-QKFMDRJYSA-N (6r)-7-[(2-amino-2-phenylacetyl)amino]-3-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@@H]2N(C1=O)C(=C(CS2)OC)C(O)=O)NC(=O)C(N)C1=CC=CC=C1 RASPLVISAYEZCJ-QKFMDRJYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- MDGSWTXVAFUBGP-SSDMNJCBSA-N 2,2,2-trichloroethyl (6r)-3,8-dioxo-7-[(2-phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(C(CS2)=O)C(=O)OCC(Cl)(Cl)Cl)NC(=O)COC1=CC=CC=C1 MDGSWTXVAFUBGP-SSDMNJCBSA-N 0.000 description 1
- SOUQLWFWOSMCPJ-SSDMNJCBSA-N 2,2,2-trichloroethyl (6r)-3,8-dioxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound C1([C@@H]2N(C1=O)C(C(CS2)=O)C(=O)OCC(Cl)(Cl)Cl)NC(=O)CC1=CC=CC=C1 SOUQLWFWOSMCPJ-SSDMNJCBSA-N 0.000 description 1
- MXMUSCXSYCBAAC-UHFFFAOYSA-N 2-(azetidin-1-yl)-3-methylbut-3-enoic acid Chemical compound CC(=C)C(C(O)=O)N1CCC1 MXMUSCXSYCBAAC-UHFFFAOYSA-N 0.000 description 1
- OTTZHAVKAVGASB-UHFFFAOYSA-N 2-heptene Natural products CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FQPGQMFPDZVAIG-UHFFFAOYSA-N 4-sulfanylazetidin-2-one Chemical class SC1CC(=O)N1 FQPGQMFPDZVAIG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 101100061127 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-15 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FIDHUEJNXPLJNN-UHFFFAOYSA-N [ClH]=C Chemical compound [ClH]=C FIDHUEJNXPLJNN-UHFFFAOYSA-N 0.000 description 1
- 150000004720 acetoacetic acids Chemical class 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- WQNPYTGUDVXQTO-IQHZPMLTSA-N benzhydryl (6r)-3-hydroxy-8-oxo-7-[(2-phenoxyacetyl)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)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)NC(=O)COC1=CC=CC=C1 WQNPYTGUDVXQTO-IQHZPMLTSA-N 0.000 description 1
- NGOKMIIMHXFKPZ-BDPMCISCSA-N benzyl (6r)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)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)NC(=O)CC1=CC=CC=C1 NGOKMIIMHXFKPZ-BDPMCISCSA-N 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyloxyacetoaldehyde Natural products CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000005282 brightening Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 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 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 150000001781 cephams Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000005837 enolization reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- LJKNRSBEKUSSIE-UHFFFAOYSA-N hept-2-ene Chemical compound [CH2]CCCC=CC LJKNRSBEKUSSIE-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- GFLKRXCZFDBIPC-QKFMDRJYSA-N methyl (6r)-7-(1,3-dioxoisoindol-2-yl)-3,8-dioxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C1=O)[C@@H]2N1C(C(=O)OC)C(=O)CS2 GFLKRXCZFDBIPC-QKFMDRJYSA-N 0.000 description 1
- OGOVBHIDESYCEM-JOPIAHFSSA-N methyl (6r)-7-(1,3-dioxoisoindol-2-yl)-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1[C@H]2SCC(O)=C(C(=O)OC)N2C1=O OGOVBHIDESYCEM-JOPIAHFSSA-N 0.000 description 1
- HWUHNJZIIWBXQM-PVQCJRHBSA-N methyl (6r)-7-(1,3-dioxoisoindol-2-yl)-3-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1[C@H]2SCC(OC)=C(C(=O)OC)N2C1=O HWUHNJZIIWBXQM-PVQCJRHBSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 108010045994 tricholysine Proteins 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom 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)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 156575 B
Den foreliggende opfindelse angâr en særlig fremgangsmâde tΠ frem-stilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxyl-syrederivater med formlen 5 A\ As N SN «, /\-r ^ c >—r ^ I eller A2 |
» J V^OH
cox cox 15 hvor a2/ betegner phthalimido, phenylacetamido eller phenoxyacetamido, og X betegner hydroxy eller en carboxylbeskyttende gruppe i form af 20 methoxy, 2,2,2-trichlorethoxy, p-nitrobenzyloxy, diphenylmethoxy eller benzyloxy, hvilken fremgangsmâde er ejendommelig ved, at man ringslutter en forbin-delse med den almene formel 25 aJ sh
/W
/-y- cox 30 hvor ni Α2·>Ν A a1 A1'^
2 s o i/N
35 har den ovenfor for A anf0rte betydning eller a kan sammen med -SH-gruppen udg0re en gruppe i form af -N=C-S eller -N=C-S- , ch2c6h5 ch2oc6h5 X har den ovenfor anfprte betydning, og Y betegner hydroxy, morpholin-4-
DK 156575 B
2 y1, piperidin-l-yl eller dimethylamino, ved behandling med syre, base eller oplpsningsmiddel, om npdvendigt i nærvær af en katalysator.
Ifplge opfindelsen tilvejebringes en hidtil ukendt fremgangsmâde 5 til effektiv fremstilling i stor skala af nyttige npgle-mellemprodukter ved produktionen af cephalosporiner.
Ringslutningsfremgangsmâden ifpige opfindelsen udgpr sluttrinet i en flertrinsfremgangsmâde til fremstilling af 3-hydroxycephalosporin-forbindelser, sâledes som det fremgâr af nedenstâende reaktionsskema.
10 1 , ---'s ^11* V l's v -^SR haloqenerinq ^ 15 0^-^=GCjH3 0«=-N-^=<f2Hal cox cox (1) (2) A1''' \ A1'
21 ^SR afbeskyttelse . ^SH
20 . A I : ' A I
(2) COX (3) Cox A1* A1 25 A2' J ringslutninq A* J Γ 7
çyX N\C=C^H2Hal oJ-OH
COX COX
(3) (4) 30 hvor 1f 9/ 1 p A , A , A , A , X og Y har den ovenfor anfprte betydning, R betegner hydrogen eller en substituent, or 2 og den punkterede linie viser, at nâr R og R betegner hydrogen, og A betegner carbocyclisk acyl kan substituenterne være forenet til en 35 azetidinothiazolinbicyclisk ring.
Mange forspg pâ syntese af en 3-cephem-ring i stor mâlestok er blevet rapporteret, men ingen fremstiller kommercielt cephalosporiner ved syntese af kernen, bortset fra cephalexin. Den foreliggende opfin-
DK 156575 B
3 delse tilvejebringer en ringslutning ti1 dannelse af 3-hydroxy-3-cephem-forbindelser via 4-mercaptoazetidinon-derivater.
Forspg pâ at ringslutte den type forbindelser med formlen (2) eller (3), hvor Y er forskellig fra hydroxy eller substitueret amino, 5 fprte til utilfredsstillende resultâter. Nâr imidlertid Y er en gruppe, som fremmer enolisering til dannelse af en dobbeltbinding mod exo-positionen, fandt ringslutningen glat sted til dannelse af den ti1 -svarende 3-hydroxy-3-cephemforbindelse (4).
3-Hydroxy-3-cephemforbindelsen (4) er et værdifuldt mellemprodukt 10 til syntese af værdifulde cephemforbindelser (f.eks. de nyligt udviklede 3-methoxy-7-(a-phenylglycinamido)-3-cephem-4-carboxylsyre, 3-chlor-7-(a-phenylglycinamido)-3-cephem-4-carboxylsyre og 3-brom-7-(2-thienylacet-amido)-3-cephem-4-carboxylsyre). Fremgangsmâden ifplge den foreliggende opfindelse kan sâledes anvendes til fremstilling af produkter, som er 15 omhandlet i de tyske patentskrifter DE nr. 2.408.698 og DE nr.
2.331.133.
Udgangsforbindelserne (1) for ringslutningsreaktionerne, 4-sub-stitueret thio-3-(amino eller substitueret amino)-2-oxo-a-(l-ethyliden)-azetidin-l-eddikesyre eller derivaterne heraf ved carboxygruppen, kan 20 fremstilles ud fra penicillin-l-oxid ved omsætning af phosphitestere, eddikesyreanhydrid, osv., til dannelse af a-isopropenyl-azetidin-1-eddikesyre eller derivater deraf, som oxideres med ozon til dannelse af udgangsmaterialet, hvor α-substituenten er 1-hydroxyethyliden eller 1-acetyl, som igen behandles med acyleringsreagenser, amineringsreagenser, 25 reagenser til indf0ring af reaktivt nitrogen, etc., til dannelse af de tilsvarende udgangsmaterialer. Endvidere kan udgangsmaterialerne ogsâ fremstilles ud fra et azetidin-2-on-derivat og reaktionsdygtige derivater af acetoeddikesyrer.
Fremgangsmâden 1) kan udfpres ved at behandle forbindelsen (1) med 30 et halogeneringsreagens. Halogeneringsreagenset kan være et sâdant, som halogenerer gennem en halogenkation eller et halogenradikal eller ækvi-valenter deraf.
Omsætningen af udgangsmaterialerne med halogeneringsreagenserne udf0res fortrinsvis i et inert oplpsningsmiddel.
35 Særligt foretrukne oplpsningsmidler er aromatiske carbonhydrider, halogenerede carbonhydrider, estere, ethere, amider og sure oplpsningsmidler.
Afbeskyttelsen 2) af forbindelsen (2) kan udfpres ved behandling
DK 156575B
4 af denne forbindelse (2) med vandig syre for thiazolinoazetidin-forbin-delsen, og ved behandling af forbindelsen (2), hvor R betegner carbonisk acyl, med en Lewis syre.
Ringslutningen 3) kan udf0res ved behandling af forbindelsen (3) 5 med i) en syre ii) en base, eller iii) et opl0sningsmiddel, om nodvendigt i nærvær af en katalysator, 10 eller under hvilke som helst betingelser, der ringslutter udgangs-materialet til dannelse af 3-cephem-kernen. Udgangsforbindelserne synes at hâve en tendens til at ringslutte næsten automatisk, og under for-skellige milde betingelser kan de 0nskede cephem-forbindelser isoleres i godt udbyttte. Mercaptogruppen i udgangsmaterialernes position 4 kan 15 være i form af en mercaptid anion. Det er unpdvendigt at anvende et iso-leret udgangsmateriale (3) til omsætningen. Typiske eksempler pâ metoden er behandling af a-[3-(phenoxymethyl eller benzyl)-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-a-(2-halogenacetyl)eddikesyre, a-[4-mercapto-3-(phenoxyacetyl eller phenylacetyl)amino-2-oxoazetidin-l-yl]-20 a-(2-halogenacetyl)eddikesyre eller derivater deraf ved carboxygruppen under vandige sure betingelser. Behandlingen er i fuld overensstemmelse med betingelserne for ringslutning anf0rt ovenfor i), og det opnâede produkt er den 0nskede cephemforbindelse (4).
Syrerne, som anvendes til at g0re reaktionsmediet surt, omfatter 25 mineralsyre (f.eks. saltsyre, hydrogenbromidsyre, svovlsyre, salpeter-syre, phosphorsyre, perchlorsyre, svovlsyrling), sulfonsyre (f.eks. alkansulfonsyre, arylsu!fonsyre), phosphonsyre, carboxylsyre (f.eks. myresyre, eddikesyre, halogenalkansyre, oxalsyre, phthalsyre) og andre organiske eller uorganiske syrer eller salte deraf med en svag base 30 (f.eks. aromatisk eller aliphatisk base, ammoniak, jordalkalimetal, aluminium, S0lv) eller sure salte af syrer med en almindelig base, her-under alkalimetalsalte. Lewis syre kan ogsâ med fordel anvendes i et aprot oplosningsmiddel.
Baserne, som anvendes til at g0re midi et basisk, omfatter for-35 trinsvis den svage base. Stærke baser (f.eks. alkalimetalhydroxid, alkalimetalcarbonat, tertiær ammoniumhydroxid) kan anvendes under ud-valgte milde betingelser, fordi de nedbryder udgangsforbindelserne eller fremstillede forbindelser, især /î-lactam-delen. En Lewis-base kan ogsâ
DK 156575 B
5 anvendes.
Katalysatoren til ringslutningen kan være en neutral eller basisk silicagel, aluminiumoxid, diatoméjord, florisil, eller andre kataly-satorer.
5 I visse tîlfælde finder ringslutningen sted ved indvirkning af et oplpsningsmiddel (f.eks. et opl0sningsmiddel af h0jere molaritet, her-under amider (hexamethylphosphortriamid, dimethylformamid, formamid, etc.) alkohol, vand) alene. I disse tîlfælde fremmer polære oplpsningsmidler omsætningen. Det kan antages, at reaktionen er en f0lge af kata-10 lyse med hydrogenhalogenid fremstillet ved den initiale reaktion.
Omsætningen udf0res fortrinsvis i et opl0sningsmiddel som omtalt ovenfor under opvarmning eller afk0ling eller ved stuetemperatur. Om n0dvendigt omrpres reaktionsmediet under inert gas.
Foretrukne oplpsningsmidler er polære oplpsningsmidler, f.eks.
15 al koholcarboxylsyreamid, nitril, nitrocarbonhydrid, sulfoxid, vandige oplpsningsmidler, og oplpsningsmidler med væsentlig evne til at oplpse-liggpre udgangsmaterialerne, f.eks. estere, ethere, halogencarbon-hydrider, som undertiden letter reaktionen. Reaktionen forlpber i almin-delighed hurtigt ved stuetemperatur til dannelse af de pnskede cephem-20 eller cephamforbindelser i hpjt udbytte.
Reaktionsproduktet (2) - (4) kan isoleres fra reaktionsblandingen ved hjælp af konventionelle metoder, f.eks. fjernelse af uomsat materiale, biprodukt, oplpsningsmiddel eller lignende, og kan renses ved hjælp af konventionelle metoder, f.eks. omkrystallisation, kromatografi, 25 omfældning.
Slutproduktet er en 3-hydroxy-3-cephem-4-carboxylsyre eller 3-oxo-cepham-4-carboxylsyre (4). I nogle tîlfælde ændres substituenterne i position 3 eller 7 pâ cephem-ringen under omsætningen eller oparbejd-ningen, og som fplge heraf kan de til hinanden svarende substituenter i 30 udgangsmaterialerne og de fremstillede materialer variere. Om pnsket kan sâdanne substituenter udvindes eller transformeres til andre pnskede substituenter ved hjælp af konventionelle metoder. Sâdanne tîlfælde faider ogsâ indenfor opfindelsens rammer.
I produkternes cephem-kerne er der en dobbeltbinding bundet til 35 carbonatomet i position 3. Dobbeltbindingen kan styres til position 2,4-eller 3-substituenten oxygen, eller blandinger deraf, i afhængighed af betingelserne for omsætning, oparbejdning, etc., men sædvanligvis er hoved-produktet udelukkende 3-cephem eller 3-oxo dobbeltbundet isomer.
DK 156575 B
6
Under ringslutningen dannes givetvis mellemprodukter (3), uanset om der er foretaget isolering eller ikke.
Halogeneringen 1), afbeskyttelsen 2) og ringslutningen 3) kan ud-fdres i en beholder, nemlig uden isolering af mellemprodukter, og endog 5 uden fjernelse af de pâgældende reaktionsoplpsningsmidler. Derfor kan omsætningerne i praksis udfdres simpelt som en reaktion i et triη. I dette tilfælde vælges et oplisningsmiddel, som er hensigtsmæssigt ved aile reaktionstrin. Et typisk eksempel er et etheropldsningsmiddel (f.eks. tetrahydrofuran, tetrahydropyran eller dioxan), amidoplds-10 ningsmiddel (f.eks. dimethylformamid, dimethylacetamid eller hexamethyl-phosphortriamid) eller halogeneret carbohydridopldsningsmiddel (f.eks. chloroform, methylenchlorid eller dichlorethan).
De værdifulde npglemellemprodukter, 3-hydroxy-3-cephem-forbindelserne, opnâs ifplge opfindelsen i h0je udbytter og ved hjælp af 15 enkle fremgangsmâder ud fra billige penicilliner.
Opfindelses belyses i det fplgende ved eksempler.
Eksempel 1 23 (1) Til en oplpsning af methyl a-[4-cyclopropylmethoxycarbonylthio-3-phth ali mi do-2-oxoazet i d i η-1-yl]-a-(2-brom-1-cyclopropy1methoxy-carbonyloxyethylidenjacetat (500 mg) i methylenchlorid (20 ml) sættes aluminiumchlorid (510 mg) pâ en gang, og blandingen omrores ved stue-temperatur. Efter 1 time hældes blandingen i kold 3% saltsyre (20 ml) og 25 ekstraheres med methylenchlorid. Ekstraktoplosningen vaskes med vand, tprres over magnesiumsulfat og inddampes til dannelse af methyl ar-[4-mercapto-3-phthalimido-2-oxoazetidin-l-yl]-tt-(2-brom-l-hydroxy-ethyliden)acetat (252 mg).
Udbytte: 72,3%.
30 IR: yCHCl, 1790, 1783, 1728, 1670, 1620 cm"1, max 6 NMR: δ CDC13 l,80d(llHz)lH, 3,87s3H, 4,22+2,56AB2(10Hz)2H, 5,38dd(ll, 5Hz)lH, 5,70d(5Hz)lH, 7,76m4H, 12,3slH.
35 (2) Methyl tt-[4-mercapto-3-phthalimido-2-oxoazetidin-l-yl]-a-(2-brom- l-hydroxyethyliden)acetat (a) behandles under fplgende betingelser til dannelse af methyl 3-hydroxy-7-phthalimido-3-cephem-4-carboxylat (b): smeltepunkt 223-226°C.
DK 156575 B
7 IR: tCHC13 1797, 1779, 1728, 1667, 1616 cm-1, max ύ NMR: 5CDC13 3,26+4,50ABq(14)2H, 5,60s3H, 5,63+6,15ABq(4)2H, 7,16m4H.
5 (i) Til en opl0sning af (a) (80 mg) i benzen (8 ml) sættes N,N-dimethylanilin (20 mg), og blandingen tilbagesvales under nitrogen-atmosfære. Efter 30 minutter afkples reaktionsblandingen, gpres sur med 5% saltsyre og ekstraheres med ethylacetat. Ekstraktoplpsningen vaskes 10 med vand, tprres over magnesiumsulfat og inddampes. Remanensen (71 mg) blandes med ethylacetat (1 ml) og henstâr en stund til dannelse af (b) (25 mg). Smeltepunkt 223-226°C. Udbytte: 38,9%.
(ii) En oplpsning af (a) i (150 mg) i hexamethylphosphortriamid (1 ml) 15 omrpres ved stuetemperatur i 1 time. Reaktionsblandingen blandes med isvand (6 ml) og ether (0,5 ml) til fraskillelse af krystaller af (b) (50 mg), som kan opsamles ved filtrering. Udbytte: 40,8%.
(iii) En oplpsning af (a) (200 mg) anbringes pâ en forbelagt "PLC"-plade 20 (silicagel "F-254"), som forhandles af E. Merck AG, og fremkaldes med en blanding af benzen og ethylacetat (2:1). Bândet for hovedproduktet ekstraheres med ethylacetat indeholdende 3% methanol og ekstrakten inddampes under reduceret tryk. Remanensen oplpses i chloroform, befries for uoplpseligt materiale og inddampes til dannelse af (b) (62 mg).
25 Udbytte: 37,9%.
Methyl 3-oxo-7-phthalimidocepham-4-carboxylat (b) fremstillet i henhold til ovenstâende fremgangsmâder oplpses i dioxan, blandes med en oplpsning af diazomethan i ether og omrpres i 1 time ved stuetemperatur. Reaktionsblandingen inddampes under reduceret tryk til dannelse af 30 methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylat i næsten kvanti-tativt udbytte. Omkrystallisation fra en blanding af acetone og ether giver rene krystaller, smeltepunkt 225-227°C.
Eksempel 2 35 (1) Til en oplpsning af 2,2,2-trichlorethyl a-[4-cyclopropylmethoxy-carbonylthio-3-phenoxyacetamido-2-oxoazetidin-l-yl]“a-[2-brom-l-(piperidin-l-yl)ethyliden]acetat (573 mg) i methanol (30 ml) sættes 10%
DK 156575 B
8 saltsyre (7~ml), og blandingen omrpres ved stuetemperatur eller ved 40-45°C. Efter 30 minutter hældes reaktionsblandingen i isvand og ekstra-heres med benzen. Ekstraktoplpsningen vaskes med vand, t0rres og ind-dampes til dannelse af 2,2,2-trichlorethyl a-[4-cyclopropylmethoxy-5 carbonylthio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxy-ethyliden)-acetat (434 mg). Udbytte: 83,5%.
IR: yCHCI, 3450, 1790, 1720 (sh), 1700 cm"1, max ύ NMR 8 CDC13 0,l-l,4m7H, 3,98d(7Hz)2H, 4,27d(5Hz)2H, 4,57s2H, 10 4,82d(3Hz)2H, 5,27d(6;8Hz)lH, 5,93d(5Hz)lH, 6,8-7,5m6H, ll,67br-slH.
(2) ΤΠ en omrdrt oplpsning af 2,2,2-trichlorethyl a-[4-cyclopropyl-methoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethy1iden)acetat (330 mg) i methylenchlorid (6 ml) sættes 15 aluminiumchlorid (330 mg) ved stuetemperatur, og blandingen omr0res i 60 minutter. Reaktionsblandingen hældes i iskold fortyndet saltsyre og ekstraheres med ethylacetat. Ekstraktoplpsningen vaskes med fortyndet saltsyre og vand, t0rres og inddampes til dannelse af 2,2,2-trichlorethyl 7-phenoxyacetamido-3-oxocephem-4-carboxylat (300 mg). Skum.
IR:yCHC13 3420, 1780, 1685 cm'1, max NMR 8 CDCl3 3,37s2H, 4,53s2H, 4,85s2H, 5,07d(4)lH, 5,20-5,73m2H, 6,8-7,7m6H.
25 Eksempel 3
Ved en lignende fremgangsmâde som beskrevet i eksempel 2 (1) hydrolyseres 2,2,2-trichlorethyl a-[4-carbobenzoxythio-3-phenoxyacet-amido-2-oxoazetidin-l-yl]-a-[2-brom-l-(piperidin-l-yl)ethyliden]acetat i methanolisk saltsyre til dannelse af 2,2,2-trichlorethyl a-[4-carbo-30 benzoxythio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxy-ethyliden)-acetat, og produktet ringsluttes med aluminiumchlorid i methylenchlorid til dannelse af 2,2,2-trichlorethyl 7-phenoxyacetamido- 3-oxocepham-4-carboxylat, som er identisk med produktet fra eksempel 2(2).
35 DK 156575B ' 9
Eksempel 4 (1) Til en oplpsning af p-nitrobenzyl a-[4-cyclopropyl-methoxy-carbonylthio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-ûr-[2-brom-l- 5 (morpholin-4-yl)ethyliden]acetat (300 mg) i en blanding af methanol (22 ml) og methylenchlorid (3,5 ml), og blandingen omrpres ved stuetem-peratur under nitrogenatmosfære efter tilsætning af 10% saltsyre (4 ml).
Efter 2 timer hældes reaktionsblndingen pâ isvand og ekstraheres med chloroform. Ekstraktopl0sningen vaskes med vand, tprres og inddampes til 10 dannelse af p-nitrobenzyl 4-cyclopropyl-methoxycarbonylthio-3-phenoxy-acetamido-2-oxo-a-(2-brom-l-hydroxyethyliden)azetidin-l-acetat (252 mg).
Skum. Udbytte: 92,8%.
IR: yCHCI- 3426, 1781, 1710, 1690, 1601 cm-1 max J
15 NMR: δ CDC13 0,23-1,33m5H, 3,84-4,36m4H, 4,55s2H, 5,10-5,32m3H, 5,88d(5Hz)lH, 6,83-8,33m9H, 12,0slH.
(2) Til en oplpsning af p-nitrobenzyl a-[4-cyclopropylmethoxycarbonyl-thio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxy- 20 ethyliden)acetat (218 mg) i methanolfri methylenchlorid (2,1 ml) sættes aluminiumchlorid (220 mg) under isafkpling, og blandingen omrpres under argonatmosfære. Efter 35 minutter hældes reaktionsblandingen pâ isvand indeholdende 4N saltsyre (4 ml), omrpres i 10 minutter og ekstraheres med chloroform. Ekstraktoplpsningen vaskes med vand, tprres og inddampes 25 til dannelse af p-nitrobenzyl a-[4-mercapto-3-phenoxyacetamido-2-oxo-azetidin-l-yl]-Qf-(2-brom-l-hydroxyethyliden)acetat (150 mg). Gult skum.
Udbytte: 94,6%.
IR: 7CHC13 3400, 1780, 1692, 1610, 1603 cm"1 max J
30 NMR: δ CDC13 2,25d(10Hz)1H, 4,25d(2Hz)2H, 4,58s2H, 5,20-5,37m4H, 6,84-8,24m9H, 12,lslH.
(3) Til en oplpsning af p-nitrobenzyl a-[4-mercapto-3-phenoxyacet-amido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethyliden)acetat (106 mg) i 35 benzen (5 ml) sættes silicagel "F-254" (500 mg), der forhandles af E.
Merck AG, og blandingen rystes ved stuetemperatur i 1 time. Det uop-Ipselige materiale fjernes ved filtrering, og vaskes adskillige gange med chloroform. Filtratet og den vaskede oplpsning forenes og inddampes
DK 156575 B
10 under reduceret tryk til dannelse af p-nitrobenzyl 3-hydroxy-7-phenoxy-acetamido-3-cephem-4-carboxylat (60 mg). Udbytte: 66,3%. Smeltepunkt 95,5-99,5°C.
IR: yCHCl, 3400, 1785, 1685, 1605.
c max J
5 NMR: 8 CDC13 2,03s2H, 4,60s2H, 5,07+5,37ABq(4)2H, 5,37d(4(lH), 5,68dd(9;4)lH, 6,83-8,32m9H.
(4) En oplpsning p-nitrobenzyl a-[4-mercapto-3-phenoxyacetamido-2-10 oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethyliden)-acetat (70 mg) frem- stillet ved fremgangsmàden i eksempel 4(2) i en blanding af methylen-chlorid (2 ml) og methanol (2 ml) omrdres i 3 timer ved stuetemperatur. Reaktionsblandingen hældes pâ isvand og ekstraheres med methylenchlorid. Ekstraktoplpsningen vaskes med vand, terres over magnesiumsulfat og 15 inddampes til dannelse af p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylat (42 mg), der er identisk med produktet fra eksempel 4(3). Udbytte: 70%.
(5) En oplpsning af p-nitrobenzyl a-[4-mercapto-4-phenoxyacetamido-2-20 oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethyliden)acetat fremstillet ved fremgangsmàden i eksempel 4(2) (70 mg) i en blanding af methylenchlorid (2 ml), methanol (2 ml) og 10% saltsyre (0,3 ml) omreres ved stuetemperatur i 2 timer. Reaktionsblandingen hældes pâ isvand og ekstraheres med methylenchlorid. Esktraktoplpsningen vaskes med vand, tprres over 25 magnesiumsulfat og inddampes til dannelse af p-nitrobenzyl 3-oxo-7-phenoxyacetaamidocepham-4-carboxylat (44,5 mg), der er identisk med produktet fra eksempel 4(3), udbytte: 74%.
Eksempel 5 30 (1) En oplpsning af p-nitrobenzyl a-[4-carbobenzoxythio-3-phenoxyacet-amido-2-oxoazetidin-l-yl]-a-[2-brom-l-(morpholin-4-yl)ethyliden]acetat (469 mg) i en blanding af methylenchlorid (4 ml), methanol (4 ml) og 10% saltsyre (0,8 ml) omrpres ved stuetemperatur i 2 timer. Reaktions-35 blandingen fortyndes med isvand og ekstraheres med methylenchlorid. Ekstraktoplpsningen vaskes med vand, t0rres over magneisumsulfat og inddampes til dannelse af p-nitrobenzyl a-[4-carbobenzoxythio-3-phenoxy-acetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethyliden)acetat (426 *- * - L·: ^ ·>.· 11 . DK 15657513 mg). Udbytte: kvantitativt.
IR: rCHCl, 3408, 1788, 1725, 1696, 1615, 1602 cm-1, max 6 5 NMR: δ CDC13 4,27d(3Hz)2H, 4,48s2H, 5,16s2H, 5,22s2H, 5,29mlH, 5,86d(5Hz)lH, 6,74-8,20m9H.
(2) Til en oplpsning af p-nitrobenzyl a-[4-carfoobenzoxythio-3-phenoxy-acetamido-2-oxoazetidin-l-yl]-a-(2-brom-l-hydroxyethyliden)acetat (480 10 mg) i methylenchlorid (5 ml) indeholdende 20% nïtromethan sættes en op-Ipsning af aluminiumchlorid (270 mg) i methylenchlorid indeholdende 20% nitromethan (4 ml), og blandingen omrpres ved s&uetemperatur i 1 time. Reaktionsblandingen hældes pâ fortyndet saltsyre og ekstraheres med methylenchlorid. Ekstraktoplpsningen vaskes med wand, tprres over 15 magnesiumsulfat og inddampes til dannelse af p-nitrobenzyl a-[4-mercapto-3-phenoxyacetanrido-2-oxoazetidin-l-yl]~'a-(2-brom-l-hydroxy-ethyliden)acetat (samme produkt som i eksempel 4((;2)) (376 mg). Udbytte: 99,5%.
20 Eksempel 6
Til en opldsning af p-nitrobenzyl a-[4-cydlmpropylmethoxycarbonyl-thio-3-phenoxyacetamido-2-oxoazetidin-l-yl]-a-[2~brom-l-(morpholin-4-yl)ethyliden]acetat (151 mg) i methylenchlorid (1,5 ml) sættes aluminiumchlorid (142 mg), og blandingen omrdres π 50 minutter under 25 isafkpling. Blandingen fortyndes med isvand (2 ml), omrpres i 5 minutter og omrpres med en blanding (15 ml) af methanol mg methylenchlorid (5:1) efter tilsætning af 10% saltsyre (3 ml) ved stuetemperatur i 80 minutter. Reaktionsblandingen fortyndes med isvand og ekstraheres med chloro-form. Ekstraktoplpsningen vaskes med vand, tprres over magnesiumsulfat 30 og inddampes til dannelse af p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido- 3-cephem-4-carboxylat (63 mg). Udbytte: 63%. Dette produkt er identisk med produktet fra eksempel 4(3) fremstillet ved hydrolyse af 4-morpholinogruppen, der erstattes med en tilsvarende hydroxygruppe.
35 Eksempel 7
Til en oplpsning af p-nitrobenzyl a-[3-phenoxymethyl-7-oxo-4-thia- 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-a-[2-brom-l-(morpholin-4-yl)-ethyliden]acetat (63 mg) i en blanding af methanol (4 ml) og methylen-
12 DK 156575 B
chlorid (3 ml) sættes 10% saltsyre (0,38 ml), og blandingen omr0res ved stuetemperatur i 75 minutter. Reaktionsblandingen hældes pâ isvand og ekstraheres med methylenchlorid. Ekstraktoplpsningen vaskes med vand, tprres over magnesiumsulfat og inddampes til dannelse af p-nitrobenzyl 5 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylat (41 mg). Smeltepunkt 95,5-99,5°C. Udbytte: 82,9%.
Eksempel 8
Til en oplpsning af p-nitrobenzyl a-[3-phenoxymethyl-7-oxo-4-thia-10 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-o:-[2-chlor-l-(morpholin-4-yl)-ethyliden]acetat (106 mg) i en blanding (6 ml) af methanol og methylenchlorid (2:1) sættes 2 N saltsyre (0,93 ml), og blandingen omrpres ved stuetemperatur under argonatmosæfre. Efter 40 minutters forlpb fortyndes reaktionsblandingen med isvand og ekstraheres med methylenchlorid.
15 Ekstraktoplpsningen vaskes med vand, tprres over magnesiumsulfat og inddampes til dannelse af en gui olie (94 mg). Rensning af olien ved kromatografering over tyndtlag pâ silicage! giver fra fraktionen elueret med en blanding af benzen og ethylacetat (1:2) p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylat (20 mg). Udbytte: 22%.
20
Eksempel 9
Til en oplpsning af 2,2,2-trichlorethyl a-[3-benzyl-7-oxo-4-thia- 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-ar-[2-brom-l-(morpholin-4-yT)-ethyliden]acetat (117 mg) i en blanding (4 ml) af methanol og chloroform 25 (1:1) sættes 10% saltsyre (0,5 ml), og blandingen omrpres i 2 timer ved stuetemperatur. Reaktionsblandingen ekstraheres med chloroform. Ekstraktoplpsningen udvaskes med vand, tprres og inddampes. Rensning af den opnâede remanens ved kromatografering over silicagel giver 2,2,2-trichlorethyl 3-oxo-7-phenylacetamido-cepham-4-carboxylat (41 mg).
30 Udbytte: 44%.
NMR: S CDC13 3,33s2H, 3,60s2H, 4,83s2H, 5,00d(5)lH, 5,13-5,70m2H, 6,82d(8)lH, T,25m5H.
Eksempel 10 35 Til en oplpsning af p-nitrobenzyl a-[3-benzyl-7-oxo-4-thia-2,6- di azabi cyclo[3,2,0]hept-2-en-6-yl]-a-[2-brom-l-(morpholi n-4-yl)-ethyliden]acetat (248 mg) i en blanding af methanol (8 ml) og methylenchlorid (6 ml) sættes 10% saltsyre (1,5 ml) under isafkpling, og blan-
DK 156575 B
13 dingen omr0res i 2 timer. Reaktionsblandingen hældes pâ isvand og ekstraheres med methylenchlorid. Ekstraktoplpsningen udvaskes med vand, tprres over magnesiumsulfat og inddampes til dannelse af en remanens (184 mg). Rensning af remanensen ved kromatografering over silicagel 5 indeholdende 10% vand (10 g) giver fra fraktionen elueret med en blan-ding af benzyl og ethylacetat (2:1) p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylat (66 mg). 01ie. Udbytte: 35%.
IR: yCHCl- 3400, 1782, 1678, 1612 cm"1, max ύ 10 NMR: 8 CDC13 3,32d2H, 3,63s2H, 4,97dlH, 5,34dsH, 5,60qlH, 7,3m6H, 7,47-8,30q4H.
Eksempel 11
Til en oplpsning af p-nitrobenzyl a-[3-phenoxymethyl-7-oxo-4-thia-15 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-[2-brom-l-(morpholin-4-yl)-ethyliden]acetat (580 mg) i tetrahydrofuran (10 ml) sættes 60% perchlor-syre vandig oplpsning (1,5 ml) ved -10°C, og blandingen omrpres i 30 minutter. Reaktionsblandingen fortyndes med vand og ekstraheres med methylenchlorid. Ekstraktoplpsningen vaskes med vand, tprres over vand-20 fri natriumsulfat og inddampes til dannelse af et bleggult skum (512 mg). Skummet renses ved kromatografering over silicagel indeholdende 10% vand (50 g) til udskillelse fra fraktioner elueret med en blanding af benzen og ethylacetat (1:1) af p-nitrobenzyl a-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(2-brom-l-hydroxy-25 ethyliden)acetat (skum: 207 mg, udbytte 40%).
IR: yCHCl3 1781 cm"1, max 6 NMR: 8 CDC13 3,75+3,95ABq(10Hz)2H, 4,72s2H, 5,25s2H, 5,73d(4Hz)lH, 6,07d(4Hz)lH, 6,73-8,15m9H, 12,07slH.
30
Eksempel 12
Man oplpser diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-diaza-bicyclo[3,2,0]hept-2-en-6-yl]-a-(l-hydroxyethyliden)acetat (4,84 g) i tetrahydrofuran (60 ml), afk0let til -20°C, tilsætter triethylamin 35 (2,84 ml) under omr0ring, tilsætter dràbevis methansulfonylchlorid (0,82 ml) til den gule opl0sning og lader den reagere i 30 minutter. Til den fremstillede opl0sning af diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-di azabi cyclo[3,2,0]hept-2-en-6-yl]-α-(1-methansulfonyloxyethyli den)- 14 acetat tilsætter man morpholin (0,96 ml) ved -40°C, omrprer i 3,5 timer, tilsætter pyridin (0,77 ml) til den fremstillede oplpsning af diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(morpholinoethyliden)acetat, afkdlet til -40°C, tilsætter 5 brom (0,49 ml) og omrprer i 30 minutter til dannelse af diphenylmethyl a-[3-benzyl-7-oxo-4-thia-2,6-dibicyclo[3,2,0]hept-2-en-6-yl]-a-(2-brom- 1-morpholinoethyliden)acetat. Til denne opldsning tilsætter man drâbevis 5% saltsyre (72 ml) og methanol (60 ml), omrorer i 3 timer ved stuetem-peratur og holder i et kpleskab natten over. Reaktionsblandingen ind-10 dampes til opnâelse af en remanens, der oploses i methylenchlorid, vaskes med vand, torres over natriumsulfat og inddampes. Rensning af den opnâede remanens (5,83 g) ved kromatografering over silicage! inde-holdende 10% vand (150 g) giver ud fra fraktionen elueret med en blan-ding af benzen og ethylacetat (4:1) diphenylmethyl 7-phenylacetamido-3-15 hydroxy-3-cephem-4-carboxylat (3,51 g) ved omkrystallisation fra n-hexan. Smeltepunkt 93-96°C. Udbytte: 70%.
IR: 7CHC13 3410, 1782, 1674, 1610 cm-1, max * NMR: 8 CDC13 3,20s2H, 3,64s2H, 4,97d(4Hz)lH, 5,66dd(9;4Hz)lH, 20 6,77d(9Hz)lH, 6,90slH, 7,35ml5H.
Eksempel 13
Man sætter triethylamin (5,68 ml) til en omrdrt suspension af p-nitrobenzyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-25 yl]-a-[l-hydroxyethyliden)acetat (9,06 g) i tetrahydrofuran (120 ml) under nitrogenatmosfære ved -20°C til dannelse af en klar opl0sning, tilsætter methansulfonylchlorid (1,65 ml) til oplpsningen, omrdrer i 30 minutter ved samme temperatur, tilsætter morpholin (1,92 ml), opvarmer til 0°C, omr0rer i 5 timer, afkdler til -30°C til -35°C. tilsætter 30 pyridin (1,54 ml) og brom (3,12 g), omrprer i 20 minutter, opvarmer til is-vand temperatur, tilsætter 5% saltsyre (144 ml) og methanol (120 ml), omrorer i 3 timer ved stuetemperatur og lader henstâ natten over ved 0°C. Opsamling af de udskilte krystaller i reaktionsblandingen ved filtrering giver p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-35 carboxylat (6,678 g). Smeltepunkt 201°C. Udbytte: 71%.
DK 156575 B
15 (1) Til en t0ris-acetone afkdlet opl0sning af diphenylmethyl a-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiazbicyclo[3,2,0]hept-2-en-6-yl]-a!-(l-chlor-2-propen-2-yl)acetat (160 mg) i en blanding af methylenchlorid (3,2 ml) og methanol (0,3 ml) sættes ozon til reaktionsblanding viser 5 bâl farve. Dernæst renses overskydende ozon med oxygen, blandes med en vandig opldsning af 95% natriumhydrogensulfit (100 mg), opvarmes til stuetemperatur til opldsning af ozonidet. Efter 1,5 time vaskes oplds-ningen med 5% natriumhydrogencarbonat og vand, tprres og koncentreres til fjernelse af methylenchlorid. Den resulterende olie (132 mg) renses 10 over en tyndtlags kromatografisk plade (Merck "60F-254") under anven-delse af benzen og ethylacetat (1:1) som udviklingsvæske til dannelse af diphenylmethyl a-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]-hept-2-en-6-yl]-a-(2-chlor-l-hydroxyethyliden)acetat (44 mg) som glas.
IR: yCHCL· 1784, 1672, 1620, 1603 cm-1.
15 max NMR: 8 CDCI3 4,00s2H, 4,66/4,96ABq(14Hz)2H, 5,23s2H.
(2) Til en isafkdlet opldsning af diphenylmethyl a-[3-phenoxy-methyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-a-(2-chlor-l- 20 hydroxyethyliden)acetat (36 mg) i en blanding af methanol og tetrahydro-furan (1:1) (1,1 ml) sættes 1 N saltsyre (0,39 ml) opvarmet til stuetemperatur, og blandingen omrpres i 1,5 time. Reaktionsblandingen hældes pâ isvand, og ekstraheres med methylenchlorid. Ekstraktopldsningen vaskes med 5% vandig natriumhydrogencarbonatoplpsning og vand, t0rres over 25 natriumsulfat og inddampes. Rensning af den opnâede remanens ved tyndt-lagskromatografi under anvendelse af en blanding af benzen og ethylacetat (3:2) giver diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem- 4-carboxylat (6 mg). Smeltepunkt 125-126°C.
IR: 7CHCI- 3420, 1788, 1738, 1692, 1600 cm'1.
30 max NMR: 8 CDCI3 3,33s2H, 4,54s2H, 5,02d(4Hz)lH, 5,26s2H, 5,62dd(10:4Hz)lH, 6,81-7,45mlOH, ll,5brslH.
Eksempel 14 35 Til en opldsning af p-nitrobenzyl a-[3-benzyl-7-oxo-4-thia-2,6- diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(2-brom-l-dimethylaminoethyliden)-acetat (380 mg) i tetrahydrofuran (10 ml) sættes 5% svovlsyre (2 ml) og methanol (10 ml), og blandingen omrpres i 2 timer ved stuetemperatur.
&
DK 156575 B
16
Reakt1onsblandingen holdes ved 0°C natten over til udskillelse af p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylat (240 mg), smeltepunkt 201°C.
DK 156575 B
17 3 tff
Λ CM
I ». | .—- o '— a ro (Μ Τί H. I—1 "fi!.
» r- σ' » σ* ^ in ro o lo (5 —s n * VD 3 m CD N *» 10 ,> JT ‘Π 8. .SK 3 . 10 3 -i g1 >-H î 8 W « + ►i & m ίσ h ^ τ3 3 , to -M r^- ^ si< o *>
Hmrjo σ1 ro o m cjd-P in 3· m ^*5 a·
ï SS - ro § * -¾ S
i Sî s «'S s ss § en en + <o ό ω _* ko ch θ’ in i> *· Γ" ro i> « m c oo o oo σι · oo m j, (3 h s»* a ^ ^ g *
Hjj_n vo oo σ* h a œ S v a m iû a ro a °o ζ co en en >* en oo en Ό h ·> r-) Γ0Ι Oa 00 I OiN “τ' n in oo eo h vo r- ko co ts* pCj Q %» K ^-v K ^ K — fû
ÛjO' ^ KD ^ ^ 00 - 00 VO
C- ·* Γ- O
*. ». ·*> o*\ — — — lo · .« a a a ^ a > as ·* a a nn cm *σ çn a cm cn s en g enO ό *ΰ en S +g
g f" CO CO 00 CM g ΓΟΟ ko KO
m t> ο io co en ro c\i H
kw V, fck— — ** — — — — mn cMin en r» rom m r*
H
ü » »· » · » » 0 min cm cm en r-' X JH oo oo o oo H e" ko /ro F? m r-· t'» ko t> ko r» «s
J a a 3 H HH HH HH
/ Λ Q U g » « » » » » » » · \vQ p. ο ιη οιη ο oo γόμο
cæ )— o ·· cm co o oo o I en cm H
\ / a sJ*eo sf ko ^ ko I t'- f- vo
\ g H ΓΟΗ COH (Ο H I HHH
0) U
-fi *fi l O CD
/ \ h rM en m io o a) sa i »» i i coio
h g 0 i moi i i cm CM
a m ci i en en i i cm cm a m a a g x o o o o o
1 I I I I
eu eu
CM CM
O O
13 3 ro sj* sy ro h a · m h U mou eM O U U O fΌ a cm CM CM CM a a k k k cj
u u u u I
I I I I
3 II / \ a -à a -à ι i oo o = u o = u a - s a - s oo CM CM 0 = 0 0 = 0 Y/ H a K CM CM /=\ a o o m w \ /) o o o o a! X! Xi Xi βι PU Pu Pu
U
ι a fi a -h eu H ^jcnHcMcoscm a mh n eu
DK 156575B
18
Eksempel 15
Til en oplpsning af p-nitrobenzyl a-[4-methoxymethylthio-3-phen-oxyacetamido-2-oxoazeti d i η-1-y1]-a-(2-brom-1-hydroxyethy1i den)acetat (200 mg) i en blanding af dioxan (5 ml) og éthanol (2 ml) sættes en op-5 lpsning af merkurichlorid (300 mg) i vand (2 ml), og blandingen omrpres i 12 timer ved 50°C. Reaktionsblandingen koncentreres under reduceret tryk, ekstraheres med ethylacetat, vaskes med vand, t0rres og inddampes til dannelse af en remanens, der opl0ses i en blanding af methylen-chlorid og methanol, ledes gennem et lag af silicagel, koncentreres og 10 behandles med ether. Det opnâede skum er p-nitrobenzyl 7-phenoxy-acetamido-3-hydroxy-3-cephem-4-carboxylat, der er identisk med den autentiske prpve.
Eksemoel 16 15 Man sætter til en opl0sning af benzyl ar-[3-benzyl-7-oxo-4-thia- 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-[l-hydroxy-ethyliden)acetat (1,424 g) i tetrahydrofuran (15 ml), triethylamin (0,96 ml) og methan-sulfonylchlorid (0,28 ml) ved -30°C til -20°C, omrprer i 55 minutter til dannelse af benzyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-20 h ept-2-en-6-yl]α-(1-meth an su!fonyloxyethyli den)acetat, tilsætter morpholin (0,40 ml) og omrprer i 5 timer ved -10°C til -3°C til dannelse af benzyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept- 2-en-6-yl]-a-(l-morpholinoethyliden)acetat, afkpler til -35°C til -30°C, tilsætter pyridin (0,27 ml) og brom i carbontetrachlorid (1 25 mmol/ml: 3,2 ml) og omrprer i 20 minutter til dannelse af benzyl a-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(l-morpholino-2-bromethyliden)acetat, tilsætter 5% saltsyre (13 ml) og methanol (50 ml) og holder ved 0°C natten over til hydrolysering og rings!utning giver cephemproduktet. Oplpsningsmidlet fjernes under 30 reduceret tryk, og den tilbageblevne opldsning ekstraheres med ethylacetat. Ekstraktoplpsningen vaskes med mættet saltoplpsning og vand, tprres over natriumsulfat og renses ved kromatografering over silicagel indeholdende 10% vand. Fraktionerne, der indeholder produktet, forenes og inddampes. Omkrystallisation af remanensen fra en blanding af 35 methanol, ether og hexan giver benzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylat. Smeltepunkt 149-162°C.
NMR: δ CDC13 3,28d2H, 3,63s2H, 4,98s(5Hz)1H, 5,30s2H, 5,60dd (5;8Hz)lH, 6,37d(8Hz)lH, 7,4+7,4slOH, ll,6brslH.
DK 156575 B
19 IR: yCHCL 3420, 1785, 1680, 1615 cm"1, max ύ
Eksempel 17 5 (i) Til en opl0sning af benzyl a-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-isopropenylacetat (4,22 g) i dichlormethan og methanol (5:1) indfpres ozoniseret oxygen, indtil op-Idsningens blâ farve ikke udtoner. Dernæst blandes opldsningen med 10 dimethylsulfid, vaskes med vand, tdrres og koncentreres. Den opnâede remanens renses ved kromatografering over silicagel indeholdende 10% vand til dannelse af benzyl ûr-[3-phenoxymethyl-7-oxo-4-thia-2,6-diaza-bicyclo[3,2,0]hept-2-en-6-yl]-a-(l-hydroxyethyliden)acetat (2,98 g, 70,28%).
15 (i i) Man tilsætter triethylamin (1,42 ml) og methansulfonylchlorid (0,41 ml) til en opl0sning af benzyl a-[3-phenoxymethyl-7-oxo-4-thia- l,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-a-(l-hydrqxyethyliden)acetat (2,12 g) i tetrahydrofuran (30 ml) ved -30°C, omrqrer i 70 minutter 20 til dannelse af benzyl a-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo-[3,2,0]hept-2-en-6-yl]-a-(methansulfonyloxyethyli den)acetat, tilsætter morpholin (0,6 ml) og omrqrer i 4 timer 50 minutter ved 0°C til dannelse af o:-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept- 2-en-6-yl]-a-(l-morpholinoethyliden)acetat, afkplier til -50°C, til-25 sætter pyridin (0,385 ml) og brom (0,25 ml) og omrorer i 30 minutter til dannelse af benzyl a-[3-phenoxymethyl-7-oxo-4-thia-2,6-bicyclo[3,2,0]-hept-2-en-6-yl]-a-(l-morpholino-2-bromethyliden)acetat, tilsætter 5% saltsyre (36 ml), methanol (42,5 ml) og tetrahydrofuran (12,5 ml) til dannelse af en klar opldsning. Opl0sningen koncentreres, den resul-30 terende opldsning ekstraheres med ethylacetat, vaskes med mættet salt-opldsning, tprres over natriumsulfat og koncentreres til dannelse af en remanens (2,31 g). Rensning af remanensen ved kromatografering over silicagel indeholdende 10% vand giver benzyl 7£-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylat (1,11 g), smeltepunkt 126-127°C.
35
Claims (5)
1. Fremgangsmàde til fremstilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxylsyrederivater med den almene formel 5 . 1 -, Ann —r ί 2^—r Ί I eller ^ | J Ύ^οη 0^-ΗνΛ° 10 cox cox hvor 1 a2> 15 a betegner phthalimido, phenylacetamido eller phenoxyacetamido, og X betegner hydroxy eller en carboxylbeskyttende gruppe i form af methoxy, 2,2,2-trichlorethoxy, p-nitrobenzyloxy, diphenylmethoxy eller benzyloxy,
20 KENDETEGNET ved, at man ringslutter en forbindelse med den almene formel SH 25 j—v<cvai 0 | cox 30 hvor i* A2 , 1' A A1 A 2 Λ har den ovenfor anfprte for A anfprte betydning eller kan sammen med -SH-gruppen udgpre en gruppe i form af -N=C-S- eller
35 CH2C6H5 -N=C-S- , tH20C6H5 X har den ovenfor anfprte betydning, Hal betegner chlor eller brom, og DK 156575 B Y betegner hydroxy, morpholin-4-yl, piperidin-l-yl eller dimethylamino, ved behandling med syre, base eller oplpsningsmiddel, om npdvendigt i nærvær af en katalysator.
2. Fremgangsmâde ifpige krav 1, KENDETEGNET ved, at der som syre 5 anvendes saltsyre eller vandholdig svovlsyre.
3. Fremgangsmâde ifpige krav 1, KENDETEGNET ved, at basen er en svag base.
4. Fremgangsmâde ifpige krav 1, KENDETEGNET ved, at oplpsnings-midlet er et amid, en alkohol eller et vandigt oplpsningsmiddel.
5. Fremgangsmâde ifplge krav 1, KENDETEGNET ved, at der som kata lysator anvendes en neutral eller basisk silicagel, aluminiumoxid, diatoméjord eller florisil. 15 20 25 4
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK76882A DK76882A (da) | 1975-02-17 | 1982-02-22 | Mellemprodukter til dannelse af en sephemring og fremgangsmaader til fremstilling deraf |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1961275 | 1975-02-17 | ||
| JP50019612A JPS5198265A (da) | 1975-02-17 | 1975-02-17 | |
| JP50022229A JPS51105051A (da) | 1975-02-21 | 1975-02-21 | |
| JP2222975 | 1975-02-21 | ||
| JP2845275 | 1975-03-07 | ||
| JP50028452A JPS609516B2 (ja) | 1975-03-07 | 1975-03-07 | セフエム骨格の環化製法 |
| JP3380875 | 1975-03-20 | ||
| JP50033808A JPS5817460B2 (ja) | 1975-03-20 | 1975-03-20 | チアゾリンカンノ カイカンホウホウ |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK61976A DK61976A (da) | 1976-08-18 |
| DK156575B true DK156575B (da) | 1989-09-11 |
| DK156575C DK156575C (da) | 1990-02-05 |
Family
ID=27457226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK061976A DK156575C (da) | 1975-02-17 | 1976-02-16 | Fremgangsmaade til fremstilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxylsyrederivater |
Country Status (24)
| Country | Link |
|---|---|
| US (4) | US4079181A (da) |
| AR (1) | AR225878A1 (da) |
| AU (1) | AU508160B2 (da) |
| BE (1) | BE838656A (da) |
| BG (5) | BG25076A3 (da) |
| CA (5) | CA1136132A (da) |
| CH (5) | CH627160A5 (da) |
| DD (5) | DD127901A5 (da) |
| DE (1) | DE2606278A1 (da) |
| DK (1) | DK156575C (da) |
| ES (1) | ES445250A1 (da) |
| FR (1) | FR2334669A1 (da) |
| GB (3) | GB1548641A (da) |
| GR (1) | GR60437B (da) |
| IE (1) | IE42479B1 (da) |
| IL (5) | IL49048A (da) |
| MX (1) | MX3818E (da) |
| NL (1) | NL190721C (da) |
| NZ (1) | NZ180037A (da) |
| PH (1) | PH18022A (da) |
| PT (1) | PT64806B (da) |
| RO (4) | RO68460A (da) |
| SE (4) | SE421691B (da) |
| YU (5) | YU40272B (da) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1136132A (en) * | 1975-02-17 | 1982-11-23 | Teruji Tsuji | Cyclization to form cephem ring and intermediates therefor |
| AT342197B (de) * | 1975-02-20 | 1978-03-28 | Ciba Geigy Ag | Neues verfahren zur herstellung von 3-cephemverbindungen |
| US4550162A (en) * | 1975-02-20 | 1985-10-29 | Ciba-Geigy Corporation | Process for the manufacture of enol derivatives |
| US4579684A (en) * | 1975-02-20 | 1986-04-01 | Ciba-Geigy Corporation | Process for the manufacture of enol derivatives |
| GB1543048A (en) * | 1976-02-04 | 1979-03-28 | Beecham Group Ltd | 4-mercapto-3-phenoxyacetamido-2-azetidinone |
| US4271305A (en) * | 1979-02-01 | 1981-06-02 | Eli Lilly And Company | Thiazolinoazetidinones and process therefor |
| JPS55133355A (en) * | 1979-04-03 | 1980-10-17 | Shionogi & Co Ltd | Inversion of 3-amino group of beta-lactam ring |
| US4518531A (en) * | 1979-04-30 | 1985-05-21 | Eli Lilly And Company | Allylic chlorination process and compounds prepared thereby |
| US4430268A (en) | 1979-04-30 | 1984-02-07 | Eli Lilly And Company | Allylic chlorination process |
| CA1145339A (en) * | 1979-04-30 | 1983-04-26 | Eli Lilly And Company | Allylic chlorination process and compounds prepared thereby |
| CA1148938A (en) * | 1979-05-08 | 1983-06-28 | John R. Corfield | Preparation of cephalosporins and intermediates employed therein |
| US4237279A (en) * | 1979-07-27 | 1980-12-02 | Eli Lilly And Company | Crystalline 3-hydroxycephalosporin solvates |
| DE3265390D1 (en) * | 1981-05-19 | 1985-09-19 | Ciba Geigy Ag | Process for the preparation of 4-thio-azetidinone compounds |
| FR2511376A1 (fr) * | 1981-08-17 | 1983-02-18 | Rhone Poulenc Sante | Nouveaux derives de la cephalosporine et leur prepration |
| JPS5832884A (ja) * | 1981-08-20 | 1983-02-25 | Otsuka Chem Co Ltd | ３−エキソメチレンセフアム誘導体の製造方法 |
| JPS59101485A (ja) * | 1982-11-29 | 1984-06-12 | Otsuka Chem Co Ltd | アセチジノン誘導体 |
| US4533497A (en) * | 1982-12-27 | 1985-08-06 | Eli Lilly And Company | N-ethylidene azetidinones |
| KR850000291B1 (ko) * | 1983-02-07 | 1985-03-16 | 한국과학기술원 | 3-메틸렌 세팜 화합물의 제조방법 |
| JPS59164771A (ja) * | 1983-03-10 | 1984-09-17 | Otsuka Chem Co Ltd | 塩素化アゼチジノン誘導体の製造方法 |
| EP0133670A3 (de) * | 1983-08-09 | 1985-12-18 | Bayer Ag | Verfahren zur Herstellung von 7-Acylamino-3-hydrocy-cephem-4-carbonsäuren und 7-Acylamino-3-hydroxy-1-de-thia-1-oxacephem-4-carbonsäuren |
| DE3725375A1 (de) * | 1987-07-31 | 1989-02-09 | Bayer Ag | Stabile oxapenem-3-carbonsaeuren |
| JP3007986B2 (ja) * | 1990-03-02 | 2000-02-14 | 大塚化学株式会社 | β―ラクタム誘導体の製法 |
| US5206361A (en) * | 1990-03-08 | 1993-04-27 | Otsuka Kagaku Kabushiki Kaisha | Thiazolinoazetidinone derivative |
| US5604222A (en) * | 1993-12-27 | 1997-02-18 | Lupin Laboratories, Ltd. | Method for the preparation of 2-chloro sulfinyl azetidinones |
| US5578721A (en) * | 1994-07-11 | 1996-11-26 | Lupin Laboratories Limited | Process for preparation of 3-exomethylene cepham sulfoxide esters |
| IT1277048B1 (it) * | 1995-12-06 | 1997-11-04 | 3 Exo S R L | Procedimento per la preparazione di cefalosporine attraverso ciclizzazione riduttiva dicarbonilica per trattamento con |
| US5986091A (en) * | 1996-03-13 | 1999-11-16 | Otsuka Kagaku Kabushiki Kaisha | Process for preparation of β-lactam compounds |
| CA2935651A1 (en) | 2007-10-09 | 2009-04-16 | Gladius Pharmaceuticals Corporation | Broad spectrum beta-lactamase inhibitors |
| CN101525341B (zh) * | 2009-04-01 | 2012-07-04 | 浙江东邦药业有限公司 | 一种3-羟基头孢化合物的制备方法 |
| EP3441071A1 (en) | 2013-03-12 | 2019-02-13 | Gladius Pharmaceuticals Corporation | Derivatized cephalosporins |
| CN108727409A (zh) * | 2017-04-24 | 2018-11-02 | 浙江省化工研究院有限公司 | 一种3-羟基头孢菌素的制备方法 |
| CN118993936A (zh) * | 2020-04-17 | 2024-11-22 | 帝斯曼知识产权资产管理有限公司 | 用于制备取代的烯胺化合物的方法 |
| CN111647638A (zh) * | 2020-04-17 | 2020-09-11 | 江苏正泰药业有限公司 | 一种7-anca的制备工艺 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK68976A (da) * | 1975-02-20 | 1976-08-21 | Ciba Geigy Ag | Fremgangsmade til fremstilling af enolderivater |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3862164A (en) * | 1971-02-03 | 1975-01-21 | Lilly Co Eli | Thiazolidine azetidinones |
| GB1457421A (en) * | 1973-01-04 | 1976-12-01 | Glaxo Lab Ltd | Cepham derivatives |
| AU498131B2 (en) * | 1974-02-26 | 1979-02-15 | Ciba-Geigy Ag | Production of cephems by cyclization |
| JPS5188955A (da) * | 1975-01-30 | 1976-08-04 | ||
| CA1136132A (en) * | 1975-02-17 | 1982-11-23 | Teruji Tsuji | Cyclization to form cephem ring and intermediates therefor |
| US4147864A (en) * | 1975-02-20 | 1979-04-03 | Ciba-Geigy Corporation | Process for the manufacture of 7β-amino-3-cephem-3-ol-4 carboxylic acid compounds |
| JPS5214789A (en) * | 1975-07-22 | 1977-02-03 | Shionogi & Co Ltd | Process for preparing 3-substiuted cephem compounds by ring closure |
| US4008230A (en) * | 1975-10-29 | 1977-02-15 | Eli Lilly And Company | Process for preparing 3-hydroxy cephalosporins |
| JPS6019315B2 (ja) * | 1976-01-23 | 1985-05-15 | 塩野義製薬株式会社 | アゼチジノン化合物 |
| GB1529913A (en) * | 1976-02-04 | 1978-10-25 | Beecham Group Ltd | Beta-lactam compounds |
| US4264597A (en) * | 1978-06-06 | 1981-04-28 | Masashi Hashimoto | Cephalosporin analogues and processes for the preparation thereof |
-
1976
- 1976-02-09 CA CA000245317A patent/CA1136132A/en not_active Expired
- 1976-02-16 IL IL49048A patent/IL49048A/xx unknown
- 1976-02-16 SE SE7601715A patent/SE421691B/xx not_active IP Right Cessation
- 1976-02-16 PT PT64806A patent/PT64806B/pt unknown
- 1976-02-16 DK DK061976A patent/DK156575C/da active
- 1976-02-17 DD DD7600195997A patent/DD127901A5/xx unknown
- 1976-02-17 BG BG034108A patent/BG25076A3/xx unknown
- 1976-02-17 NZ NZ180037A patent/NZ180037A/xx unknown
- 1976-02-17 YU YU384/76A patent/YU40272B/xx unknown
- 1976-02-17 AU AU11181/76A patent/AU508160B2/en not_active Expired
- 1976-02-17 IE IE313/76A patent/IE42479B1/en unknown
- 1976-02-17 BE BE164401A patent/BE838656A/xx not_active IP Right Cessation
- 1976-02-17 DD DD7600195993A patent/DD127899A5/xx unknown
- 1976-02-17 CH CH191876A patent/CH627160A5/de not_active IP Right Cessation
- 1976-02-17 NL NL7601613A patent/NL190721C/xx not_active IP Right Cessation
- 1976-02-17 BG BG034106A patent/BG25216A3/xx unknown
- 1976-02-17 DD DD7600195998A patent/DD127902A5/xx unknown
- 1976-02-17 US US05/658,665 patent/US4079181A/en not_active Expired - Lifetime
- 1976-02-17 GB GB6187/76A patent/GB1548641A/en not_active Expired
- 1976-02-17 RO RO7684836A patent/RO68460A/ro unknown
- 1976-02-17 BG BG032385A patent/BG24948A3/xx unknown
- 1976-02-17 RO RO7694587A patent/RO74958A/ro unknown
- 1976-02-17 AR AR262283A patent/AR225878A1/es active
- 1976-02-17 GR GR50078A patent/GR60437B/el unknown
- 1976-02-17 MX MX76898U patent/MX3818E/es unknown
- 1976-02-17 BG BG034107A patent/BG27557A4/xx unknown
- 1976-02-17 DD DD191283A patent/DD124986A5/xx unknown
- 1976-02-17 BG BG034105A patent/BG24949A3/xx unknown
- 1976-02-17 DE DE19762606278 patent/DE2606278A1/de active Granted
- 1976-02-17 ES ES445250A patent/ES445250A1/es not_active Expired
- 1976-02-17 RO RO7694586A patent/RO75006A/ro unknown
- 1976-02-17 FR FR7604318A patent/FR2334669A1/fr active Granted
- 1976-02-17 GB GB41074/78A patent/GB1548643A/en not_active Expired
- 1976-02-17 DD DD7600195995A patent/DD127900A5/xx unknown
- 1976-02-17 GB GB41073/78A patent/GB1548642A/en not_active Expired
- 1976-03-03 PH PH18164A patent/PH18022A/en unknown
- 1976-07-17 RO RO197694535A patent/RO74936A/ro unknown
-
1977
- 1977-12-01 US US05/856,806 patent/US4160085A/en not_active Expired - Lifetime
-
1978
- 1978-11-26 IL IL56050A patent/IL56050A0/xx not_active IP Right Cessation
- 1978-11-26 IL IL56049A patent/IL56049A0/xx not_active IP Right Cessation
-
1979
- 1979-05-28 IL IL57418A patent/IL57418A0/xx not_active IP Right Cessation
- 1979-06-11 IL IL57541A patent/IL57541A0/xx unknown
- 1979-09-20 SE SE7907813A patent/SE434637B/sv not_active IP Right Cessation
- 1979-09-20 SE SE7907812A patent/SE434950B/sv not_active IP Right Cessation
- 1979-09-20 SE SE7907811A patent/SE444811B/sv not_active IP Right Cessation
- 1979-10-19 CA CA000337973A patent/CA1144924A/en not_active Expired
- 1979-10-19 CA CA000337975A patent/CA1095026A/en not_active Expired
- 1979-10-19 CA CA000337974A patent/CA1077936A/en not_active Expired
- 1979-10-22 CA CA000338132A patent/CA1132547A/en not_active Expired
-
1980
- 1980-01-30 CH CH75180A patent/CH628031A5/de not_active IP Right Cessation
- 1980-01-30 CH CH74880A patent/CH630074A5/de not_active IP Right Cessation
- 1980-01-30 CH CH74980A patent/CH634579A5/de not_active IP Right Cessation
- 1980-01-30 CH CH75080A patent/CH628030A5/de not_active IP Right Cessation
- 1980-02-27 US US06/125,233 patent/US4346218A/en not_active Expired - Lifetime
-
1982
- 1982-01-11 US US06/338,651 patent/US4440683A/en not_active Expired - Lifetime
- 1982-08-10 YU YU1739/82A patent/YU40412B/xx unknown
- 1982-08-10 YU YU1738/82A patent/YU40411B/xx unknown
- 1982-08-10 YU YU1742/82A patent/YU40414B/xx unknown
- 1982-08-10 YU YU1741/82A patent/YU40413B/xx unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK68976A (da) * | 1975-02-20 | 1976-08-21 | Ciba Geigy Ag | Fremgangsmade til fremstilling af enolderivater |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK156575B (da) | Fremgangsmaade til fremstilling af 3-hydroxy-3-cephem- eller 3-oxo-cepham-carboxylsyrederivater | |
| US4071512A (en) | Preparation of 1-oxapenicillins and intermediates therefor | |
| CA1090806A (en) | Oxazolines | |
| US4081440A (en) | Sulfinyl halides and their preparation from penicillin sulfoxides | |
| US4060688A (en) | Cephalosporin intermediates | |
| US4031084A (en) | Process for cephalosporin antibiotic intermediates | |
| US4159266A (en) | Method of preparation of 3-methylenecephams | |
| IL44361A (en) | Process for preparing 3-fluorocephalosporins | |
| HU179966B (en) | Process for preparing 3-exomethylene-cefem-sulphoxide derivatives from 6-acylamido-penam-sulphoxides | |
| US4048162A (en) | Process for preparing 3-hydroxy cephalosporins | |
| US4103086A (en) | 8-Oxo-4-thia-1-azabicyclo (4.2.0)-oct-2-ene derivatives | |
| JPS609514B2 (ja) | ７−アミノ−３′−ノルセファロスポラン酸類 | |
| JPS6114153B2 (da) | ||
| US3985737A (en) | 3-Sulfonate esters of cephalosporin | |
| CS196420B2 (en) | Method of producing 1-dethia-1-oxacephamderivatives | |
| KR810000716B1 (ko) | 1-옥사데티아 세팜 화합물의 제조방법 | |
| KR970001531B1 (ko) | 화합물의 제조 방법 | |
| HU177431B (en) | Process for producing 3-methylene-cephame-sulfoxides | |
| PL114624B1 (en) | Process for preparing novel cephem derivatives | |
| EP0759437B1 (en) | Processes for the production of 2-isocephem derivatives | |
| US4099000A (en) | Process for preparing di-7-azido cephalosporin compounds | |
| KR810001820B1 (ko) | 세펨 화합물 유도체의 제조 방법 | |
| PL111107B1 (en) | Process for the praparation of novel derivatives of beta-lactam | |
| JPH0613528B2 (ja) | セフエム化合物のメトキシ化法 | |
| KR810000713B1 (ko) | 1-옥사데티아세팜 화합물의 제조방법 |