KR830000710B1 - Process for preparing cefem compound - Google Patents
Process for preparing cefem compound Download PDFInfo
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- KR830000710B1 KR830000710B1 KR1019790002615A KR790002615A KR830000710B1 KR 830000710 B1 KR830000710 B1 KR 830000710B1 KR 1019790002615 A KR1019790002615 A KR 1019790002615A KR 790002615 A KR790002615 A KR 790002615A KR 830000710 B1 KR830000710 B1 KR 830000710B1
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- 150000001875 compounds Chemical class 0.000 title claims description 38
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- -1 amine salt Chemical class 0.000 claims description 101
- 239000002253 acid Substances 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 238000004517 catalytic hydrocracking Methods 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000001477 organic nitrogen group Chemical group 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 229940086542 triethylamine Drugs 0.000 description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 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 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 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 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 150000005332 diethylamines Chemical class 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- KDISMIMTGUMORD-UHFFFAOYSA-N 1-acetylpiperidine Chemical compound CC(=O)N1CCCCC1 KDISMIMTGUMORD-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000001301 oxygen Chemical group 0.000 description 6
- HKLBEHRJWPWLOB-UHFFFAOYSA-N albene Chemical compound C1C2CCC1C1(C)C2(C)C=CC1 HKLBEHRJWPWLOB-UHFFFAOYSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical class CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- XNVRKLCQBZTGNA-UHFFFAOYSA-N ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CSC(N)=N1 XNVRKLCQBZTGNA-UHFFFAOYSA-N 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 description 2
- SVHFBAAZRDCASE-UHFFFAOYSA-N 2-(2-methylphenyl)propan-2-amine Chemical class CC1=CC=CC=C1C(C)(C)N SVHFBAAZRDCASE-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 2
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N n-cyclohexyl-n-ethylcyclohexanamine Chemical class C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UWHSPZZUAYSGTB-UHFFFAOYSA-N 1,1,3,3-tetraethylurea Chemical compound CCN(CC)C(=O)N(CC)CC UWHSPZZUAYSGTB-UHFFFAOYSA-N 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 1
- SPJSKGPKMAWDSM-UHFFFAOYSA-N 1-morpholin-4-ylpyrrolidin-2-one Chemical compound O=C1CCCN1N1CCOCC1 SPJSKGPKMAWDSM-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- QANVSPFERJBPTO-UHFFFAOYSA-N 1-piperidin-1-ylbutan-1-one Chemical compound CCCC(=O)N1CCCCC1 QANVSPFERJBPTO-UHFFFAOYSA-N 0.000 description 1
- MTJVUMGKHCIMJL-UHFFFAOYSA-N 1-piperidin-1-ylpropan-1-one Chemical compound CCC(=O)N1CCCCC1 MTJVUMGKHCIMJL-UHFFFAOYSA-N 0.000 description 1
- QEAWNPFOQLJDAY-UHFFFAOYSA-N 1-pyrrolidin-1-ylbutan-1-one Chemical compound CCCC(=O)N1CCCC1 QEAWNPFOQLJDAY-UHFFFAOYSA-N 0.000 description 1
- NLARCUDOUOQRPB-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- QVEMWYGBLHQEAK-UHFFFAOYSA-N 2-ethylbutanamide Chemical compound CCC(CC)C(N)=O QVEMWYGBLHQEAK-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ALTFIMDUFNNVBD-UHFFFAOYSA-N 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid Chemical compound OC(=O)C(=O)C1=CSC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 ALTFIMDUFNNVBD-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)C(SC(*)=C(C)C(O)=N)=CC Chemical compound CC(C)C(SC(*)=C(C)C(O)=N)=CC 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000831576 Chlorophthalmus acutifrons Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HPMHJECNIQUNKV-UHFFFAOYSA-N [chloro(diphenyl)methoxy]benzene Chemical compound O(C1=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)Cl HPMHJECNIQUNKV-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005138 alkoxysulfonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000005111 carboxyalkoxy group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- ZKZLGKUOFCFROA-UHFFFAOYSA-N ethyl 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate Chemical compound CCOC(=O)C(=O)C1=CSC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 ZKZLGKUOFCFROA-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- CDQSTBHGKNNPSY-UHFFFAOYSA-N n,n-diethylbutanamide Chemical compound CCCC(=O)N(CC)CC CDQSTBHGKNNPSY-UHFFFAOYSA-N 0.000 description 1
- YKOQQFDCCBKROY-UHFFFAOYSA-N n,n-diethylpropanamide Chemical compound CCN(CC)C(=O)CC YKOQQFDCCBKROY-UHFFFAOYSA-N 0.000 description 1
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical group C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 항생제로 유효한 다음 일반식(I)의 세펨화합물의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of cefem compounds of the general formula (I) which are effective as antibiotics.
상기 일반식에서In the above general formula
A는 수소, 1가의 알카리금속 또는 알카리토금속, 또는 유기 질소염기 또는 에스테르 그룹이고,A is hydrogen, a monovalent alkali metal or alkaline earth metal, or an organic nitrogen base or ester group,
R1은 수소, 임의로 치환된 알킬, 알케닐, 알키닐, 사이클로알킬, 아실, 아릴, 아릴설포닐, 알킬설포닐 또는 헤테로 사이클그룹이고,R 1 is hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl or hetero cycle group,
R2는 탄소수 l개 내지 4개의 알킬, 아릴 또는 임의로 보호된 아미노 기로 치환된 푸릴, 티아졸릴 또는 페닐이고,R 2 is furyl, thiazolyl or phenyl substituted with an alkyl, aryl or optionally protected amino group of 1 to 4 carbon atoms,
B는 저급알콕시, 메틸, 아세톡시메틸, 카바모일메틸, 할로겐 또는 Het가 1내지 4의 이중원자를 함유하는 5-내지 6-원환을 나타내는 -CH2S-Het이고 n는 0, 1 또는 2이며,B is lower alkoxy, methyl, acetoxymethyl, carbamoylmethyl, halogen or -CH 2 S-Het which represents a 5- to 6-membered ring containing 1 to 4 double atoms and n is 0, 1 or 2 Is,
R1O 기룹은 syn-위치에 존재한다.The R 1 O group is at the syn-position.
일반식(I)의 화합물이 있어서, R1이 전술한 바와 같은 다음 일반식의 옥스이미노에테르그룹은 syn-또는 anti 형태로 존재할 수 있으며, 이 두 가지 형태화합물의 생물학적 활성이 서로 다르다는 것이 밝혀져 왔다.In the presence of compounds of formula (I), it has been found that the oximinoether groups of the following general formula, wherein R 1 is as described above, may exist in syn- or anti form, and the biological activities of these two form compounds differ from one another. .
이 syn-옥시이미노에테르 화합물은 여러가지 반응조건하에서 쉽게 anti- 화합물로 전환될 수 있으며 따라서 이와 같은 이성화를 피하고 균일한 syn-생성물을 얻기 위해서는 특별한 방법이 필요하게 된다.This syn-oxyiminoether compound can be easily converted to an anti-compound under various reaction conditions, and thus a special method is necessary to avoid such isomerization and to obtain a uniform syn-product.
예를들어 DOS 7, 02, 501에는 R1O 그룹이 syn-위치로 결합된 일반식(I)의 화합물을 2-알콕시 이미노아세트산의 대칭형 무수물과 아실화를 시켜서 얻을수 있는 방법이 기록되어 있다. 그러나 이 방법은 2-알콕시 이미노아세트산을 아실화될 아미노기로부터 계산된 양의 두배를 사용해야하는 단점이 있다.For example, DOS 7, 02, and 501 describe a method by which a compound of general formula (I) in which the R 1 O group is bonded at the syn-position is obtained by acylation with a symmetric anhydride of 2-alkoxy iminoacetic acid. . However, this method has the disadvantage of using twice the amount calculated from the amino group to be acylated with 2-alkoxy iminoacetic acid.
DOS 22, 23, 375 및 22, 65, 234호에 의하면 상응하는 카복실산을 옥살릴염화물과 촉매량의 디메틸포름아미노를 사용하여 반응시키거나 유리산을 오염화인과 반응시키면 일반식(Ⅱ)의 산염화물이 이의 anti-화합물과의 혼합물의 형태로 얻어질 수 있다. 아미노 티아졸릴 화합물에 대해서는, DOS 25, 56, 736호에 따르면 산염화물 형성제로서 옥살릴염화물을 사용하였을때 그 나트륨염은 NMR 스팩트럼에서 anti-형태로 존재 하는 화합물을 부여한다.According to DOS 22, 23, 375 and 22, 65, 234, when the corresponding carboxylic acid is reacted with oxalyl chloride and catalytic amount of dimethylformamino or free acid with phosphorus pentachloride, the acid chloride of formula (II) It can be obtained in the form of a mixture with its anti-compound. For amino thiazolyl compounds, according to DOS 25, 56 and 736, when oxalyl chloride is used as the acid chloride former, the sodium salt gives the compound present in anti-form in the NMR spectrum.
syn H 6. 75(D2O) DOS 27, 02, 501syn H 6. 75 (D 2 O) DOS 27, 02, 501
anti H 7. 58(D2O) DOS 25, 56, 736anti H 7. 58 (D 2 O) DOS 25, 56, 736
문헌에 기술된 바와 같이, 디메틸포름아미노 및 옥시염화인, 티오닐클로라이드 또는 포스겐을 사용하였을때, 7-아미노-세펨화합물을 2-(2-아미노-4-티아졸릴)-알콕시이미노아세트산으로 아실화시키는 반응은 매우 유리하게 이루어진다.As described in the literature, when using dimethylformamino and phosphorus oxychloride, thionylchloride or phosgene, the 7-amino-cefemyl is acyl as 2- (2-amino-4-thiazolyl) -alkoxyiminoacetic acid. The reaction to oxidize is very advantageous.
본 발명의 제조방법에 따른 생성물은 중정도의 수율을 가지며 어느정도 불순하므로 크로마토그라피로 정제하여 사용한다. 한 가지 염두에 둘것은 디메틸포름아미드는 티오닐클로라이드와 작용하여 생긴 화합물이 매우 불안정하며 흔적량의 Fe 3+에 의해서도 쉽게 분해 해버리는 단점을 가지고 있다.The product according to the preparation method of the present invention has a medium yield and is somewhat impure, so that the product is purified by chromatography. The two-dimethylformamide is very unstable compound is caused to act with thionyl chloride to one mind and re haebeo easily decomposed by the F e 3+ of the trace has a disadvantage.
그러나 본 발명의 제조방법에 따르면 놀라웁게도 하기 일반식(Ⅳ)의 화합물을 사용할 때 산할라이드 형성제로서 포스겐, 옥살릴클로라이드 오염화인이나 옥시염화인을 첨가하면 전술한 생성물보다 훨씬 안정성이 있는 화합물이 얻어진다. 일반식(Ⅱ)의 카복실산과 반응시킬때 이들 반응생성물은 활성 착화합물을 형성하며 이착화합물은 다시 일반식(Ⅲ)의 7-아미노세펨 화합물과 작용하여 고수율, 고순도의 일반식(Ⅰ)의 화합물을 생성한다.However, according to the preparation method of the present invention, surprisingly, when phosgene, phosphorus oxalyl chloride or phosphorus oxychloride is added as an acid halide forming agent when using the compound of formula (IV), the compound is much more stable than the above-mentioned product. Is obtained. When reacted with the carboxylic acid of formula (II), these reaction products form an active complex, and the decomposed compound acts again with the 7-aminocefe compound of formula (III) to yield a high yield, high purity compound of formula (I). Create
더우기 2-옥시이미노에텔그룹의 syn-체를 anti-체로 재조정하지 않고서도 아실화반응이 일어날 수 있다는 놀라운 장점을 지니고 있다.Furthermore, it has the surprising advantage that acylation can occur without the readjustment of the 2-oxyiminoether group syn-body to anti-body.
본 발명에 따라, 일반식(I) 화합물의 제법은 다음 일반식(Ⅱ)의 화합물 또는 이의 염을 0. 1내지 3. 0몰의 다음 일반식(Ⅳ)의 화합물 존재하에 산할라이드 형성제와 반응시킨 다음 생성된 착화합물을 다음 알반식(Ⅲ)의 세펨카복실산을 아민염 형태로, 산가수분해 또는 수첨분해에 의해 임의로 분리시킬 수 있는 에스테르 형태로, 또는 실릴에스테르 형태로 반응시키고 필요에 따라 수득된 일반식(I)의 세펨 카복실산의 카복실 그룹을 전술한 A에 언급된 다른 기중의 하나로 전환시킨다.According to the present invention, the preparation of the compound of general formula (I) is carried out by preparing a compound of the following general formula (II) or a salt thereof with an acid halide forming agent in the presence of 0.1-3. After the reaction, the resulting complex compound is reacted in the form of an ester, which can be optionally separated by acid hydrolysis or hydrocracking of the following albene (III) cefecarboxylic acid in the form of an amine, or in the form of silyl ester, if necessary. The carboxyl group of cefem carboxylic acid of formula (I) is converted to one of the other groups mentioned in A above.
상기 일반식에 있어서In the above general formula
R3, R4및 R5는 탄소수 1내지 6의 동일하거나 다른 알킬그룹이고R 3 , R 4 and R 5 are the same or different alkyl groups of 1 to 6 carbon atoms
R3및 R4, 또는 R3및 R5는 함께 이종원자가 임의로 개입된 환을 형성하며, 이때 R5는 임의로 디알킬아미노 (여기서 알킬그룹은 각기 1내지 6의 탄소원자를 함유할 수 있고 이종원자가 임의로 개입된 환을 형성할 수 있다)를 나타낸다.R 3 and R 4 , or R 3 and R 5 together form a ring which is optionally interrupted by a heteroatom, wherein R 5 is optionally dialkylamino, wherein the alkyl group may contain 1 to 6 carbon atoms each Can optionally form an intervening ring).
일반식(I)의 세펨 화합물에 있어서, A는 수소, 알칼리금속, 특히 나트륨, 알카리토금속, 특히 칼슘, 유기질소염기, 특히 디에틸아민, 디에탄올아민이나 프로카인을 나타내며; 3급부틸 에스테르와 같은 저분자알킬에스테르, 비스-P-메톡시 벤즈히드릴에스테르와 같은 임의로 치환된 벤즈히드릴 에스테르, P-메톡시벤질에스테르, 프탈릴에스테르, 아세톡시메틸에스테르 또는 피발로일옥시메틸에스테르와 같은 저분자 알콕시그룹을 함유하는 P-알콕시-벤질에스테르를 나타낸다.In the cefe compound of formula (I), A represents hydrogen, an alkali metal, in particular sodium, an alkaline earth metal, in particular calcium, an organonitrogen base, in particular diethylamine, diethanolamine or procaine; Low molecular weight alkyl esters such as tertiary butyl esters, optionally substituted benzhydryl esters such as bis-P-methoxy benzhydryl esters, P-methoxybenzyl esters, phthalyl esters, acetoxymethyl esters or pivaloyloxy P-alkoxy-benzyl ester containing a low molecular alkoxy group such as methyl ester is shown.
R1은 예를들면 수소, 메틸, 에틸, 프로필, 부틸 특히 메틸기와 같은 탄소수 1 내지 4의 알킬기, 예를들어 사이클로푸로필, 사이클로부틸, 사이클로펜틸 또는 사이클로헥실과 같은 탄소수 3내지 8의 사이클로알킬, 특히 탄소수 3내지 6의 사이클로알킬기가 바람직하며 이들 알킬기 또는 사이클로알킬기는 탄소수 1내지 4의 알킬기, (바람직하게는 메틸기), 사이클로펜틸 또는 사이클로헥실기와 갈은 탄소수 3내지 8의 사이클로알킬, (특히 탄소수 3내지 6의 사이클로알킬기), 또는 알킬잔기에 탄소수 l내지 4의 알콕시카보닐, (특히 메톡시카보닐 또는 에톡시카보닐), 카복시, 시아노, 카바모일과 같은 치환체로 모드 또는 디치환되며, 이 치환체는 임의로 치환된 예를들어 하이드록실 치환된 탄소수 1 내지 4의 알킬기에 의해 (두 치환체는 페환하여 O나 N이 개입된 5-또는 6-원환, 그예로 모르폴리노, 피페라지노, N-메틸피페라지노 또는 피롤리디노를 형성할 수 있다), 탄소수 1내지 4의 알킬카보닐(특히 아세틸)에 의해, 설포 또는 설파모일에 의해, 탄소수 1내지 4의 알콕시설포닐(특히 메톡시-또는 에톡시설포닐)에 의해, 포스포노그룹에 의해, 하이드록실에 의해, 할로겐(바람직하게는 염소 또는 브롬)에 의해, 탄소수 1내지 4의 알콕시(특히 메톡시 또는 에톡시)에 의해, 탄소수 1내지 4의 알킬티오(특히 메틸티오 또는 에틸티오)에 의해, 아실옥시(특히 아세톡시 또는 벤조일옥시와 같은 탄소수 1내지 4의 지방족 아실옥시)에 의해, 탄소수 1내지 4의 카복시알콕시(특히 카복시메톡시) 또는 아릴(바람직하게는 페닐기)에 의해 모노-또는 디치환될 수 있으며, 이 아릴은 예를들면 -CH2S-Het SubB 그룹에서 Het기로 정의된 복소환상기 ; 탄소수 1내지 4의 알킬기(바람직하게는 메틸), 탄소수 1내지 4의 알케닐 (바람직하게는 알릴) ; 탄소수 1내지 4의 알킬옥시(바람직하게는 메톡시) ; 탄소수 1내지 4의 알킬티오(바람직하게는 메틸티오) ; 할로겐(바람직하게는 염소 또는 브롬), 설파모일 ; 카바모일 ; 카복시 ; 트리플루오로메틸 ; 메톡시카보닐 같은 탄소수 1내지 4의 알콕시카보닐 ; 시아노 ; 니트로 ; 아미노 탄소수 1내지 4의 알킬아미노 ; (예를들면 메틸아미노 또는 에틸아미노) ; 탄소수 1내지 4의 디알킬아미노(예, 디메틸-또는 디에틸아미노) ; 아미디노기와 같은 치환체를 임의로 수반하며, R1은 또한 탄소수 2내지 6, 바람직하게는 탄소수 3내지 5의 알케닐, 알릴 또는 크로토닐기를 나타낼 수 있거나 [여기서 이들 그룹은 탄소수 1내지 4의 알킬기에 의해, 할로겐(특히 염소나 브롬)에 의해, Sub 알킬(Rl)에서 언급된 치환체로 임의로 치환된 카복실 또는 카바모일에 의해, 알킬탄소수 1내지 4의 알킬옥시카보닐(특히 메톡시카보닐 또는 에톡시카보닐)에 의해 임의로 더 치환된다] 또는R 1 is, for example, hydrogen, methyl, ethyl, propyl, butyl, in particular an alkyl group having 1 to 4 carbon atoms, such as a methyl group, for example cycloalkyl having 3 to 8 carbon atoms such as cyclofurophyll, cyclobutyl, cyclopentyl or cyclohexyl In particular, cycloalkyl groups having 3 to 6 carbon atoms are preferred, and these alkyl groups or cycloalkyl groups are alkyl groups having 1 to 4 carbon atoms (preferably methyl groups), cyclopentyl or cyclohexyl groups and cycloalkyl having 3 to 8 carbon atoms, ( Especially cycloalkyl groups having 3 to 6 carbon atoms, or alkoxycarbonyl having 1 to 4 carbon atoms (especially methoxycarbonyl or ethoxycarbonyl), substituents such as carboxy, cyano, carbamoyl The substituents are optionally substituted, for example, by an alkyl group having 1 to 4 carbon atoms which is substituted by hydroxyl (both substituents are substituted and O or N intervene). Sulfo by a 5- or 6-membered ring, for example morpholino, piperazino, N-methylpiperazino or pyrrolidino), alkylcarbonyl having 1 to 4 carbon atoms (especially acetyl) Or by sulfamoyl, by alkoxysulfonyl having 1 to 4 carbon atoms (particularly methoxy- or ethoxysulfonyl), by phosphono groups, by hydroxyl, by halogen (preferably chlorine or bromine), Alkoxy (particularly methoxy or ethoxy) having 1 to 4 carbon atoms, alkylthio (particularly methylthio or ethylthio) having 1 to 4 carbon atoms, acyloxy (particularly 1 to 4 carbon atoms such as acetoxy or benzoyloxy) Aliphatic acyloxy), mono- or di-substituted by carboxyalkoxy (particularly carboxymethoxy) or aryl (preferably phenyl group) of 1 to 4 carbon atoms, which aryl is for example -CH 2 S Complex defined as Het group in Het SubB group Above; Alkyl groups having 1 to 4 carbon atoms (preferably methyl), alkenyl having 1 to 4 carbon atoms (preferably allyl); Alkyloxy having 1 to 4 carbon atoms (preferably methoxy); Alkylthio (preferably methylthio) having 1 to 4 carbon atoms; Halogen (preferably chlorine or bromine), sulfamoyl; Carbamoyl; Carboxy; Trifluoromethyl; Alkoxycarbonyl having 1 to 4 carbon atoms such as methoxycarbonyl; Cyano; Nitro; Alkylamino having 1 to 4 amino carbon atoms; (Eg methylamino or ethylamino); Dialkylamino having 1 to 4 carbon atoms (eg, dimethyl- or diethylamino); Optionally carries a substituent such as an amidino group, and R 1 may also represent an alkenyl, allyl or crotonyl group having 2 to 6 carbon atoms, preferably 3 to 5 carbon atoms, wherein these groups are alkyl groups having 1 to 4 carbon atoms By halogen (especially chlorine or bromine), by carboxyl or carbamoyl optionally substituted with the substituents mentioned in Sub alkyl (R l ), alkyloxycarbonyl having 1 to 4 alkyl carbon atoms (especially methoxycarbonyl or Optionally further substituted by ethoxycarbonyl); or
R1은 탄소수 3내지 5의 알키닐 [바람직하게는 프로파길이며, 이 기는 예를들면 아릴 바람직하게는 페닐기에 의해, 탄소수 1내지 7의 지방족, 포화 또는 불포화아설기(예를들면 포르밀, 아세틸, 프로피오닐, 부티릴,헥사노일, 아크릴로일, 크로토닐, 프로피오노일이 있으며, 이들은 예를들면 염소, 브롬 또는 불소와 같은 할로겐에 의해 임의로 치환되어 클로로아세틸, 디클로로아세틸 또는 브로모아세틸기를 형성할 수있다)] ; 아미노 ; 탄소수 1내지 4의 알킬아미노(바람직하게는 메틸 또는 에틸아미노), 탄소수 1내지 4의 디알킬아미노(특히 디메틸아미노 또는 디에틸아미노로서 예를들면 모르폴리노, 피페라지노 또는 퍼하이드 로티아진과 같은 질소, 산소 또는 황과 같은 이종원자가 개입된 환을 형성할 수 있다); 방향족 아실 예를들면 벤조일 또는 나프토일이며 [이 기는 임의로 (특히 메틸)에 의해, 할로겐(바람직하게는 염소 또는 브롬)에 의해, 탄소수 1내지 4의 알킬옥시 특히 메톡시에 의해, 디메틸-또는 디에틸아미노와 같은 탄소수 1내지 4의 디알킬아미노(이들은 임의로 산소 또는 질소와 같은 이종원자가 개입된 환을 형성함);트리플루오로메틸에 의해 치환된다];황, 산소 및 질소와 같은 1내지 4의 이종원자를 갖는 복소환 5-또는 6-원환에서 유도된 복소환 아실기 예를들면 테오닐, 푸로일, 니코티노일, 이소니코티노일 또는 피콜리노일이 있으며 (이들 치환체는 방향족 아실(R1)에서 언급된 치환체로 임의로 더 치환된다), 임의로 치환된 아릴설포닐(특히 페닐설포닐, P-톨릴설포닐 및 P-아미노페닐설포닐) ; 탄소수 1내지 7, 바람직하게는 탄소수 1내지 4의 임의로 치환된 알킬설포닐 (특히 메틸 또는 에틸설포닐) ; 아릴(바람직하게는 페닐) 또는예를들면 방향족아실(R1)에서 언급한 치환체로 임의 치환된 1-또는 2-나프틸 ; 티에닐, 푸릴, 피리딜 또는 피콜티닐과 같은, 황, 산소 및 질소와 같은 1내지 4의 이종원자가 개입된 복소환 5-또는 6-원환에서 유도된 복소환기를 나타낼 수 있으며 방향족아실(R1)에서 언급된 치환체로 임의로 더 치환될 수 있다.R 1 is an alkynyl having 3 to 5 carbon atoms [preferably propargyl, which is an aryl, preferably a phenyl group, for example an aliphatic, saturated or unsaturated sulfonic group having 1 to 7 carbon atoms (eg formyl, Acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonyl, propionoyl, which are optionally substituted by halogen such as chlorine, bromine or fluorine, for example, chloroacetyl, dichloroacetyl or bromoacetyl Can form groups)]; Amino; Alkylamino having 1 to 4 carbon atoms (preferably methyl or ethylamino), dialkylamino having 1 to 4 carbon atoms (especially dimethylamino or diethylamino, for example morpholino, piperazino or perhydrothiazine) Heteroatoms such as nitrogen, oxygen or sulfur may form a ring); Aromatic acyls, for example benzoyl or naphthoyl, which are optionally (especially methyl), halogen (preferably chlorine or bromine), alkyl of 1 to 4 carbon atoms, especially methoxy, dimethyl- or di Dialkylamino having 1 to 4 carbon atoms such as ethylamino, which optionally forms a ring with heteroatoms such as oxygen or nitrogen; substituted by trifluoromethyl; 1 to 4 such as sulfur, oxygen and nitrogen Heterocyclic acyl groups derived from heterocyclic 5- or 6-membered rings having heteroatoms of, for example, theonyl, furoyl, nicotinoyl, isicotinoyl or picolinoyl (the substituents are aromatic acyl (R Optionally further substituted with the substituents mentioned in 1 )), optionally substituted arylsulfonyl (particularly phenylsulfonyl, P-tolylsulfonyl and P-aminophenylsulfonyl); Optionally substituted alkylsulfonyl (particularly methyl or ethylsulfonyl) having 1 to 7 carbon atoms; 1- or 2-naphthyl optionally substituted with aryl (preferably phenyl) or for example the substituents mentioned in aromatic acyl (R 1 ); Heterocyclic groups derived from heterocyclic 5- or 6-membered rings with 1 to 4 heteroatoms such as sulfur, oxygen and nitrogen, such as thienyl, furyl, pyridyl or picoltinyl, may be represented by aromatic acyl (R 1 May be optionally further substituted with a substituent as mentioned.
R2가 전술한 복소환기릍 나타내는 경우에는 특히 2-푸릴 및 4-티아졸릴기 일수 있다. 이런 기들은 바람직하게는 2-위치에서, 탄소수 1내지 4의 알킬기 (바람직하게 메틸), 아릴(바람직하게는 페닐), 아미노 또는 보호된 아미노와 같은 치환체를 수반할 수 있다. 적합한 아미노보호그룹은 특히 산 가수분해나 수첨분해로 분리될 수 있는 그룹들이다. 그 예로서는 할로게노아세틸, 바람직하게는 클로로-또는 브로모 아세틸, 카보벤족시, 3급 부틸옥시카보닐 또는 특히 예를들어 할로겐이나 알킬로 더 치환될 수 있는 트리틸이 있다.When R <2> represents the heterocyclic group mentioned above, it may especially be a 2-furyl and 4-thiazolyl group. Such groups may carry substituents such as alkyl groups (preferably methyl), aryl (preferably phenyl), amino or protected amino, preferably in the 2-position. Suitable aminoprotecting groups are in particular those groups which can be separated by acid hydrolysis or hydrocracking. Examples are halogenoacetyl, preferably chloro- or bromo acetyl, carbobenzoxyl, tertiary butyloxycarbonyl or trityl which may be further substituted, for example with halogen or alkyl.
B는 메틸, 아세톡시메틸, 카바모일옥시메틸, 할로겐(바람직하게는 염소), 저분자 알콕시, (바람직하게는 메톡시) 또는 -CH2S-Het 그룹이며, 이 구조중의 Het 기는 예를들어 티아디아졸, 바람직하게는 1, 3, 4-티아디아졸릴 또는 테트라졸릴과 같은, 1내지 4의 이종원자(예. 질소 또는 황)를 함유하는 5- 또는 6-원환을 나타낸다.B is methyl, acetoxymethyl, carbamoyloxymethyl, halogen (preferably chlorine), low molecular alkoxy, (preferably methoxy) or -CH 2 S-Het group, for example the Het group in the structure 5- or 6-membered rings containing 1 to 4 heteroatoms (eg nitrogen or sulfur), such as thiadiazoles, preferably 1, 3, 4-thiadiazolyl or tetrazolyl.
n은 0, 1 또는 2이다.n is 0, 1 or 2.
일반식(Ⅱ)의 카복실산 합성법은 특허 문헌, 예를들변 DOS 27, 02, 501호에 기술되어 있지만, R1이 페닐 또는 벤질인 일반식(Ⅱ)의 화합물은 신규의 것이다.Although the carboxylic acid synthesis method of general formula (II) is described in patent documents, for example, DOS 27, 02, 501, the compound of general formula (II) whose R <1> is phenyl or benzyl is novel.
일반식(Ⅲ)의 출발물질의 합성은 문헌상에 공지되어 있으며, n이 1 또는 2를 나타낼 경우에는 문헌에 기술된 방법에 따라 미리 산화시켜 제조해야 된다. [참조 : E. H. FIynn, Cephalosporins and Penicillins,Academic Press, New York and London (l972)].The synthesis of starting materials of general formula (III) is known in the literature, and when n represents 1 or 2, it must be prepared by oxidizing in advance according to the methods described in the literature. See E. H. FIynn, Cephalosporins and Penicillins, Academic Press, New York and London (l972).
본 발명의 제조공정에 필요한 일반식(Ⅱ)의 카복실산의 착화합물은 형성된 즉시 7-아미노세펨 화합물과 반응시키는 것이 바람직하다.It is preferable that the complex compound of the carboxylic acid of the general formula (II) required for the production process of the present invention is reacted with the 7-aminocepem compound immediately after formation.
일반식(Ⅱ)의 카복실산이 유리산으로서 바람직하게 사용된다. 그러나 이들의 염류, 예를들면 알카리금속염 (특히 나트륨염) 또는 아민염(예를들면 트리에틸아민염)도 사용될 수 있다.The carboxylic acid of general formula (II) is used preferably as a free acid. However, salts thereof, such as alkali metal salts (especially sodium salts) or amine salts (eg triethylamine salts) may also be used.
적절한 산할라이드 형성제로는 티오닐 클로라이드 또는 티오닐 브로마이드와 같은 티오닐 할라이드, 특히 오염화인, 옥시염화인 및 옥살릴클로라이드 특히 포스겐이 있다.Suitable acid halide formers are thionyl halides such as thionyl chloride or thionyl bromide, in particular phosphorus pentachloride, phosphorus oxychloride and oxalyl chloride, in particular phosgene.
일반식(Ⅳ)의 화합물에 있어서 R3, R4및 R5가 각각 탄소수 1내지 6의 알킬기를 나타내는 경우에는 이들 알킬그룹으로서 메틸, 에틸, 프로필, 부틸, 헥실등이 있으나 특히 이들 알킬그룹은 1내지 4의 탄소원자를 가지며 메틸기가 특히 바람직하다.In the compound of formula (IV), when R 3 , R 4 and R 5 each represent an alkyl group having 1 to 6 carbon atoms, these alkyl groups include methyl, ethyl, propyl, butyl, hexyl, etc. A methyl group having 1 to 4 carbon atoms is particularly preferred.
R3및 R4또는 R3및 R5가 페환되어 이종원자가 임의로 개입된 환을 형성할 경우, 이들 이종원자는 특히 산소 및 질소가 될수 있다. 적절한 환으로서는 피페리딘, 모르폴리노, 피롤리돈, 피롤리딘, 아세티디논-2-또는 피페라진환과 같은 4내지 8원환, 특히 5내지 6원환을 갖는 환이다.When R 3 and R 4 or R 3 and R 5 are cyclized to form a ring in which the heteroatoms are optionally involved, these heteroatoms may be oxygen and nitrogen, in particular. Suitable rings are rings having 4 to 8 membered rings, particularly 5 to 6 membered rings, such as piperidine, morpholino, pyrrolidone, pyrrolidine, acetidinone-2- or piperazine ring.
일반식(Ⅳ)의 화합물중 구조중의 두 알킬그룹이 바람직하게 저분자량 형태인 디알킬아세트 아미드와 같은 N-디치환 카복실산 아미드가 있으며, 디알킬기는 임의로 폐환되어 환, 바람직하게는 질소 또는 산소와 같은 이종원자가 개입된 4내지 8원환을 이룬다.Among the compounds of formula (IV) are N-disubstituted carboxylic acid amides, such as dialkylacetamides, in which the two alkyl groups in the structure are preferably in low molecular weight form, and the dialkyl group is optionally ring-closed to give a ring, preferably nitrogen or oxygen Heterologous atoms such as 4 to 8 won ring to form.
이러한 환의 예로서는 N-메틸-피롤리돈, N-메틸아세티디논, N, N-디에틸부티라미 드, 디알킬프로피온아미드 및 디알킬아세트아미드가 있으며, 이들의 알킬치환체는 디메틸아세트아미드, 디에틸아세트아미드, N-아세틸-피페리딘, N-아세틸-모르폴린, N-프로피오닐-피페리딘, N-부티릴-피롤리딘, N-부티릴-피페리딘, N, N-디메틸-N, N'-펜타메틸렌우레아, 테트라메틸우레아, 테트라에틸우레아와 같은 저분자량형이 바람직하다. 특히 바람직한 일반식(Ⅳ)의 화합물로서는 디에틸아세트아미드, N, N디메틸프로피온아미드, N, N-디에틸 프로피온아미드, N-아세틸피페리딘 및 테트라메틸우레아 특히 디메틸아세트아미드가 있다.Examples of such rings include N-methyl-pyrrolidone, N-methylacetidinone, N, N-diethylbutyramid, dialkylpropionamide and dialkylacetamide, and their alkyl substituents are dimethylacetamide, di Ethylacetamide, N-acetyl-piperidine, N-acetyl-morpholine, N-propionyl-piperidine, N-butyryl-pyrrolidine, N-butyryl-piperidine, N, N- Low molecular weight types such as dimethyl-N, N'-pentamethyleneurea, tetramethylurea and tetraethylurea are preferred. Particularly preferred compounds of general formula (IV) include diethylacetamide, N, Ndimethylpropionamide, N, N-diethyl propionamide, N-acetylpiperidine and tetramethylurea, in particular dimethylacetamide.
본 발명의 방법에 따르면 일반식(Ⅳ)의 화합물을 사용하는데 있어서 산할라이드 형성제와의 상응하는 반응 생성물이 매우 안정하다는 것이 큰 장점이다. 이점에 비해서 티오닐 클로라이드와 디메틸포름아미드의 반응생성물은 상술한 바와 같이 흔적량의 Fe3+와 접촉하면 폭발적으로 분해해버린다.According to the process of the invention it is a great advantage that the corresponding reaction product with the acid halide former is very stable in using the compound of general formula (IV). In comparison, the reaction product of thionyl chloride and dimethylformamide decomposes explosively when contacted with trace amounts of Fe 3+ as described above.
활성 착화합물은 반응을 더 이상 방해하지 않는 무수의 불활성용매 중에서 일반식(Ⅱ)의 카복실산과 함께 반응시켜 만든다. 적합한 용매로서는 메틸렌클로라이드 또는 클로로포름과 같은 할로겐화 탄화수소, 아세트산 에틸에스테르와 같은 에스테르, 톨루엔 또는 크실렌과 같은 방향족 탄화수소 또는 디에틸에테르 또는 디이소프로필 에테르와 같은 에테르류가 있다.The active complex is made by reacting with a carboxylic acid of formula (II) in anhydrous inert solvent which no longer interferes with the reaction. Suitable solvents include halogenated hydrocarbons such as methylene chloride or chloroform, esters such as acetic acid ethyl ester, aromatic hydrocarbons such as toluene or xylene or ethers such as diethyl ether or diisopropyl ether.
최적상태에서 본 발명의 제조공정을 수행하기 위해서는 일반식(Ⅱ)의 카복실산을 7-아미노세펨 화합물로 계산하여 적어도 화학량을 사용한다.In order to carry out the production process of the present invention in an optimal state, at least a stoichiometry is calculated by calculating the carboxylic acid of the general formula (II) as a 7-aminocepem compound.
활성 착화합물을 분리할 필요는 없으므로, 다음과 같은 방법이 적합하다. 일반식(Ⅳ)의 화합물을 처음에 0. 1내지 3당량의 양, 바람직하게는 0. 1내지 1. 5당량을 반응용기에 넣고 상응량의 할로겐화제를 가한다음 일반식(Ⅱ)의 카복실산을 상술한 바와 같이 반응시킨다. 첨가순서는 그렇게 중요하지는 않다.Since the active complex need not be separated, the following method is suitable. The compound of general formula (IV) is initially added in an amount of 0.01 to 3 equivalents, preferably 0.01 to 1.5 equivalents, and a corresponding amount of a halogenating agent is added to the carboxylic acid of formula (II). React as described above. The order of addition is not so important.
일반식(Ⅱ)의 카복실산을 전술한 바와 같은 착화합물을 형성시킴으로써 활성화시키는 반응은 -70내지 +30℃에서 이루어질 수 있으나 특히 -20내지 +10℃의 온도가 유익하다.The reaction for activating the carboxylic acid of general formula (II) by forming a complex as described above can be made at -70 to + 30 ° C, but a temperature of -20 to + 10 ° C is particularly advantageous.
본 발명 방법에서 제2단계 반응, 즉 아실화 반응은 활성 착화합물의 형성시 즉시 일어난다. 이 목적을 위해서는 일반식(Ⅲ)의 카복실산을 아민염의 형태로, 특히 트리에틸 아민염과 같은 트리알킬아민염, 트리메틸벤질아민염이나 에틸디사이클로헥실아민염 또는 N, N-디메틸아닐린 염과 같은 디알킬아릴아민염의 형태로 사용할 수 있다. 이와 달리, 에스테르의 형태로도 사용할 수 있으며, 유리 카복실그룹으로의 연이은 전환이 바람직할 경우, 이들 에스테르는 산가수분해나 수첨분해로 제거할 수 있는 에스테르이다. 문헌상에 공지된 방법으로 상응하는 실릴화제를 사용하여 얻는 실릴에스테르 특히 트리알킬실릴에스테르, 바람직하게는 트리메틸실릴에스테르도 사용할 수 있다.In the process of the invention, the second stage reaction, ie the acylation reaction, takes place immediately upon formation of the active complex. For this purpose the carboxylic acid of formula (III) is in the form of an amine salt, in particular trialkylamine salts such as triethyl amine salts, trimethylbenzylamine salts or ethyldicyclohexylamine salts or N, N-dimethylaniline salts It can be used in the form of a dialkylarylamine salt. Alternatively, they can also be used in the form of esters, and if the subsequent conversion to the free carboxyl group is desired, these esters are esters that can be removed by acid hydrolysis or hydrocracking. Silyl esters obtained using the corresponding silylating agents, in particular trialkylsilyl esters, preferably trimethylsilyl esters, by methods known in the literature can also be used.
아실화 동안에 생성되는 할로겐화수소는 염기를 가하여 중화시키는데, 필요시 트리에틸아민과 같은 트리알킬아민, 트리메틸벤질아민, 에틸디사이클로헥실아민 또는 N, N-디메틸아닐린과 같은 디알킬아릴아민 등을 이 목적에 바람직하게 사용한다. 이 아실화 반응은 -80내지 +30℃의 온도, 바람직하게는 -20내지 20℃의 온도에서 이루어질 수 있다. 반응은 이 온도에서, 일반적으로 30내지 60분 후에 완결된다.Hydrogen halides generated during acylation are neutralized by addition of a base, if necessary, such as trialkylamines such as triethylamine, trimethylbenzylamine, ethyldicyclohexylamine or dialkylarylamines such as N, N-dimethylaniline, etc. It is preferably used for the purpose. This acylation reaction can be carried out at a temperature of -80 to + 30 ° C, preferably at a temperature of -20 to 20 ° C. The reaction is complete at this temperature, usually after 30 to 60 minutes.
수득된 아실화 반응 생성물은 기지의 방법으로, 예를들면 존재 가능한 보호 그룹을 제거함으로써 용이하게 분리시킬 수 있다.The acylation reaction product obtained can be easily separated by known methods, for example by removing possible protecting groups.
이 그룹은 문헌[참조 : DOS 27 02 501, Houben-Weyl vol. xv/1, 272]에 기술된 방법에 따라 제거할수 있다.This group is described in DOS 27 02 501, Houben-Weyl vol. xv / 1, 272].
본 발명의 방법에 따라 수득된 에스테르는 상기와같이 분리하여 사용하거나, 예를들어 산가수분해 또는 수첨분해에 의해 유리산으로 전환시킬 수 있다. 본 발명의 방법에 따라 일반식(I)의 화합물을 아민 염의 형태로 수득할 경우, 이들 염은 이와달리, 기지의 방법으로 알카리금속염의 유리산으로 전환시킬 수 있다.The esters obtained according to the process of the invention can be used separately as described above or converted to the free acid, for example by acid hydrolysis or hydrocracking. When the compounds of general formula (I) are obtained in the form of amine salts according to the process of the invention, these salts can alternatively be converted into the free acids of the alkali metal salts by known methods.
다음 실시예들은 본 발명을 설명하기 위해 제시한 것이다.The following examples are presented to illustrate the present invention.
[실시예 1]Example 1
3-아세톡시메틸-7-[2-(2-트리틸아미노-4-티아졸릴) -2-(syn) -메톡스이미노-아세트아미드]-세프-3-엠-4-카복실산의 디에틸아민염Diethyl of 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetamide] -cep-3-m-4-carboxylic acid Amine salt
54g(0. 1몰)의 2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트산(82%)을 4구 플라스크 중의 800㎖ 톨루엔에 현탁시킨다. 욕의 온도를 50℃로 하여 400㎖의 톨루엔을 진공하에 증류해버린다. 다음에 이 현탁액을 -5℃로 냉각시키고 -5℃이서 9. 3ml(0. 1몰)의 N, N-디메틸아세트아미드를 가한다음 60㎖의 톨루엔에 12. 2g(0. 12몰)의 포스겐을 녹인 용액을 적가한다. -50℃에서 16시간동안 계속 교반한다.54 g (0.1 mol) of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetic acid (82%) is suspended in 800 ml toluene in a four neck flask. 400 ml of toluene is distilled off under vacuum by making the temperature of the bath 50 degreeC. The suspension is then cooled to −5 ° C. and 9.3 ml (0.1 mol) of N, N-dimethylacetamide at −5 ° C. is added to 12.2 g (0.12 mol) of 60 ml of toluene. A solution of phosgene dissolved is added dropwise. Continue stirring at −50 ° C. for 16 hours.
500㎖의 메틸렌 클로라이드의 28. 6g의 7-아미노 세팔로스포란산(95%=0. 1몰)과 55. 3ml(0. 4몰)의 트리에틸아민을 가한 용액을 활성탄으로 여과하여서-5℃내지 -7℃에서 적가하여 현탁액을 만든다. 다음에-5℃에서 30분동안, 온도를 10℃에서 15℃로 올리면서 60분간 교반한다. pH를 2N염산으로 조절하여 2로 맞추어서 500ml의 메틸렌 클로라이드 및 500ml의 물 혼액에다 부어서 상을 분리시킨다. 유기상을500ml 물로 1회 세척하고 황산 나트륨 상에서 탈수시키고 진공하에 농축한다. 잔사를 270ml의 아세톤에 용해하고 10.3ml의 디에틸아민을 가한다음 30분간 교반하면서 환류한다. 잠시 후에 결정이 석출한다. 실온에서 수시간 방치 후에 생성물을 빙욕중에서 냉각시키고 흡인여과 하고 냉아세톤으로 세척한 뒤 건조시킨다. 고수율로 얻어진 디에틸아민염은 syn-배열을 나타낸다.28.6 g of 7-amino cephalosporanic acid (95% = 0. 1 mol) of 55 ml of methylene chloride and 55.3 ml (0.4 mol) of triethylamine were filtered through activated carbon- The suspension is added dropwise at 5 ° C to -7 ° C. The mixture is then stirred for 60 minutes at -5 ° C while raising the temperature from 10 ° C to 15 ° C. The pH is adjusted with 2N hydrochloric acid, adjusted to 2, and poured into 500 ml of methylene chloride and 500 ml of water mixture to separate the phases. The organic phase is washed once with 500 ml water, dehydrated over sodium sulfate and concentrated in vacuo. The residue is dissolved in 270 ml of acetone, 10.3 ml of diethylamine is added and refluxed with stirring for 30 minutes. After a while, a crystal precipitates. After standing for several hours at room temperature, the product is cooled in an ice bath, suction filtered, washed with cold acetone and dried. Diethylamine salt obtained in high yield shows syn-array.
NMR(DMSO, 60 MHz) : 6. 68ppm=티아졸환양자.NMR (DMSO, 60 MHz): 6. 68 ppm = thiazole quantum.
[실시예 2]Example 2
3-아세톡시메틸-7-[2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트아미도]-세프-3-엠-4-카복실산의 디에틸 아민염Diethyl amine salt of 3-acetoxymethyl-7- [2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
54g(0. 1몰)의 2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트산(82%)을 4구 플라스크중의 600ml의 톨루엔에 현탁시킨다음 50내지 60℃온도의 욕에서 진공하에 톨루엔을 증류해 버린다. 잔사는 400ml의 톨루엔에 현탁하고-10℃로 냉각하여 9. 3ml(0. 1몰)의 N,N-디메틸아세트아미드를 가한다음 여기에 20분에 걸쳐 -10℃에서 10. 2ml(0. 12몰)의 옥살릴클로라이드를 적가하고 40ml의 톨루엔으로 희석한다. 반응혼액을 -15℃에서, 2. 5시간 동안-15℃내지 -5℃에서 2.5시간 동안 교반한다.54 g (0.1 mol) of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetic acid (82%) was suspended in 600 ml of toluene in a four neck flask. The toluene is then distilled off under vacuum in a bath at 50 to 60 ° C. The residue was suspended in 400 ml of toluene, cooled to -10 [deg.] C. and 9.3 ml (0.1 mol) of N, N-dimethylacetamide was added thereto, followed by 10.2 ml (0. 12 mole) of oxalylchloride is added dropwise and diluted with 40 ml of toluene. The reaction mixture is stirred at −15 ° C., 2.5 h at −15 ° C. to −5 ° C. for 5 h.
28. 6g의 7-아미노세팔로스포란산(95%)(0.1몰) 및 55. 3ml(0.4몰)의 트리에틸 아민을 500ml의 메틸렌클로라이드에 용해시키고 탄소를 통하여 여과한 용액을 상기 생성된 현탁액에다 -8℃내지 -5℃에서 20분동안 적가한다. 반응액은 -5℃에서 30분 동안-5℃내지 10℃에서 60분 동안 교반한다. 다음에 반응액의 pH를 2N 염산으로 2로 맞추고 500ml의 메틸렌클로라이드 및 500ml의 물 혼액에다 부어서 흔든다음 상을 분리한다. 유기층은 500ml의 물로 세척하고 진공하에 농축한다.28. 6 g of 7-aminocephalosporanic acid (95%) (0.1 mol) and 55. 3 ml (0.4 mol) of triethyl amine were dissolved in 500 ml of methylene chloride and filtered through carbon. To the suspension is added dropwise at -8 ° C to -5 ° C for 20 minutes. The reaction solution is stirred at -5 ° C for 30 minutes at -5 ° C to 10 ° C for 60 minutes. The pH of the reaction solution is then adjusted to 2 with 2N hydrochloric acid, poured into 500 ml of a mixture of methylene chloride and 500 ml of water and shaken to separate the phases. The organic layer is washed with 500 ml of water and concentrated in vacuo.
담황색 잔사를 270ml의 아세톤에 녹이고 10. 3ml 디에틸 아민을 가한다음 30분간 교반하변서 환류시킨다. 실온에서 2시간 동안 방치한 다음 빙욕중에서 냉각하고 흡인 여과하고 아세톤으로 세척하여 건조한다. 고수율로 얻어진 디에틸아민 염은 syn-배열이다.The pale yellow residue is dissolved in 270 ml of acetone, 10. 3 ml of diethyl amine is added, and the mixture is refluxed under stirring for 30 minutes. It is allowed to stand at room temperature for 2 hours, then cooled in an ice bath, suction filtered, washed with acetone and dried. The diethylamine salt obtained in high yield is syn-array.
NMR(DMSO, 60 MHz) : 6. 68 ppm=티아졸 환양자.NMR (DMSO, 60 MHz): 6. 68 ppm = thiazole quantum.
[실시예 3]Example 3
3-아세톡시메틸-7-[2-(2-트리 틸아미노-4-티 아돌릴)-2-(syn) -메톡스이미노-아세트아미도]-세프-3-엠-4-카복실산의 디에탈아민염3-acetoxymethyl-7- [2- (2-tritylamino-4-thiodolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid Diethamine salt
5. 4g(10밀리몰)의 2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트(82%)을 80ml의 톨루엔에 현탁시킨다. 50°내지 60℃에서 용매의 반을 진공하에 증류해 버리고 -25℃로 냉각한다. 1.02ml(11밀리몰)의 N, N-디메틸아세트 아미노를 첨가한 다음2. 2g(11밀리몰)의 오염화인을 가한다. 반웅액을 -20℃에서 30분간, -5℃에서 3시간동안 교반한다. 100ml의 무수 디이소프로필에테르를 가한다음 고형물질을 흡인 여과하고 진공 건조기중에 보관한다. 얻어진 착화합물을 2. 8g(10밀리몰)의 7-아미노세팔로스프란산(95%) 및 5. 4ml(20밀리몰)의 트리에틸아민을 50ml의 메탈렌클로라이드에 녹인 용액5. Suspend 4 g (10 mmol) of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acet (82%) in 80 ml of toluene. Half of the solvent is distilled under vacuum at 50 ° to 60 ° C. and cooled to −25 ° C. Add 1.02 ml (11 mmol) of N, N-dimethylacetamino, and 2. 2 g (11 mmol) of phosphorus pentachloride are added. The reaction solution is stirred at -20 ° C for 30 minutes and at -5 ° C for 3 hours. 100 ml of anhydrous diisopropyl ether are added followed by suction filtration of the solids and storage in a vacuum drier. A solution obtained by dissolving 2.8 g (10 mmol) of 7-aminocephalosfranic acid (95%) and 5. 4 ml (20 mmol) of triethylamine in 50 ml of metalene chloride.
25℃에서 가한다. 실온까지 가열한 다음 실온에서 1시간 동안 교반한다.Add at 25 ° C. Heat to room temperature and stir at room temperature for 1 hour.
실시예 1 및 2에서 기술한대로 처리한다. 생성물도 유사하게 syn-배열을 나타낸다.Treatment is as described in Examples 1 and 2. The product similarly shows syn-array.
[실시예 4]Example 4
3-아세톡시메틸-7-[2-(2-트리틸아미노-4-디아졸린)-2-(syn)-메톡스이미노-아세트아미노]-세프-3-엠-4-카복실산의 디에틸아민염Diethyl of 3-acetoxymethyl-7- [2- (2-tritylamino-4-diazoline) -2- (syn) -methoximino-acetamino] -cep-3-m-4-carboxylic acid Amine salt
4. 8g(24밀리몰)의 오염화인을 100ml의 톨루엔에다 현탁시킨다음 실온에서 교반하면서 2.2ml(24밀리몰)의 N, N-디메틸아세트 아미드를 10ml의 톨루엔에 녹인 용액을 첨가하고 실온에서 1시간 동안 교반한다. 생성된 착화합물은 결정으로 석출된다.4. Suspend 8 g (24 mmol) of phosphorus pentachloride in 100 ml of toluene and add 2.2 ml (24 mmol) of N, N-dimethylacetamide in 10 ml of toluene while stirring at room temperature for 1 hour at room temperature. Stir while. The resulting complex precipitates out as crystals.
상등액을 사이폰으로 제거한 후 상기 조각을 100ml의 톨루엔을 사용하여 반복한 다음 잔사에 다시 100ml의 톨루엔을 가하고 이 현탁액을 -5℃로 냉각한다. 8. 8g (20밀리몰)의 2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트산을 가하고 반응액은 -5℃에서 20시간 동안 교반한다.After removing the supernatant with siphon, the pieces were repeated with 100 ml of toluene and then 100 ml of toluene was added to the residue again and the suspension was cooled to -5 ° C. 8. 8 g (20 mmol) of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetic acid is added and the reaction is stirred at -5 ° C for 20 hours.
다음에 100ml의 메틸렌클로라이드에 5. 4g(20밀리몰)의 7-아미노-세팔로스포란산 및 11. 5ml(83밀리몰)의 트리에틸아민을 녹dls 용액을 상기 현탁액에 -5℃에서 적가하고 실온에서 1시간 동안 교반한다. 생성물을 실시예 1내지 3에 따라서 처리하고 디에틸아민염으로 전환시킨다. 생성물은 syn-배열을 나타낸다.Next, 5.4 g (20 mmol) of 7-amino-cephalosporanic acid and 11.5 mL (83 mmol) of triethylamine were added dropwise to 100 ml of methylene chloride at -5 ° C. Stir at room temperature for 1 hour. The product is treated according to Examples 1 to 3 and converted to diethylamine salt. The product shows syn-array.
[실시예 5]Example 5
아세톡시메틸-7-[2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트아미노]-세프-3-엠-4-카복실산의 디에틸아민염Diethylamine salt of acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetamino] -cep-3-m-4-carboxylic acid
2-(2-트리틸아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트산의 나트륨염46. 5g(0. 1몰)을 600ml의 톨루엔에 용해한 다음 진공하에 60℃의 욕에서 톨루엔을 증류해버린다.Sodium salt of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetic acid 46. 5 g (0.1 mol) are dissolved in 600 ml of toluene and the toluene is distilled off in a 60 ° C. bath under vacuum.
잔사를 400ml의 톨루엔에 현탁시키고 여기에 9. 3ml(0. 1몰)의 N, N-디메틸아세트아미드를 가하고-10℃로 냉각시킨다.The residue is suspended in 400 ml of toluene and 9.3 ml (0.1 mol) of N, N-dimethylacetamide is added thereto and cooled to -10 ° C.
다음에 30분 동안 교반시키면서 150ml의 톨루엔에 12g(0.12몰)의포스겐을 녹인 액을 -l0℃내지 -5℃에서 적가한다·Then, a solution of 12 g (0.12 mol) of phosgene dissolved in 150 ml of toluene was added dropwise at −10 ° C. to −5 ° C. with stirring for 30 minutes.
이 반응액을 -10℃에서 17시간 동안 교반하여 현탁액을 만들고 이를 10분에 걸쳐-10℃에서 25. 8g의7-아미노 세팔로스포란산, 55. 3ml의 트리에틸아민 및 500ml의 메틸렌클로라이드 혼액에다 가한다. 90분에 걸쳐 반응액을 +15℃로 가열하고 pH를 2N 염산으로 2로 맞추고 500ml의 메틸렌 디클로라이드 및 500ml의 물의 혼액에 부어넣고 상을 분리한다. 유기층을 500ml의 물로 세척하고 진공하에 농축한다. 담황색 잔사를 270ml의 아세톤dp 용해하고 10.3ml의 디에틸아민을 가한다음에 30분동안 가열하면서 비등 가열한다. 실온에서 1시간 방치후에 흡인여과 및 아세톤으로 세척하고 건조한다. 고수율로 얻어진 디에틸아민염은 syn-배열을 나타낸다.The reaction solution was stirred at -10 ° C for 17 hours to form a suspension, which was diluted over 10 minutes at -10 ° C with 25.8 g of 7-amino cephalosporranic acid, 55.3 ml of triethylamine and 500 ml of methylene chloride. Add to the mixture. Heat the reaction to + 15 ° C. over 90 minutes, adjust the pH to 2 with 2N hydrochloric acid, pour into a mixture of 500 ml of methylene dichloride and 500 ml of water and separate phases. The organic layer is washed with 500 ml of water and concentrated in vacuo. The light yellow residue is dissolved in 270 ml of acetone dp and 10.3 ml of diethylamine is added followed by boiling heating with heating for 30 minutes. After standing for 1 hour at room temperature, washed with suction filtration, acetone and dried. Diethylamine salt obtained in high yield shows syn-array.
NMR(DMSO) 6. 68ppm(티아졸 환양자).NMR (DMSO) 6. 68 ppm (thiazole quantum).
착화합물이 형성되는 동안 톨루엔대신 벤젠을 사용하면 디에틸아민 염이 동일하게 우수한 수율로 수득되나 용매로서 에테르를 사용할 경우 수율은 다소 떨어지는 경향이 있다.If benzene is used instead of toluene during complex formation, the diethylamine salt is obtained in equally good yield, but the yield tends to be somewhat lower when ether is used as solvent.
할로겐화제로서 포스겐 대신에 옥살릴클로라이드를 사용하고 나머지 반응은 상기와 갈이 진행시키면 수득되는 표제화합물의 수율은 l/3정도 덜어진다.When oxalyl chloride is used instead of phosgene as the halogenating agent and the remaining reaction proceeds with the above, the yield of the title compound obtained is reduced by l / 3.
[실시예 6]Example 6
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴) -2-(syn)-메톡스이미노-아세트아미노]-세프-3-엠 -4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamino] -cep-3-m-4-carboxylic acid
4g(0. 02몰)의 2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노아세트산을 200ml의 톨루엔에 현탁시킨후, 톨루엔은 60℃의 욕온도에서 진공하에 증류해버린다. 잔사는 100ml의 메틸렌클로라이드에 현탁시키고 여기에 1. 86g (0. 02몰)의 N, N-디메틸 아세트아미노를 가하고 -10℃로 냉각한다. 3g(0. 03몰)의 포스겐을 10ml의 톨루엔에 가하여 10분간 교반하고 -5℃에서 5시간 동안 더 교반한다. 다음에 5. 4g의 7-아미노 세팔로스포란산(0. 02몰) 및 11ml의 트리에틸아민을 100ml의 메틸렌 디클로라이드에 녹이고 활성탄을 통하여 여과시킨다음 -5°내지 -8℃에서 형성된 상기의 맑은 담황색 용액에 10분 동안에 적가한다. 혼액을-5℃에서 반시간 동안 실온 내지 -15℃에서 1시간 동안 교반하고 진공하에 용매를 제거한다.황갈색 무정형 잔사를 45ml의 80%포름산에 용해하고 1시간반에 절쳐서 300ml의 35%황산 암모니움 액에다 적가한다. 석출되어 나오는 침전을 흡인여과시키고 150ml의 물로 세척하며 진공하에 수산화나트륨 펠렛으로 건조시킨다. 조생성물을 100ml의 98%에탄올에 현탁하고 30분간 50℃에서 교반한다. 이 물질을냉각, 흡인여과, 알콜로 세척 및 건조시켜 syn-배열을 가진 표제화합물을 얻는다.After 4 g (0.02 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -methoximinoacetic acid was suspended in 200 ml of toluene, toluene was vacuumed at a bath temperature of 60 ° C. Distill it. The residue is suspended in 100 ml of methylene chloride and 1.86 g (0.02 mole) of N, N-dimethyl acetamino is added thereto and cooled to -10 ° C. 3 g (0.03 mol) of phosgene is added to 10 ml of toluene and stirred for 10 minutes and further stirred at -5 ° C for 5 hours. 5. 4 g of 7-amino cephalosporanic acid (0.02 mole) and 11 ml of triethylamine were dissolved in 100 ml of methylene dichloride and filtered through activated charcoal and formed at -5 ° to -8 ° C. To the clear pale yellow solution of was added dropwise for 10 minutes. The mixture is stirred for half an hour at -5 ° C. for 1 hour at room temperature to -15 ° C. and the solvent is removed in vacuo. The tan amorphous residue is dissolved in 45 ml of 80% formic acid and cut in half an hour to 300 ml of 35% sulfuric acid. Add it to the Ammonium solution. The precipitate which precipitates out is suction filtered, washed with 150 ml of water and dried under sodium hydroxide pellets in vacuo. The crude product is suspended in 100 ml of 98% ethanol and stirred at 50 ° C. for 30 minutes. The material is cooled, aspirated, washed with alcohol and dried to give the title compound with syn-array.
NMR(DMSO, 60 MHZ) : 6. 68ppm(타이졸 환양자).NMR (DMSO, 60 MHZ): 6. 68 ppm (Tazole quantum quantum).
[실시예 7]Example 7
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴) -2-(syn) -메톡스이미노-아세트아미도] -세프-3-엠-4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
4g(0.02몰)의 2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노아세트산을 200ml의 톨루엔에 현탁시키고 이 톨루엔은 60℃진공하에서 증류시켜 버린다. 잔사를 100ml의 메틸렌클로라이드에 현탁시키고이 현탁액에 연속하여 -10℃로 냉각된 2.8g(10.03몰)의 N, N-디메틸아세트아미드 및 10ml의 메틸렌클로라이드에 2.55g(0.03몰)의 옥살릴클로라이드를 녹안 용액을 교반하면서 적가한다. 형성된 맑은 담황색 용액을 -10。C에서 5시간 동안 교반하고 어기에 5. 2g의 7-아미노세팔로스프란산, 11ml의 트리에틸아민 및 100ml의 메틸렌클로라이드를 가한다.4 g (0.02 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -methoximinoacetic acid is suspended in 200 ml of toluene and the toluene is distilled off under vacuum at 60 캜. The residue was suspended in 100 ml of methylene chloride and successively to this suspension 2.55 g (0.03 mol) of oxalyl chloride in 2.8 g (10.03 mol) of N, N-dimethylacetamide and 10 ml of methylene chloride cooled to -10 ° C in succession. The green eye solution is added dropwise while stirring. The resulting clear pale yellow solution is stirred at −10 ° C. for 5 hours and 5.2 g of 7-aminocephalosfranic acid, 11 ml of triethylamine and 100 ml of methylene chloride are added thereto.
온도가 +15℃까지 오르도록 1. 5시간 동안 교반하고 용매는 진공하에 제거한다. 잔사를 50ml의 80%포름산에 용해하고 1. 5시간에 걸쳐 350ml의 35%황산 암모니움액에다 적가한다. 침전은 흡인여과, 수세 및건조하여 15ml의 98%에탄올에 현탁시키고 30분간 +50℃에서 교반한다. 냉각, 흡인여과 및 에탄올로 세척하여 건조시켜 syn-배열구조를 갖는 담회색 물질을 얻는다.Stir for 5 hours to allow the temperature to rise to + 15 ° C. and remove the solvent under vacuum. The residue is dissolved in 50 ml of 80% formic acid and added dropwise to 350 ml of 35% ammonium sulfate solution over 1.5 hours. The precipitate is suction filtered, washed with water and dried, suspended in 15 ml of 98% ethanol and stirred at + 50 ° C. for 30 minutes. Cooling, suction filtration and washing with ethanol to dry yield a pale gray material with syn-array structure.
NMR(DMSO) 6. 68ppm(티아졸 환양자)NMR (DMSO) 6. 68 ppm (thiazole quantum)
[실시예 8]Example 8
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn) -메톡스이미노-아세트아미노] -세프-3-엠-4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamino] -cep-3-m-4-carboxylic acid
실시예 7과유사하게 4. 5g의 2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트산의 나트륨염을 1.86ml의 N, N-디메틸아세트아미드 및 3g의 포스겐과 반응시킨다. 포름산 염을 사용하여 아실화 및 정제하던 syn-배열의 담황색 생성뭍이 수득된다.Similar to Example 7, 4.5 g of 2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetic acid sodium salt was added to 1.86 ml of N, N-dimethylacetamide and 3 g. React with phosgene. The pale yellow product of the syn-array obtained by acylation and purification using formic acid salt is obtained.
[실시예 9]Example 9
7-[2-(2-아미노-티아졸-4-일)-2-syn-벤질옥스이미노-아세트아미도] -세팔로스포란산7- [2- (2-Amino-thiazol-4-yl) -2-syn-benzyloximino-acetamido] -cephalosporanic acid
160ml의 무수 톨루엔에 18.2g의 2-(2-트리틸아미노-티아졸-4-일)-2-syn-벤질옥스이미노아세트산을 녹인 용액에 3. 05g의 N, N-디메틸아세트아미드를 가하고 -8℃로 냉각시킨다음 13. 5ml의 38%포스겐-함유 톨루엔 용액을 적가한다. 잠시 후에 무색 결정성물질이 석출된다.3.05 g of N, N-dimethylacetamide was added to a solution of 18.2 g of 2- (2-tritylamino-thiazol-4-yl) -2-syn-benzyloximinoacetic acid in 160 ml of anhydrous toluene. After cooling to −8 ° C. 13. 5 ml of a 38% posgen-containing toluene solution is added dropwise. After a while colorless crystalline precipitates.
5시간 후에 이 현탁액을 -5℃에서 160ml의 무수 메틸렌 클로라이드에 9. 6g의 7-아미노세팔로스포란산 및 19. 6ml의 트리에틸아민을 가한 용액에 가하고 -1℃에서 45분간 교반하고 5℃에 일야 방치시킨다음 마지막으로 125ml의 메틸렌클로라이드 및 150ml의 빙수를 가한다.After 5 hours, this suspension was added to a solution of 9.6 g of 7-aminocephalosporanic acid and 19. 6 ml of triethylamine in 160 ml of anhydrous methylene chloride at -5 deg. C, stirred at -1 deg. After standing at room temperature overnight, 125 ml of methylene chloride and 150 ml of ice water are added.
반응액의 pH를 2N 염산을 가하여 1로 맞추고 유기층은 분리하여 빙수로 3회 세척하고 황산나트륨 상에서 탈수시킨다음 증발건조한다. 이렇게 하여 7-[2-(2-트리탈아미노티아졸-4-일)-2-syn-벤질옥시이미노-아세트아미노]-세팔로스포란산을 엷은 베이지색 고형 물질로 얻는다.The pH of the reaction solution was adjusted to 1 by adding 2N hydrochloric acid, and the organic layer was separated, washed three times with ice water, dehydrated over sodium sulfate, and evaporated to dryness. This affords 7- [2- (2-tritalaminothiazol-4-yl) -2-syn-benzyloxyimino-acetamino] -cephalosporranic acid as pale beige solid material.
이렇게 얻어진 트리틸화합물 20g을 110ml의 50%포름산에 가하고 50℃로 가열한다. 잠시후 트리페닐카비놀이 무색결정의 형태로 분리된다·20 g of the trityl compound thus obtained is added to 110 ml of 50% formic acid and heated to 50 ° C. After a while, triphenylcarbinol is separated into a colorless crystal.
1시간 후에 혼액을 여과하고 여액을 진공하에 농축시킨다음 잔사릍 교반하면서 250ml의 물과 교반하면무색 결정성물질이 석출한다. 생성물을 흡인여과하고 이소프로판올과 에테르로 세척한다. 7-[2-(2-아미노티아졸-4-일)-2-syn-벤질옥시이미노-아세트아미도]-세팔로스포란산을 무색결정의 형태로 얻는다.After 1 hour, the mixture was filtered, the filtrate was concentrated in vacuo, and the residue was stirred with 250 ml of water with stirring to precipitate a colorless crystalline material. The product is suction filtered and washed with isopropanol and ether. 7- [2- (2-Aminothiazol-4-yl) -2-syn-benzyloxyimino-acetamido] -cephalosporanic acid is obtained in the form of colorless crystals.
TLC : Rf 0. 35(n-Bu-OH; H2O : EtOH : AcOH=20 : 4 : 3 : 3)TLC: Rf 0.35 (n-Bu-OH; H 2 O: EtOH: AcOH = 20: 4: 3: 3)
[실시예 10]Example 10
7-[2-(2-아미노티아졸-4-일) -2-syn-벤질옥스이미노-아세트아미노] -3-(1-메틸-테트라졸-2-일) -티오메틸- Δ3-세펨 -4-카복실산7- [2- (2-Aminothiazol-4-yl) -2-syn-benzyloximino-acetamino] -3- (1-methyl-tetrazol-2-yl) -thiomethyl-Δ 3- Sepem-4-carboxylic acid
120ml의 무수 톨루엔에 11.4g의 2-(2-트리틸아미노티아졸-4-일)-2-syn-벤질옥스이미노아세트산을 녹인 용액에 2.0g의 N,N-디메틸아세트아미도를 가하고 -8℃에서 5ml의 38%포스겐함유 톨루엔액을 적가한다. 5시간후에 9. 6g의 트리에틸아민과 160ml의 메틸렌클로라이드의 혼액에다. 7. 35g의 3-(1-메틸테트라졸-2-일)-티오메틸-Δ3-세펨-4-카복실산을 가한 용액을 -5℃에서 1시간 더 교반하고+2℃에서 16시간 동안 보관한 후 70ml의 물을 가하고 반응액의 pH를 1N염산으로 1에 맞춘다. 잠시동안 교반한 다음 여과하고 유기층을 물로 2회 세척하고 농축, 건조한다. 7-[2-(2-트리틸아미노-티아졸-4-일)-2-벤질옥스이미노-아세트아미도] -3-(1-메틸테트라졸-2-일-티오메틸-Δ3-세펨-4-카복실산이 크림색 고형물질로 얻어진다.To a solution of 11.4 g of 2- (2-tritylaminothiazol-4-yl) -2-syn-benzyloximinoacetic acid in 120 ml of anhydrous toluene was added 2.0 g of N, N-dimethylacetamido- 5 ml of 38% porsgen-containing toluene solution is added dropwise at 8 占 폚. After 5 hours, there is a mixture of 9.6 g triethylamine and 160 ml methylene chloride. 7. Add 35 g of 3- (1-methyltetrazol-2-yl) -thiomethyl-Δ 3 -cepem-4-carboxylic acid and stir at −5 ° C. for 1 hour and store at + 2 ° C. for 16 hours. After the addition of 70ml of water and adjust the pH of the reaction solution to 1N hydrochloric acid. After stirring for a while, the mixture is filtered and the organic layer is washed twice with water, concentrated and dried. 7- [2- (2-tritylamino-thiazol-4-yl) -2-benzyloximino-acetamido] -3- (1-methyltetrazol-2-yl-thiomethyl-Δ 3- Cefem-4-carboxylic acid is obtained as a cream solid.
이렇게 얻어진 15g의 고형물질을 65ml의 50%포름산이 가하고 50℃에서 가열한다. 생성된 트리페닐 카비놀을 1. 5시간후에 흡인여과한다. 여액에 2g의 활성탄을 가하고 여액을 여과한 다음 농축, 건조시킨다. 잔사를 250ml의 냉수에 가하고 생성된 크림색 분말을 흡인여과하고 수세 및 건조시킨다.15 g of the solid material thus obtained is added with 65 ml of 50% formic acid and heated at 50 ° C. The resulting triphenyl carbinol is aspirated by 1.5 hours. 2 g of activated carbon is added to the filtrate, and the filtrate is filtered, concentrated and dried. The residue is added to 250 ml of cold water and the resulting creamy powder is suction filtered, washed with water and dried.
얻어진 결정성물질을 100ml의 에테르와 2시간동안 교반하고 건조한다. 7-[2-아미노티아몰-4-일-2-syn-벤질옥스이미노-아세트아미노]-3-(1-메틸-테트라졸-2-일)-티오메틸- Δ3-세펨 -4-카복실산이 베이지색 고체로서 얻어진다.The resulting crystalline material is stirred with 100 ml of ether for 2 hours and dried. 7- [2-Aminothiamol-4-yl-2-syn-benzyloximino-acetamino] -3- (1-methyl-tetrazol-2-yl) -thiomethyl- Δ 3 -cef-4- Carboxylic acids are obtained as beige solids.
TLC : Rf0. 35(n-BuOH : H2O : EtOH : AcOH=20 : 4 : 3 : 3)TLC: R f 0.35 (n-BuOH: H 2 O: EtOH: AcOH = 20: 4: 3: 3)
[실시예 11]Example 11
7-[2-(2-아미노티아졸-4-일)-2-syn-벤질옥스이미 노-아세트아미도]-3-(2-메틸-1, 3, 4-티아디아졸-5-일-티오메틸) - Δ3-세펨 -4-카복실산7- [2- (2-aminothiazol-4-yl) -2-syn-benzyloximino-acetamido] -3- (2-methyl-1, 3, 4-thiadiazole-5- Yl-thiomethyl) -Δ 3 -cepem-4-carboxylic acid
7-아미노-3-(2-메틸-1, 3, 4-티아디아졸-5-일-티오메틸)-Δ3-세펨-4-카복실산 및 2-(트리페닐메틸아미노티아졸-4-일)-2-syn-벤질옥스이미노-아세트산을 사용할 경우, 7-[2-(2-트리틸아미노티아졸-4-일-)-2-syn-벤질옥스이미노-아세트아미도]-3-(2-메틸-1, 3, 4-티아디아졸-5-일-티오메틸)-Δ3-세펨-4-카복실산을 얻는데 이 물질은 60℃에서 50%의 포름산과 작용시키면 7-[2-(2-아미노티아졸-4-일)-2-syn-벤질옥스이미노아세트아미도]-3-(2-메틸-1, 3, 4-티아졸-5-일)티오메틸-Δ3-세펨-4-카복실산(크림색 고형)으로 전환된다.7-amino-3- (2-methyl-1, 3, 4-thiadiazol-5-yl-thiomethyl) -Δ 3 -cepem-4-carboxylic acid and 2- (triphenylmethylaminothiazole-4- Il) -2-syn-benzyloximino-acetic acid, 7- [2- (2-tritylaminothiazol-4-yl-)-2-syn-benzyloximino-acetamido] -3 -(2-Methyl-1,3,4-thiadiazol-5-yl-thiomethyl) -Δ 3 -cepem-4-carboxylic acid is obtained, which reacts with 50% formic acid at 60 ° C. to give 7- [ 2- (2-aminothiazol-4-yl) -2-syn-benzyloximinoacetamido] -3- (2-methyl-1, 3, 4-thiazol-5-yl) thiomethyl- Δ 3 -cepem-4-carboxylic acid (creamy solid).
NMR : Rf 0. 38(n-BuOH : H2O : EtOH : AcOH=20 : 4 : 3 : 3)NMR: Rf 0.338 (n-BuOH: H 2 O: EtOH: AcOH = 20: 4: 3: 3)
[실시예 12]Example 12
7-[2-(2-아미노티아졸-4-일)-2-syn-페녹스이미노-아세트아미도]-세팔로스포란산7- [2- (2-aminothiazol-4-yl) -2-syn-phenoximino-acetamido] -cephalosporanic acid
톨루엔중의 2-(트리페닐메틸아미노-티아졸-4-일)-2-syn-페녹스이미노-아세트산에 N, N-디메틸아세트아미드 및 포스겐을 가하여서 상응하는 착화합물을 얻는데 이 물질은 에틸탄클로라이드/트리메틸아민액에 7-아미노세팔로스포란산을 녹인 액과 반응시킬 때 7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2-syn-페녹스이미노] -세팔로스포란산을 얻는다.N, N-dimethylacetamide and phosgene were added to 2- (triphenylmethylamino-thiazol-4-yl) -2-syn-phenoximino-acetic acid in toluene to obtain the corresponding complex compound. 7- [2- (2-triphenylmethylaminothiazol-4-yl) -2-syn-phenoximino] when reacted with a solution of 7-aminocephalosporanic acid dissolved in a carbon chloride / trimethylamine solution. Get cephalosporan acid
이렇게 얻어진 트리틸화된 물질은 1시간동안 60℃에서 50%의 포름산에서 교반시키고 분리되어나온 트리페틸카비놀을 제거하고 여액은 증발농축한 후 에테르로 처리한다. 베이지색의 7-[2-(2-아미노티아졸-4-일)-2-syn-페녹스이미노]-세팔로스포란산을 고형물질로 얻으며 이 물질은 TLC에서 Rf치=0. 54(Bu-OH : H2O : EtOH : ACOH=10 : 4 : 3 : 3)를 갖는 균질상 물질로서 나타났다·The tritylated material thus obtained was stirred in 50% formic acid at 60 ° C. for 1 hour, the separated trifetylcarbinol was removed and the filtrate was concentrated by evaporation and treated with ether. Beige 7- [2- (2-aminothiazol-4-yl) -2-syn-phenoximino] -cephalosporanic acid was obtained as a solid, which was obtained by TLC = 0. 54 (Bu-OH: H 2 O: EtOH: ACOH = 10: 4: 3: 3) appeared as homogeneous material with
[실시예 13]Example 13
3-아세톡시메틸-7-[2-(2-트리틸아미노-4-티아졸릴)-2-(syn) -메톡스이미노-아세 트아미도]-세프-3-엠-카복실산의 디에틸아민염Diethyl of 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-carboxylic acid Amine salt
54g(0. 1몰)의 2-(2-트리틸아미노-4-티아졸릴)-2-syn-메톡스이미노아세트산(82%)을 4구의 플라스크중의 800ml의 톨루엔에 현탁시킨다. 다음에 300ml의 톨루엔을 진공하에 50℃의 욕에서 증류해 버린다. 현탁액은 -5。C로 냉각시키고 9. 3ml(0. 1몰)의 N, N-디메틸아세트아미드를 가하고 15분에 걸쳐 70ml의 톨루엔(=0.14몰)중의 2M 포스겐을 가하여 5시간 동안 교반을 계속한다.54 g (0.1 mol) of 2- (2-tritylamino-4-thiazolyl) -2-syn-methoximinoacetic acid (82%) is suspended in 800 ml of toluene in four flasks. Next, 300 ml of toluene is distilled off in a 50 degreeC bath under vacuum. The suspension was cooled to -5 ° C. and 9.3 ml (0.1 mol) of N, N-dimethylacetamide was added and stirred for 5 hours by adding 2M phosgene in 70 ml of toluene (= 0.14 mol) over 15 minutes. Continue.
300ml의 메틸렌클로라이드에 27. 2g(0. 1몰)의 7-아미노세팔로스포란산과 48. 7g(0. 2몰)의 N, O-비스-트리메틸실릴 아세트아미드를 생성된 현탁액에 -5℃에서 교반하면서 가하고, -5℃에서 30분간 실온에서 60분간 교반한다. 500ml의 메틸렌클로라이드로 희석한 다음 반응액은 매회 500ml의 물과 3회 진탕하여 유기층을 추출하고 이를 황산나트륨 상에서 탈수시키고 진공하에 농축, 건조한다. 잔사는 250ml의 아세톤에 녹이고 10. 3ml의 디에틸아민을 30분동안 교반하여 환류한다. 냉각, 흡인여과, 아세톤으로 세척 및건조시켜 표제화합물을 고수율로 얻는다. 이 물질은 syn-배열을 나타낸다.To 300 ml of methylene chloride, 27.2 g (0.1 mol) of 7-aminocephalosporanic acid and 48.7 g (0.2 mol) of N, O-bis-trimethylsilyl acetamide were added to the resulting suspension. It is added with stirring at ℃, and stirred for 30 minutes at room temperature at -5 ℃ 60 minutes. After dilution with 500 ml of methylene chloride, the reaction solution was shaken three times with 500 ml of water each time to extract the organic layer, which was dehydrated over sodium sulfate, concentrated in vacuo and dried. The residue was dissolved in 250 ml of acetone and refluxed with 10. 3 ml of diethylamine for 30 minutes. Cooling, suction filtration, washing with acetone and drying gives the title compound in high yield. This material represents a syn-array.
NMR(DMSO, 60MHz) : 6. 68ppm=티아졸 환 양자.NMR (DMSO, 60 MHz): 6. 68 ppm = thiazole ring proton.
[실시예 14]Example 14
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn) -메톡스이미노-아세트아미도]-세프-3-엠-카록실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-carboxylic acid
20. 1g(0. 1몰)의 2-(2-아미노-4-티아졸릴)-2-메톡스이미노아세트산을 -10℃로 냉각한, 350ml의 메틸렌클로라이드에 현탁시키고 9. 3ml(0. 1몰)의 N, N-디메틸아세트아미드 및 연이어서 교반시키면서 5분이내에 75ml의 톨루엔중의 포스겐(2몰 용액=0. 15몰)을 가한다. 담황색 용액이 형성된 25분후에 21.4g(0. 08몰)의 7-아미노세팔로스포란산 및 500ml의 메틸렌클로라이드중의 39ml(0. 16몰)의 비스트리메틸실릴아세트아미드를 온도가 -3℃를 넘지 않도록 주의하면서 적가한다. 가하는 동안에 수지상 생성물이 침전되기 시작한다. 침전이 완결시키기 위해, 30분 후에 3ml의 물을 가한다. 유기용액층을 떨어버린다. 잔사는 200ml의 메틸렌클로라이드를 가하고 용매는 제거하여 잔사는 실온에서 진공하에 잔류용매를 완전히 제거한다. 담황색 무정형 잔사중에 표제 화합물이 함유된다.20. 1 g (0.1 mol) of 2- (2-amino-4-thiazolyl) -2-methoximinoacetic acid is suspended in 350 ml of methylene chloride cooled to -10 ° C and 9. 3 ml (0. 1 mole) of N, N-dimethylacetamide and successive stirrings are added within 5 minutes with 75 ml of phosgene (2 moles solution = 0.15 moles) in toluene. 25 minutes after formation of the pale yellow solution, 21.4 g (0.08 moles) of 7-aminocephalosporanic acid and 39 ml (0.16 moles) of bistrimethylsilylacetamide in 500 ml of methylene chloride were subjected to a temperature of -3 ° C. Be careful not to exceed it. During addition the dendritic product begins to precipitate. To complete the precipitation, 3 ml of water is added after 30 minutes. Drop off the organic solution layer. The residue is added with 200 ml of methylene chloride and the solvent is removed so that the residue is completely removed in vacuo at room temperature. The title compound is contained in a pale yellow amorphous residue.
이 물필을 150ml의 80% 포름산에 용해하고 생성된 용액을 700ml의 40% 수성황산 암모늄 용액에 가한다. 형성된 수지상 침전물은 제거하고 60ml씩의 빙수로 3회 처리한다. 얻어진 생성물을 흡인여과 및 증발건조한다. 이렇게하여 syn-배열을 가진 표제 화합물의 포름산 염을 얻는다.This paint is dissolved in 150 ml of 80% formic acid and the resulting solution is added to 700 ml of 40% aqueous ammonium sulfate solution. The formed dendritic precipitate is removed and treated three times with 60 ml of ice water. The resulting product is suction filtered and evaporated to dryness. This gives the formate salt of the title compound with syn-array.
NMR(DMSO : 60MHz) : 6. 68ppm(티아졸 환 양자), 8. 13ppm(포르밀)NMR (DMSO: 60 MHz): 6.68 ppm (thiazole ring proton), 8. 13 ppm (formyl)
탈포르밀화시키기 위해, 생성물을 50ml의 무수 에탄올에 가하고 50℃에서 30분간 교반하고 흡인여과한후 에탄올로 세척하고 syn-배열을 갖는 담회색 표제 화합물을 얻는다.To deformylate, the product is added to 50 ml of absolute ethanol, stirred at 50 ° C. for 30 minutes, filtered off with suction and washed with ethanol to give the pale gray title compound with syn-array.
NMR(DMSO : 60MHz) : 6. 68ppm(티아졸 환 양자).NMR (DMSO: 60 MHz): 6. 68 ppm (thiazole ring proton).
[실시예 15]Example 15
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn) -매톡스이미노-아세트아미노]-세프-3-엠-4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -matoximino-acetamino] -cep-3-m-4-carboxylic acid
10. 0g(0. 05몰)의 2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노아세트산을 200ml의 무수메틸렌클로라이드에 현탁시킨다. -10℃로 냉각한 후에 4. 65ml(0. 05몰)의 디메릴아세트아미드를 가하고 5. 75ml(0. 062몰)의 옥시염화인을 적가하며 2. 5시간 동안 교반한다·10. 0 g (0.05 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -methoximinoacetic acid is suspended in 200 ml of anhydrous methylene chloride. After cooling to −10 ° C., 4. 65 ml (0.005 mol) of dimerylacetamide is added and 5. 75 ml (0.062 mol) of phosphorus oxychloride is added dropwise and stirred for 2. 5 hours.
250ml의 메틸렌클로라이드에 10. 8g(0. 04몰)의 7-아미노세팔로스포탄산 및 19. 5ml(0. 08몰)의 비스트리메틸실릴아세트아미드를 녹인 용액을-10℃에서 상기 현탁액에 적가한다. 2시간동안 0℃에서 교반하고 생성물을 실시예 l3의 방법에 따라 처리한다. 생성된 표제화합물은 syn-배열구조를 나타낸다.A solution of 10.8 g (0.04 moles) of 7-aminocephalospotanic acid and 19.5 ml (0.08 moles) of bistrimethylsilylacetamide in 250 ml of methylene chloride was added dropwise to the suspension at -10 ° C. do. Stir at 0 ° C. for 2 h and treat the product according to the method of Example l3. The resulting title compound exhibits a syn-array structure.
NMR(DMSO : 60MHz) : 6. 68ppm(티아졸 환 양자).NMR (DMSO: 60 MHz): 6. 68 ppm (thiazole ring proton).
[실시예 16]Example 16
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트아미도]-세프-3-엠-4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
실시예 14와 유사한 방법 으로, 5g(0, 025몰)의 2-(2-아미노-4-티아졸릴)-2-syn-메톡스이미노아세트산, 3. 17g의 N-아세틸피페리딘 및 3. 8g의 포스겐을 반응시킨다. 생성물은 syn-배열구조를 갖는다.In a similar manner to Example 14, 5 g (0, 025 moles) of 2- (2-amino-4-thiazolyl) -2-syn-methoximinoacetic acid, 3. 17 g of N-acetylpiperidine and 3 React 8 g of phosgene. The product has a syn-array structure.
[실시예 17]Example 17
3-아세톡시메틸-7-[2-(2-아미노-티아졸릴)-2-(syn) -메톡스이미노-아세트아미도]-세프-3-엠 -4-카복실산3-acetoxymethyl-7- [2- (2-amino-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
실시예 14와 유사한 방법으로, 5g(0. 025몰)의 2-(2-아미노-4-티아졸릴)-2-syn-메톡스이미노아세트산, 2. 5g의 N-에틸피롤리돈 및 3. 8g의 포스겐을 반응시킨다. 반응생성물은 syn-배열구조를 갖는다.In a similar manner to Example 14, 5 g (0.025 moles) of 2- (2-amino-4-thiazolyl) -2-syn-methoximinoacetic acid, 2.5 g of N-ethylpyrrolidone and 3 React 8 g of phosgene. The reaction product has a syn-array structure.
[실시예 18]Example 18
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn) -메톡스이미노-아세트아미도]-세프-3-엠 -4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
실시예 14와 유사한 방법으로, 5g(0. 025몰)의 2-(2-아미노-4-티아졸릴)-2-syn-에톡스이미노아세트산, 2. 5g의 N, N-디메틸프로피온아미드 및 3. 8g의 포스겐을 반응시킨다. 생성물은 syn-배열의 구조를 갖는다.In a similar manner to Example 14, 5 g (0.025 moles) of 2- (2-amino-4-thiazolyl) -2-syn-ethoximinoacetic acid, 2.5 g of N, N-dimethylpropionamide and 3. React 8 g of phosgene. The product has a syn-array structure.
[실시예 19]Example 19
3-아세톡시메틸-7-[2-(2-아미노-4-티아졸릴)-2-(syn)-메톡스이미노-아세트아미도]-세프-3-엠-4-카복실산3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoximino-acetamido] -cep-3-m-4-carboxylic acid
실시예 14와 유사한 방법으로 5g의 2-(2-아미노-4-티아졸릴)-2-syn-메톡스이노아세트산, 3. 15g의 N, N-디에틸아세트아미드 및 3. 8g의 포스겐을 반응시킨다. 생성물을 syn-배열구조를 갖는다.5 g of 2- (2-amino-4-thiazolyl) -2-syn-methoxinoacetic acid, 3. 15 g of N, N-diethylacetamide and 3. 8 g of phosgene were prepared in a similar manner to Example 14. React. The product has a syn-array structure.
[실시예 9의 출발물질의 제조방법][Production method of starting material of Example 9]
a) 2-syn-벤질옥스이미노아세트 아세트산에틸에스테르a) 2-syn-benzyloximinoacetic acid ethyl ester
30. 5g의 탄산칼륨을 15℃에서 교반하면서 120ml의 아세톤에 23. 5g의 2-syn-옥스이미노 아세트아세트산 에스테르를 가한 용액에 가한다. 다음에 25. 6g의 벤질브로마이드를 4시간동안에 걸쳐 실온에서 적가한 다음 이 온도에서 교반하지 않고 16시간 동안 방치한다.30. Add 5 g of potassium carbonate to a solution of 23. 5 g of 2-syn-oximino acetic acid ester in 120 ml of acetone with stirring at 15 ° C. 25. 6 g of benzylbromide are then added dropwise over 4 hours at room temperature and then left for 16 hours without stirring at this temperature.
고형물질을 여과해내고 용액은 농축건조한다. 잔존하는 기름을 진공(0. 05mm)하에 80℃로 가열하여서 과량의 벤질브로마이드를 제거하여 냉각시킨 다음 5% 중탄산나트륨 액을 가하고 에테르로 추출한다. 에테르 층은 2회 수세하고 황산나트륨 상에서 탈수한 다음 농축한다.The solids are filtered off and the solution is concentrated to dryness. The remaining oil is heated to 80 ° C. under vacuum (0.05 mm) to remove excess benzyl bromide and cooled, followed by addition of 5% sodium bicarbonate solution and extraction with ether. The ether layer is washed twice and dehydrated over sodium sulfate and then concentrated.
2-syn-벤질옥스이미노 아세토아세트산에스테르가 담황색 기름으로 얻어진다.2-syn-benzyloximino acetoacetic acid ester is obtained as a pale yellow oil.
[TLC(CHCl3/아세트산에스테르 20 : 1) : Rf 0. 74].[TLC (CHCl 3 / acetic acid ester 20: 1): Rf 0.774].
b) 2-syn-벤질옥스이미노-4-브로모아세트아세트산 에틸에스테르 ,b) 2-syn-benzyloximino-4-bromoacetic acetic acid ethyl ester,
80ml의 무수메틸렌 클로라이드에 12.5g의 2-syn-벤질옥스이미노아세트 아세트산에스테르를 녹인 용액에 150mg의 톨루엔설폰산을 가한다음 이어서 실온에서 브롬의 필요량 8g중의 2g을 가한다. 교반하면진한 갈색이 사라진다. 나머지 브롬을 적가한 즉시 1.5시간동안 교반을 계속하고 0℃로 반응혼합물을 냉각한후 이어서 10% 중탄산나트륨으로 세척한다.To 80 ml of anhydrous methylene chloride was dissolved 150 mg of toluenesulfonic acid in a solution of 12.5 g of 2-syn-benzyloximinoacetic acetate ester followed by 2 g of 8 g of bromine required at room temperature. After stirring, the dark brown disappears. As soon as the remaining bromine was added dropwise, stirring was continued for 1.5 hours, the reaction mixture was cooled to 0 ° C, and then washed with 10% sodium bicarbonate.
유기층은 분리하고 황산나트륨 상에서 탈수시킨 다음 농축하고 잔류하는 기름은 사이클로헥산으로 재결정한다. 융점 이 66내지 68℃ 인 2-syn-벤질옥스이미노-4-브로모아세토아세트산 에틸에스테르트를 무색결정으로 얻는다.The organic layer is separated, dehydrated over sodium sulfate, concentrated and the remaining oil is recrystallized from cyclohexane. 2-syn-benzyloximino-4-bromoacetoacetic acid ethyl ester having a melting point of 66 to 68 캜 is obtained as colorless crystals.
c) 2-(2-아미노-티아졸-4-일)-2-syn-벤질옥스이미노아세트산 에틸에스테르c) 2- (2-amino-thiazol-4-yl) -2-syn-benzyloximinoacetic acid ethyl ester
98%의 에탄올 60ml의 11. 8g의 2-syn-벤질옥스이미노-4-브로모아세토아세트산 에틸에스테르를 녹인 액을 50ml의 40% 에탄올에 2. 66g의 티오우레아를 녹인 액이 가하고 실온에서 20분간에 40ml의 아세톤을 적가한다. 반응액을 25℃dp서 2시r간동안 교반하고 생성물이 석출할때까지 농축하고 결정을 분리한다. 생성물을 상승온도에서 50%에탄올에 녹이고 pH를 수성암모니아로 7에 맞춘다. 분리되어 나오는 크림색 결정을 분리하고 40%에탄올 및 디이소푸로필로 세척하고 건조하여 융점이 135내지 138℃인 2-(2-아미노티아졸-4-일)-2-syn--벤질옥스이미노-아세트산에 틸 에스테 르를 거의 무색결정 으로 얻는다.60 ml of 98% ethanol and 11.8 g of 2-syn-benzyloximino-4-bromoacetoacetic acid ethyl ester were dissolved in 50 ml of 40% ethanol and 2.66 g of thiourea was added thereto. 40 ml of acetone is added dropwise for a minute. The reaction solution is stirred for 2 hours at 25 ° C. dp, concentrated until the product precipitates and the crystals are separated. The product is dissolved in 50% ethanol at elevated temperature and the pH adjusted to 7 with aqueous ammonia. Separated cream crystals were separated, washed with 40% ethanol and diisofurophyl and dried to give 2- (2-aminothiazol-4-yl) -2-syn--benzyloximino- with a melting point of 135 to 138 ° C. Ethyl acetate is obtained almost as colorless crystals.
d) 2-(2-트리페닐메틸아미노-티아졸-4-일)-2-syn-벤조일옥스이미노-아세트산에틸에스테르d) 2- (2-triphenylmethylamino-thiazol-4-yl) -2-syn-benzoyloximino-ethyl acetate
125ml의 무수 CH2C12와 25ml의 디메틸포름아 미드에 18. 3g의 2-(2-아미노티아졸-4-일)-2-syn-벤조일옥스이미노-아세트산 에틸에스테르를 녹인 용액에-15℃에서 6. 7g의 트리에틸아민을 가하여서-35℃로 냉각하고 17. 5g의 트리페닐클로로메탄올 가한다음 -30℃에서 1시간동안 교반하고 실온에서 3시간동안 교반한다·In a solution of 18.3 g of 2- (2-aminothiazol-4-yl) -2-syn-benzoyloximino-acetic acid ethyl ester in 125 ml of anhydrous CH 2 C1 2 and 25 ml of dimethylformamide-15 6.7 g of triethylamine was added to the mixture, cooled to -35 ° C, 17.5 g of triphenylchloromethanol were added, followed by stirring at -30 ° C for 1 hour and at room temperature for 3 hours.
다음에 반응액을 0℃로 냉각하여 반복하여 2N 염산과 물로 세척하고 유기층을 분리해서 황산나트륨상에서 탈수하고 용매를 제거한다. 생성물은 크림색 고형물질인 2-(2-아미노-티아졸-4-일)-2-syn-벤질옥스이미노아세트산 에틸에스테르이며, 이 화합물은 정제치 않고 바로 다음 반응에 사용할 수 있다.The reaction solution was then cooled to 0 ° C. and washed repeatedly with 2N hydrochloric acid and water. The organic layer was separated, dehydrated over sodium sulfate and the solvent removed. The product is a cream solid, 2- (2-amino-thiazol-4-yl) -2-syn-benzyloximinoacetic acid ethyl ester, which can be used for the next reaction without purification.
(TLC CHCl3/아세트산 에스테르 1:1, Rf=0. 98, 출발물질의 Rf=0. 63).(TLC CHCl 3 / acetic acid ester 1: 1, R f = 0.98, starting material R f = 0.63).
e) 2-(2-트리페닐에틸아미노-티아졸-4-일)-2-syn-벤질옥스이미노-아세트산의 나트륨염.e) Sodium salt of 2- (2-triphenylethylamino-thiazol-4-yl) -2-syn-benzyloximino-acetic acid.
상기에서 얻어진 2-(2-트리페닐메틸아미노-티아졸-4-일)-2-syn-벤질옥스이미노 아세트산에틸에스테르를 230ml 에탄올 및 40ml의 디옥산혼액에 60℃에서 용해시키고 45ml의 물에 3g의 수산화나트륨을 녹인 용액을 가하며 2시간동안 환류시킨다. 다음이 반응액을 거의 농축시키고 350ml의 물을 잔사에가하면 2-(2-트리페닐메틸-아미노티아졸-4-일)-2-syn-벤질옥스이미노 아세트산의 나트륨염 이 융점 257내지 258℃(분해)의 무색 고형물질로서 얻어진다.2- (2-triphenylmethylamino-thiazol-4-yl) -2-syn-benzyloximinoacetic acid ethyl ester obtained above was dissolved in 230 ml ethanol and 40 ml dioxane mixture at 60 DEG C and in 45 ml water. A solution of 3 g of sodium hydroxide is added and refluxed for 2 hours. The reaction solution was then almost concentrated and 350 ml of water was added to the residue to give the sodium salt of 2- (2-triphenylmethyl-aminothiazol-4-yl) -2-syn-benzyloximinoacetic acid at a melting point of 257 to 258. Obtained as a colorless solid material at deg.
f) 2-(2-트리페닐메틸아미노-티아졸-4-일)-2-syn-벤질옥스이미노아세트산.f) 2- (2-triphenylmethylamino-thiazol-4-yl) -2-syn-benzyloximinoacetic acid.
상기에서 얻어진 2-(2-트리페닐메틸 아미노티아몰-4-일)-2-syn-벤질옥스이미노 아세트산의 나트륨염을 250ml의 메틸렌클로라이드에 현탁시키고 50℃에서 50ml의 2N염산과 교반하는데 이때 CH2C12에 잘 용해되는 산이 형성된다.The sodium salt of 2- (2-triphenylmethyl aminothiamol-4-yl) -2-syn-benzyloximinoacetic acid obtained above is suspended in 250 ml of methylene chloride and stirred with 50 ml of 2N hydrochloric acid at 50 ° C. Acids that dissolve well in CH 2 C1 2 are formed.
유기층을 분리하고 황산나트륨상에서 탈수한 다음 용매를 제거한다. 잔사에 사이클로헥산을 가하여 거의 무색 고형물질을 얻으며 이 물질을 디이소프로필에테르로 세척하여 무정형 고체의 2-(2-트리페닐-메틸아미노-티아졸-4-일)-2-syn-벤질옥스이미노아세트산을 얻는다.The organic layer is separated, dehydrated over sodium sulfate and the solvent is removed. Cyclohexane was added to the residue to give an almost colorless solid, which was washed with diisopropyl ether to give 2- (2-triphenyl-methylamino-thiazol-4-yl) -2-syn-benzyloxide as an amorphous solid. Obtain Minoacetic Acid.
(TLC : CHCI3/CH3OH 6 : 1, Rf=0. 21).(TLC: CHCI 3 / CH 3 OH 6: 1, R f = 0.21).
[실시예 12의 출발물질 제조][Preparation of Starting Material of Example 12]
a) 보로모아세틸글리옥실 산에틸에스테르 120g의 아세틸글리옥실산 에틸에스테르를 700ml의 메틸렌클로라이드에 용해하고 용액을 5℃에서 l시간내에 200ml의 메틸렌 클로라이드에 146g의 브롬을 녹인 용액과 반응시킨다·a) 120 g of boromoacetylglyoxylic acid ethyl ester is dissolved in 700 ml of methylene chloride and the solution is reacted with a solution of 146 g of bromine dissolved in 200 ml of methylene chloride within 5 hours at 5 ° C.
용액을 탈색시킨다음 용매를 제거하고 잔류한 기름을 더 정제치 않고 반응시킨다·The solution is decolorized and the solvent is removed and the remaining oil is reacted without further purification.
b) 2-아미노-티아졸-4-일-글리옥실산에틸에스테르 450ml의 물 및 450ml의 에탄올에 66g의 티오우레아를 녹인 용액에 5℃에서 195g의 보르모아세토글리옥실산 에틸에스테르를 가한 후 실온에서 30분간50℃에서 30분간 교반하고 활성탄을 가한다음 여과한다. 여액의 pH를 중탄산나트륨을 가하여 7로 맞추면 융점 147℃의 2-아미노-티아졸-4-일 글리옥실산에틸 에스테르가 결정으로 석출한다.b) 195 g of bormoacetoglyoxylic acid ethyl ester was added to a solution of 66 g of thiourea in 450 ml of water and 450 ml of ethanol, 2-amino-thiazol-4-yl-glyoxylic acid ethyl ester at 5 ° C. Stir at room temperature for 30 minutes at 50 ° C. for 30 minutes, add activated charcoal and filter. When the pH of the filtrate was adjusted to 7 by adding sodium bicarbonate, 2-amino-thiazol-4-yl glyoxylic acid ethyl ester having a melting point of 147 ° C precipitated as crystals.
c) 2-트리페닐메틸 아미노-티아졸-4-일 글리옥실산 에틸에스데르.c) 2-triphenylmethyl amino-thiazol-4-yl glyoxylic acid ethyl ester.
225ml의 디메틸포름아미노 및 375ml의 CH2C12에 90g의 2-아미노티아졸-4-일-글리옥실산 에틸에스테르를 녹인 액에다 -15℃에서 27g의 트리에틸아민 및 30℃에서 75g의 트리페닐클로로메탄을 가한다. -30℃에서 15분동안 방치후 욕을 냉각시키지 않고 3시간동안 교반하며 생성되는 반응혼액에 차례로 500ml의 CH2Cl2, 300ml의 1N 염산 및 두 차례의 200ml의 물을 가한다. 유기층을 황산나트륨 상에서 탈수하고 용매를 증발시킨다. 기름상 물질이 잔류하며 이를 정제하지 않고 바로 사용한다.In a solution of 90 g of 2-aminothiazol-4-yl-glyoxylic acid ethyl ester in 225 ml of dimethylformamino and 375 ml of CH 2 C1 2 , 27 g of triethylamine at -15 ° C. and 75 g of tree at 30 ° C. Phenylchloromethane is added. After standing at −30 ° C. for 15 minutes, the reaction mixture was stirred for 3 hours without cooling the bath, followed by addition of 500 ml of CH 2 Cl 2 , 300 ml of 1N hydrochloric acid and two 200 ml of water. The organic layer is dehydrated over sodium sulfate and the solvent is evaporated. Oily substances remain and are used directly without purification.
d) 2-트리페닐메틸 아미노-티아졸-4-일-글리 옥실산.d) 2-triphenylmethyl amino-thiazol-4-yl-glyoxylic acid.
150ml의 에탄올에 156g의 불순한 2-트리페닐메틸아미노티아졸-4-일-글리옥실산에틸 에스테르를 녹인 용액에 370ml의 메탄올중에 14. 8g의 수산화나트륨을 녹안 용액을 가하고 5분간 환류시키면 2-트리페닐메틸 아미노-티아졸-4-일-글리옥실산이 결정으로 분리한다. 얻어진 나트륨염을 380ml의 물에 현탁시키고 세게 교반하면서 76ml의 2N 염산을 가한다. 15분 후에 침전을 흡인여과하고 수세하고 건조한다.In a solution of 156 g of impure 2-triphenylmethylaminothiazol-4-yl-glyoxylic acid ethyl ester in 150 ml of ethanol, 14.8 g of sodium hydroxide in 370 ml of methanol was added, and the solution was refluxed for 5 minutes. Triphenylmethyl amino-thiazol-4-yl-glyoxylic acid separates into crystals. The resulting sodium salt is suspended in 380 ml of water and 76 ml of 2N hydrochloric acid is added with vigorous stirring. After 15 minutes the precipitate is suction filtered, washed with water and dried.
융점이 163내지 165℃(분해)인 2-트리페닐메틸아미노티아졸-4-일-글리옥실산을 황색결정으로 얻는다.2-triphenylmethylaminothiazol-4-yl-glyoxylic acid having a melting point of 163 to 165 캜 (decomposition) is obtained as yellow crystals.
e) 2-(2-트리페닐메틸아미노-티아졸-4-일)-2-syn-페녹스이미노아세트산.e) 2- (2-triphenylmethylamino-thiazol-4-yl) -2-syn-phenoximinoacetic acid.
30g의 트리페닐메틸아미노-티아졸-4-일)글리옥실산을 450ml의 빙초산 및 90ml의 물에 가하고 이어서8g의 0-페닐하이드록실아민을 가한다. 반응 혼합물이 맑아지며 잠시후 옥실이 결정화하기 시작한다. 15분후에 200ml의 물을 10내지 15℃에서 교반하면서 가한다. 분리된 결정을 흡인여과하고 아세톤과 교반한후 다시 여과하여 융점이 141내지 143℃(분해)인 2-(2-트리페닐메틸아미노티아졸-4-일)-2-syn-페녹스이미노 아세트산을 무색고형으로 얻는다.30 g of triphenylmethylamino-thiazol-4-yl) glyoxylic acid are added to 450 ml of glacial acetic acid and 90 ml of water followed by 8 g of 0-phenylhydroxylamine. The reaction mixture is clear and after some time the oxyl begins to crystallize. After 15 minutes, 200 ml of water are added with stirring at 10-15 ° C. The separated crystals were suction filtered, stirred with acetone and filtered again to obtain 2- (2-triphenylmethylaminothiazol-4-yl) -2-syn-phenoximinoacetic acid having a melting point of 141 to 143 캜 (decomposition). To obtain colorless solid.
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