KR840000865B1 - Process for preparing -lactam-containing antibacterial agents - Google Patents
Process for preparing -lactam-containing antibacterial agents Download PDFInfo
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- KR840000865B1 KR840000865B1 KR1019800000767A KR800000767A KR840000865B1 KR 840000865 B1 KR840000865 B1 KR 840000865B1 KR 1019800000767 A KR1019800000767 A KR 1019800000767A KR 800000767 A KR800000767 A KR 800000767A KR 840000865 B1 KR840000865 B1 KR 840000865B1
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- KR
- South Korea
- Prior art keywords
- formula
- compound
- reaction
- lower alkyl
- general formula
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000003242 anti bacterial agent Substances 0.000 title 1
- -1 p-methoxybenzyl Chemical group 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 93
- 238000006243 chemical reaction Methods 0.000 claims description 60
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxylic acid Natural products OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 2
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 claims description 2
- 150000000475 acetylene derivatives Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 2
- 238000006385 ozonation reaction Methods 0.000 claims description 2
- CJZSHVMLIFESHD-UHFFFAOYSA-O (3-amino-4-oxo-1-sulfanylpyridin-2-yl)oxycarbonylazanium Chemical compound NC(=O)OC1=C(N)C(O)=CC=[N+]1S CJZSHVMLIFESHD-UHFFFAOYSA-O 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 150000007514 bases Chemical class 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 238000006317 isomerization reaction Methods 0.000 claims 1
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 27
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 abstract description 3
- MZMJOCVSWOZZEO-UHFFFAOYSA-O (3-amino-1-sulfanylpyridin-1-ium-2-yl) carbamate Chemical compound NC=1C(=[N+](C=CC1)S)OC(N)=O MZMJOCVSWOZZEO-UHFFFAOYSA-O 0.000 abstract 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 abstract 1
- 150000002961 penems Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 229940093499 ethyl acetate Drugs 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 0 CC(OCC=C(COC(C)=O)S[C@@](C1)*(C*c2ccc(C)cc2)C1O)=O Chemical compound CC(OCC=C(COC(C)=O)S[C@@](C1)*(C*c2ccc(C)cc2)C1O)=O 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 150000003952 β-lactams Chemical class 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LLYSCVDKLKLODX-UHFFFAOYSA-N 3-acetyloxy-2-oxopropanoic acid Chemical compound CC(=O)OCC(=O)C(O)=O LLYSCVDKLKLODX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- TVIMIQVBDDNCCR-UHFFFAOYSA-N 4-acetyloxybut-2-ynyl acetate Chemical compound CC(=O)OCC#CCOC(C)=O TVIMIQVBDDNCCR-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 125000005633 phthalidyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- NOZZNTMQLTZXGD-UHFFFAOYSA-N CC1=CC=C(C)C(N=O)=CC1 Chemical compound CC1=CC=C(C)C(N=O)=CC1 NOZZNTMQLTZXGD-UHFFFAOYSA-N 0.000 description 1
- ATSWFLLZUBQWLP-SCSAIBSYSA-N C[C@H](C1)N(C(C)=O)C1=O Chemical compound C[C@H](C1)N(C(C)=O)C1=O ATSWFLLZUBQWLP-SCSAIBSYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 241000338702 Cupido minimus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 239000005922 Phosphane Substances 0.000 description 1
- BTXLWRWDYZKCPQ-UHFFFAOYSA-N [nitro(phenyl)methyl] carbonochloridate Chemical compound ClC(=O)OC([N+](=O)[O-])C1=CC=CC=C1 BTXLWRWDYZKCPQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- DIOVBHTUHUUROP-UHFFFAOYSA-N acetyloxymethyl 2-oxoacetate Chemical compound CC(=O)OCOC(=O)C=O DIOVBHTUHUUROP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- YCOFRPYSZKIPBQ-UHFFFAOYSA-N penicillic acid Natural products COC1=CC(=O)OC1(O)C(C)=C YCOFRPYSZKIPBQ-UHFFFAOYSA-N 0.000 description 1
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229910000064 phosphane Inorganic materials 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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Abstract
Description
본 발명은 광범위 항균작용 및 β-락타마제억제작용을 갖는 β-락탐-함유화합물, 특히 하기일반식(Ⅰ)의 페넴-카복실산의 제조방법에 관한 것이다.The present invention relates to a method for producing a β-lactam-containing compound having a broad antibacterial action and a β-lactamase inhibitory action, particularly a penem-carboxylic acid of the following general formula (I).
상기식에서In the above formula
R은 수소원자, 저급알킬, 2,2,2-트리클로로에틸, 아세토닐, 벤질,-니트로벤질,-메톡시벤질, 페닐,-니트로페닐 또는 벤즈히드릴, 생체내에서 대사적 활성화를 거쳐 유리한 약물동력학적 성질을 가지는 것으로 알려진 아세톡시메틸, 피발로일옥시메틸 또는 프탈리딜, 또는 일반식또는 -CH2NHCOR2(여기서 R2는 1내지 5개의 탄소원자를 가지는 알킬 또는 아릴이다)의 그룹이며,R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, Nitrobenzyl, Methoxybenzyl, phenyl, Nitrophenyl or benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl, known to have advantageous pharmacokinetic properties through metabolic activation in vivo, or a general formula Or -CH 2 NHCOR 2 , wherein R 2 is alkyl or aryl having 1 to 5 carbon atoms
Z는 수소 또는 할로겐원자, 하이드록시, 아미노, 카바모일옥시, 머캅토, 도는 피리디늄, 또는 일반식 OR3, OCOR3, NHCOR3및 SR4(여기서 R3및 R4는 각각 저급알킬, 아릴 또는 헤데로 사이클환이며 각각은 치환 또는 비치환될 수 있다.)의 그룹이고,Z is hydrogen or a halogen atom, hydroxy, amino, carbamoyloxy, mercapto, or pyridinium, or a general formula OR 3 , OCOR 3 , NHCOR 3 and SR 4 , where R 3 and R 4 are lower alkyl, aryl Or hetero cyclic, each of which may be substituted or unsubstituted),
R1은 수소원자, 저급알킬, 저급알콕시, 사이클로알킬 또는 하이드록시알킬(바람직하게는 저급 하이드록시알킬)이며, 이때 하이드록시알킬의 알콜성 작용기는 유리형태이거나 또는 보호되며 보호기로는-니트로 벤질옥시카보닐 또는 디메틸-t-부틸-실릴이 바람직하고 n은 0 또는 1이다.R 1 is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl (preferably lower hydroxyalkyl), wherein the alcoholic functional group of the hydroxyalkyl is free or protected and Nitro benzyloxycarbonyl or dimethyl-t-butyl-silyl are preferred and n is 0 or 1.
6위치의 치환체는 α-배위 및 β-배위를 가지며, α-배위가 바람직하다.Substituents at the 6-position have α-configuration and β-configuration, with α-configuration being preferred.
생체내에서 대사적 활성화를 거쳐 유리한 약물동력학적 성질을 가지는 것으로 알려진 R의 정의에 포함되는 잔기들의 예에는 아세톡시메틸, 피발로옥시메틸 및 프탈리딜과 일반식및 -CH2NHCOR2의 그룹이 포함된다.Examples of residues included in the definition of R known to have beneficial pharmacokinetic properties through metabolic activation in vivo include acetoxymethyl, pivalooxymethyl and phthalidyl and general formulas. And a group of -CH 2 NHCOR 2 .
R1의 대표적인 예로는 메틸, 에틸, 메톡시, 1-하이드록시에틸 및 -1-(-니트로벤질옥시카보닐옥시)-에틸을 들 수 있다.Representative examples of R 1 include methyl, ethyl, methoxy, 1-hydroxyethyl and -1- ( -Nitrobenzyloxycarbonyloxy) -ethyl is mentioned.
R3및 R4가 헤테로사이클일 경우 바람직하게는 5- 또는 6-원 헤테로사이클환 잔기로, 예를들면 5-메틸-1,3,4-티아디아졸-2-일, 1-메틸-테트라졸-5-일, 1,3,2-트리아졸-5-일 또는 피라지닐등이다.When R 3 and R 4 are heterocycles they are preferably 5- or 6-membered heterocycle ring moieties, for example 5-methyl-1,3,4-thiadiazol-2-yl, 1-methyl- Tetrazol-5-yl, 1,3,2-triazol-5-yl or pyrazinyl and the like.
이들 화합물은 광범위 항균 활성을 가지며 β-락타마제 억제 활성을 갖는다. 신규의 β-락탐 함유 화합물 및 그의 제조용 중간중의 C5에서의 입체화학은 천연적으로 존재하는 페니실린 및 세팔로스포린과 동일하다.These compounds have broad antibacterial activity and have β-lactamase inhibitory activity. The novel beta -lactam containing compounds and the stereochemistry at C 5 in the intermediate for their preparation are identical to the naturally occurring penicillins and cephalosporins.
일반식(Ⅰ)의 페넴-카복실 산의 나트륨, 칼슘, 벤자틴, 프로카인염, 및 통상적인 페니실린 및 세팔로스포린과의 염을 포함한, 일반식(Ⅰ) 화합물의 약제학적으로 무독한 염의 제조 또한 본 발명의 범위내에 속한다.Preparation of Pharmaceutically Harmonic Salts of Compounds of Formula (I), Including Sodium, Calcium, Benzatin, Procaine Salts of Penem-Carboxylic Acid of Formula (I), and Salts with Common Penicillins and Cephalosporins It also falls within the scope of the present invention.
다음 도식은 본 발명에 따르는 일반식(Ⅰ)화합물의 제조공정을 설명하는 것이다.The following scheme illustrates the process for preparing the compound of general formula (I) according to the present invention.
R1이 수소인경우, 일반식(2)의 화합물은 (5R) 6-아미노 페니실린산(6-APA)을 출발몰줄로 하여, 널리 알려진 일반적인 방법에 따라 제조된다. [참조: CINARELLA et al., Journal of Organnic Chemistry2668 and EVRARD et al., Nature1124)]. R1이 저급알킬, 사이클로알킬 또는 하이드록시알킬인경우 R1기는 디니노등의 방법에 따라 도입시킬 수 있다. [참조: Di Ninno et al., Journal of Organinc Chemistry,2960(1977)]. R1이 저급알콕시인경우 R1는 저급알콕시인 경우 R1기는 출발물질인 6-APA의 6위치에 하우스등의 방법 및 기딩등의 방법에 따라 도입시킬 수 있다. [참조 : Hauser et al., Helv. Chem. Acta,1327(1967) and Giddings et al., Tetrahedron I etters, 11, 995(1978)].When R 1 is hydrogen, the compound of formula (2) is prepared according to the well-known general method using (5R) 6-amino penicillic acid (6-APA) as the starting mole. [CINARELLA et al., Journal of Organnic Chemistry 2668 and EVRARD et al., Nature 1124)]. When R 1 is lower alkyl, cycloalkyl or hydroxyalkyl, the R 1 group can be introduced by methods such as diino. See Di Ninno et al., Journal of Organinc Chemistry, 2960 (1977). When R 1 is lower alkoxy When R 1 is lower alkoxy, the R 1 group can be introduced at the 6-position of 6-APA, starting material, according to the method of house or the like. [Hauser et al., Helv. Chem. Acta, 1327 (1967) and Giddings et al., Tetrahedron I etters, 11, 995 (1978).
또한 R1이 수소인 일반식(2)의 화합물은 다음 실시예에서 설명하는 바와 같이 강염기를 사용하여 6위치에 치환제를 도입시킴으로써 R1이 저급알킬, 사이클로알킬 또는 하이드록시알킬인 일반식(2)의 화합물로 전환시킬 수 있다. R1이 저급알킬, 사이클로알킬 또는 하이드록시알킬인 일반식(2)의 화합물들은 다음 실시예에서 설명되는 바와 같이 페니실란 산 s-옥사이드의 적합한 에스테르를 출발물질로 하여 제조될 수 있다. 6위치의 치환반응은 입체특이적으로 수행되어 6α 유도체를 생성한다.In addition, the compound of formula (2) wherein R 1 is hydrogen may be prepared by introducing a substituent at the 6 position using a strong base, as described in the following examples, in which R 1 is lower alkyl, cycloalkyl or hydroxyalkyl ( Can be converted to the compound of 2). Compounds of formula (2) wherein R 1 is lower alkyl, cycloalkyl or hydroxyalkyl can be prepared starting with a suitable ester of penicsilane acid s-oxide as described in the following examples. The 6 position substitution reaction is performed stereospecifically to produce 6α derivatives.
R5가 알킬기이고 R1이 전술된 의미를 가지는 일반식(2)의 페니실란산 S-옥사이드의 에스테르는 벤젠 또는 톨루엔 같은 불활성 용매중에서 보통 70℃ 내지 140℃ 의 온도로 일반식 X'CCY [여기서, X'는 일반식 CH2Z'(이때 Z'는 수소 또는 할로겐원자, 하이드록시, 아미노, 카바모일옥시거나 일반식 OR3, OCOR3또는NHCOR3(여기서 R3는 임의 치환된 저급알킬, 아릴 또는 헤테로사이클환이다)의 그룹이고, Y는 수소원자, 저급알킬, 시아노 또는 일반식 COOR5또는 CH2Z'(여기서 R5및 Z'는 전술된 의미를 가진다)의 그룹이다.]의 적합한 아세틸렌 유도체와 함께 가열할 수 있다.The ester of peniclanic acid S-oxide of formula (2), wherein R 5 is an alkyl group and R 1 has the aforementioned meanings, is generally of the general formula X'C in an inert solvent such as benzene or toluene at a temperature of CY [where X 'is a general formula CH 2 Z' wherein Z 'is hydrogen or a halogen atom, hydroxy, amino, carbamoyloxy or a general formula OR 3 , OCOR 3 or NHCOR 3 , wherein R 3 is optionally substituted Is a lower alkyl, aryl or heterocycle ring), Y is a hydrogen atom, lower alkyl, cyano or a group of the formula COOR 5 or CH 2 Z ', wherein R 5 and Z' have the meanings set forth above Can be heated together with a suitable acetylene derivative.
일반식(3)의 화합물에서, X'가 X와 다를경우 널리 알려진 치환 반응, 즉 다음 실시예에서 기술된 것중의 한 방법을 사용하여 X'를 그룹 X[여기에서 X는 CH2Z(이때 Z는 전술한 바와 같다)의 그룹이다.]로 전환시킬 수 있다. 생성된 일반식(3)의 화합물은 염기를 사용하여 일반식(4)의 화합물로 이성화시킬 수 있으며, 이일반식(4)의 화합물은 두가지의 다른 방법에 따라 일반식(1)의 최종목적 화합물로 전환시킬 수 있다. 첫번재 방법에서는, 일반식(4)의 화합물의 이소프로페닐 이중결합상에서 선택적으로 오존화시켜서 n=1=인 일반식(5)의 화합물을 얻으며 이는 아세틸 클로라이드중의 포스포러스 트리브로마이드 또는 나트륨 요오다이드 같은 적당한 환원제를 사용하여 n=0인 일반식(5)의 화합물로 환원시킬 수 있고 계속해서 완화한 염기조건하 또는 실리카겔상에서 n=0인 일반식(6)의 화합물로 가수분해시킬 수 있다. 글리옥실산의 적합한 에스테르로 축합시키면 n-0인 일반식(7)의 화합물이 생성되며 이는 티오닐클로라이드 및 피리딘 같은 염소화제를 사용해서 n=0인 일반식(7)의 화합물이 생성되며 이는 티오닐클로라이드 및 피리딘 같은 염소화제를 사용해서 n=0인 일반식(8)의 클로로유도체로 전환시킬 수 있으며, 그 후 n=0인 일반식(9)의 포스포란으로 전환시킬 수 있다. 더우기 동일한 그룹의 반응들은 Y가 강한 이탈기가 아닐경우, 안정한 n=1인 일반식(6)의 예외적인 화합물들을 출발물질로 하여 수행할 수도 있다. n=0인 일반식(9)의 화합물을 포함하는 경우, 화합물을 산성 조건하에서 포스포늄염으로 선택적으로 오존화시켜서 일반식(11)의 화합물을 수득하여 이는 단지 톨루엔과 같은 불활성용매중, 50℃ 내지 140℃의 온도에서 간단히 가열함으로써 일반식(1)의 화합물로 폐환시킬 수 있다.In the compound of general formula (3), when X 'is different from X, a well-known substitution reaction, i.e., X' is used as a group X [where X is CH 2 Z (where Z is as described above). The resulting compound of formula (3) can be isomerized to a compound of formula (4) using a base, and the compound of formula (4) is the final compound of formula (1) according to two different methods Can be converted to In the first method, selective ozonation on isopropenyl double bond of the compound of general formula (4) yields a compound of general formula (5) wherein n = 1 = which is phosphorus tribromide or sodium urine in acetyl chloride. Using a suitable reducing agent such as odaide, it can be reduced to the compound of formula (5) with n = 0 and subsequently hydrolyzed to the compound of formula (6) with n = 0 on relaxed base conditions or on silica gel. have. Condensation with a suitable ester of glyoxylic acid yields a compound of formula (7) with n-0, which yields a compound of formula (7) with n = 0 using chlorinating agents such as thionylchloride and pyridine. Chlorinating agents such as thionylchloride and pyridine can be used to convert to chloro derivatives of formula (8) with n = 0 and then to phosphoranes of formula (9) with n = 0. Furthermore, reactions of the same group may be carried out as starting materials with exceptional compounds of the general formula (6) with stable n = 1 when Y is not a strong leaving group. In the case of containing a compound of formula (9) with n = 0, the compound is selectively ozonated with a phosphonium salt under acidic conditions to give a compound of formula (11), which is only in an inert solvent such as toluene, 50 It can be ring-closed to the compound of the general formula (1) by simply heating at a temperature of 캜 to 140 캜.
n=1인 일반식(9) 화합물의 경우에, 화합물은 일반식(10)의 화합물로 환원시키고 계속해서 일반식(11)의 화합물로 선택적 오존화시켜 일반식(1)의 화합물이 수득된다.In the case of the compound of formula (9), wherein n = 1, the compound is reduced to the compound of formula (10) and then selectively ozonated with the compound of formula (11) to give the compound of formula (1). .
두번재 방법에서는, 일반식(4)의 화합물을 통상의 조건하에서 환원시켜서 일반식(12)의 화합물을 수득한 다음 양쪽의 이중결합상에서 오존화시켜서 일ㅂ나식(13)의 화합물을 수득한후 가수분해하여 일반식(14)의 화합물을 수득한다. 전술한 바와 동일한 방법에 따라 일반식(14)의 화합물을 글리옥실화하면 일반식(15)의 화합물이 수득되며 이를 일반식(16)의 클로로유도체로 전환시킨뒤 두 가지 방법의 공통 중간체인 일반식(11)의 포스포란으로 전환시킬 수 있다.In the second method, the compound of formula (4) is reduced under ordinary conditions to obtain a compound of formula (12), and then ozonated on both double bonds to obtain a compound of formula (13). Hydrolysis yields the compound of formula (14). Glyoxylation of the compound of formula (14) according to the same method as described above yields the compound of formula (15), which is converted to the chloro derivative of formula (16) and is then a common intermediate of the two methods. It can be converted into the phosphoran of formula (11).
R1이 하이드록 시알킬일 경우, 반응은 바람직하게는 알콜성 작용기를 보호하여 수행한다. R이 수소인 일반식(1)의 화합물은 상응하는 에스테르화 화합물의 가수분해 또는 가수소분해에 의해 수득될 수 있다. n=1인 일반식(1)의 화합물은 널리 알려진 산화 공정에 따라 n=0인 일반식(1)의 화합물을 출발물질로 하여 용이하게 제조된다. 유리하게는 과산이 사용될 수 있으며, m-클로로퍼벤조산 및 퍼아세트산이 바람직하다. 본 명세서에서 설명된 공정은 본 발명의 범위내에 포함된다.When R 1 is hydroxylalkyl, the reaction is preferably carried out by protecting the alcoholic functional groups. Compounds of formula (1) wherein R is hydrogen can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compound. The compound of the general formula (1) having n = 1 is easily prepared by using the compound of the general formula (1) having n = 0 as a starting material according to a well-known oxidation process. Advantageously peracids can be used, with m-chloroperbenzoic acid and peracetic acid being preferred. The processes described herein are included within the scope of the present invention.
(5R) 아세톡시메틸-2-아세톡시 메틸-2-페넴-3-카복실레이트(실험 부호 FCE/20077/B40/341),(5R) 아세톡시메틸-2-[(1'-메틸-1'H- 테트라졸-5'-일)-티오메틸]-2-페넴-3-카복실레이트(화합물A)와 2개의 대조 화합물(암피실린과 세폭시틴)의활성을 비교하기 위하여 일련의 시험관내 시험을 수행하였다. 아래 표1은 상기시험결과를 MIC(최소 억제 농도 로서 표시한 것이다.(5R) acetoxymethyl-2-acetoxy methyl-2-phenem-3-carboxylate (experimental code FCE / 20077 / B40 / 341), (5R) acetoxymethyl-2-[(1'-methyl-1 'H-Tetrazol-5'-yl) -thiomethyl] -2-phenem-3-carboxylate (Compound A) and a series of in vitro to compare the activity of two control compounds (Ampicillin and Sepoxycitin) The test was performed. Table 1 below shows the test results as MIC (minimum inhibitory concentration).
[표 1]TABLE 1
다음의 실시예는 본 발명을 설명하나 본 발명을 한정하는 것은 아니다.The following examples illustrate the invention but do not limit the invention.
[실시예 1]Example 1
반응 (2)-(3)Reaction (2)-(3)
40ml의 톨루엔중 2.0g의 메틸페니실리네이트 S-옥사이드와 2.8g의 부틴디올 디아세테이트가 용해된 용액을 환류온도에서 24시간동안 가열시킨다. 표제화합물은 96 : 4 디클로로메탄-에틸 아세테이트를 용출제로 실리카겔상 칼럼 크로마토그라피에 의해 정제 할 수 있다. 1.4g의 4β-비닐티오[1,2-디아세톡시메틸]-1-[1-메톡시카보닐-2-메틸-2-프로페닐]-아제티딘-2-온-S-옥사이드가 수득된다.A solution of 2.0 g of methylphenicylinate S-oxide and 2.8 g of butynediol diacetate in 40 ml of toluene is heated at reflux for 24 hours. The title compound can be purified by column chromatography on silica gel with 96: 4 dichloromethane-ethyl acetate as eluent. 1.4 g of 4β-vinylthio [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-S-oxide is obtained do.
[실시예 2]Example 2
반응 (3)-(4)Reaction (3)-(4)
1.7g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-[1-메톡시카보닐-2-메틸-2-프로페닐]-아제티딘-2-온-S-옥사이드를 80ml의 디클로로메탄에 용해시키고, 0.5ml의 트리에틸아민을 가한다음 실온에서 수시간동안 방치시킨다. 용매를 증발시킨후 표제화합물을 정량적인 수율로 순수하게 수득한다.1.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-S-oxide Dissolve in 80 ml of dichloromethane, add 0.5 ml of triethylamine and leave for several hours at room temperature. After evaporation of the solvent the title compound is obtained pure in quantitative yield.
[실시예 3]Example 3
반응(4)-(5)Reaction (4)-(5)
2.0g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-[1-메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-S-옥사이드를 150ml의 디클로로 메탄에 용해시켜 -78℃에서 냉각시킨후 산소중 오존을 약간 푸른색이 나타날때까지 냉각시킨 용액에 통해준다. 용액을 실온까지 가온하여, Na2S2O5수용액과 함께 진탕시킨 다음 Na2S2O4로 건조시킨다 생성된 유기층을 진공하에서 용매를 증발시켜 1.4g의 표제 화합물을 수득한다.2.0 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-S-oxide It is dissolved in 150 ml of dichloromethane, cooled at -78 ° C, and the ozone in oxygen is passed through a cooled solution until a slightly blue color appears. The solution is allowed to warm to room temperature, shaken with aqueous Na 2 S 2 O 5 solution and then dried over Na 2 S 2 O 4 The resulting organic layer is evaporated under vacuum to afford 1.4 g of the title compound.
[실시예 4]Example 4
반응(5)Reaction (5)
10ml의 무수 디메틸포름아마이드중 1.4g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-메톡시옥살로일-아제티딘-2-온-S-옥사이드가 용해된 용액을 -25℃에서 냉각시킨 다음 0.9ml의 3브롬화인을 가한다. 10분후 혼합물을 에틸 아세테이트로 희석시킨 다음 NaHCO3포화용액으로 2회 세척한다. Na2SO4상에서 건조시킨 다음 용매를 증발시키면 0.9g의 표제화합물이 수득된다.In a solution of 1.4 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1-methoxyoxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous dimethylformamide, After cooling at 25 ° C., 0.9 ml of phosphorus tribromide is added. After 10 minutes the mixture is diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. Drying over Na 2 SO 4 and then evaporating the solvent gave 0.9 g of the title compound.
[실시예 5]Example 5
반응 (5)-(6)Reaction (5)-(6)
1.5g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-메톡시옥살로일-아제티딘-2-온을 100ml의 메탄올에 용해시킨다음 교반하면서 수 g의 실리카겔을 가한다. 1시간후, 실리카겔을 여과제거하고 메탄올성용액을 증발 시키면 0.8g의 4β-비닐티오-[1,2-디아세톡시메틸]-아제티딘-2-온이 수득된다.Dissolve 1.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1-methoxyoxaloyl-azetidin-2-one in 100 ml of methanol and add several grams of silica gel with stirring. . After 1 hour, the silica gel was filtered off and the methanolic solution was evaporated to yield 0.8 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one.
[실시예 6]Example 6
반응 (5)-(6)Reaction (5)-(6)
0.8g의 4β-비닐티오[1,2-디아세톡시메틸)-1-1메톡시올살로일-아제티딘-2-온-S-옥사이드를 80ml의 메탄올중에 용해시킨 다음 수 g의 실리카겔을 교반하면서 가한다. 1시간후 실리카겔을 여과해내고 용매를 증발시키면 0.5g의 4β-비닐티오-[1,2-디아세톡시메틸]-아제티딘-2-온-S-옥사이드가 수득된다.0.8 g 4β-vinylthio [1,2-diacetoxymethyl) -1-1methoxyolsaloyl-azetidin-2-one-S-oxide was dissolved in 80 ml of methanol, followed by several g of silica gel. Add while stirring. After 1 hour, the silica gel was filtered off and the solvent was evaporated to yield 0.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one-S-oxide.
[실시예 7]Example 7
반응(12)-(13)Reaction (12)-(13)
0.8g의 4β-비닐티오-[1,2-디아세톡시메틸-1-[1-아세톡시메틸옥시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온을 80ml의 디클로로 메탄중에 용해시키고 -78℃로 냉각시켜 산소중의 온존을 푸른색이 나타날때까지 냉각된 용액에 통해준다. 용액을 Na2S205수용액과 진탕시킨후 Na2SO4로 건조시키면 0.45g의 표제화합물이 수득된다.0.8 g of 4β-vinylthio- [1,2-diacetoxymethyl-1- [1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one in 80 ml of dichloro Dissolve in methane and cool to −78 ° C. and allow the ozone in oxygen to pass through the cooled solution until a blue color appears. The solution was shaken with Na 2 S 2 O 5 aqueous solution and dried over Na 2 SO 4 to afford 0.45 g of the title compound.
[실시예 8]Example 8
반응 (13)-(14)Reaction (13)-(14)
0.6g의 4β-아세틸글리콜릴티오-1-메톡시 옥살로일-아제티딘-2-온을 100ml의 메탄올중에 용해시킨다음 수g의 실리카겔을 용액을 교반시키면서 가한다 1시간후 실리카겔을 여과시킨 다음 생성된 용액의 용매를 증발시켜 0.35g의 표제 화합물을 수득한다.0.6 g of 4β-acetylglycolylthio-1-methoxy oxaloyl-azetidin-2-one is dissolved in 100 ml of methanol, and then several g of silica gel is added while stirring the solution. After 1 hour, the silica gel is filtered off. The solvent in the resulting solution is then evaporated to yield 0.35 g of the title compound.
[실시예 9]Example 9
응의 (6)-(7)(6)-(7)
0.7g의 아세톡시메틸-글리옥실레이트(디아세톡시메틸푸마레이트를 가오존 분해하여 새로 제조한 것)를 30ml의 벤젠에 용해시킨 다음 생성된 용액을 딘-스타크 장치중에서 20분간 환류시킨다.0.7 g of acetoxymethyl-glyoxylate (freshly prepared by ozone decomposition of diacetoxymethylfumarate) is dissolved in 30 ml of benzene and the resulting solution is refluxed in a Dean-Stark apparatus for 20 minutes.
생성된 용액을 50° 내지 60℃에서 냉각시킨 후 10ml의 벤젠중에서 용해시킨 0.7g의 4β-비닐티오-[1,2-디아세톡시메틸]-아제티딘-2-온을 가하여 2시간동안 환류시킨다. 표제화합물이 거의 정량적인 수율로 수득되며, 다음 단계에서 조혼합물로서 사용될 수 있다. 분석용으로 순수한시료를 제조용 TLC에 의해 수득한다.The resulting solution was cooled at 50 ° to 60 ° C. and 0.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one dissolved in 10 ml of benzene was added to reflux for 2 hours. Let's do it. The title compound is obtained in almost quantitative yield and can be used as a crude mixture in the next step. Pure samples for analysis are obtained by preparative TLC.
[실시예 10]Example 10
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반응 (7)-(8)Reaction (7)-(8)
15ml테트라하이드로푸란중에 용해시킨 0.6g의 4β-비닐티오 [1,2-디아세톡시메틸]-1-[아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온을 0℃에서 냉각시킨 다음 0.115ml의 피리딘 및 0.104ml의 티오닐클로라이드를 가하여 생성된 혼합물을 10분간 교반시킨다. 불용성 물질을 여과해내고 용액을실온 및 진공하에서 증발시키면 표제 화합물이 고수율로 수득된다. 분석용으로 시료를 제조용 TLC상에서 정제하나, 조혼합물은 정제하지 않고 다음 단계에서 사용될 수 있다.0.6 g of 4β-vinylthio [1,2-diacetoxymethyl] -1- [acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one dissolved in 15 ml tetrahydrofuran was zero. After cooling at 占 폚, 0.115 ml of pyridine and 0.104 ml of thionylchloride are added and the resulting mixture is stirred for 10 minutes. The insoluble material is filtered off and the solution is evaporated at room temperature and vacuum to afford the title compound in high yield. Samples are purified on preparative TLC for analysis, but the crude mixture can be used in the next step without purification.
[실시예 11]Example 11
반응 (8)-(9)Reaction (8)-(9)
5ml의 테트라하이드로푸란과 0.520g의 트리페닐포스핀 및 0.08ml의 피리딘을 함유하는 5ml의 디옥산중에 0.430g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-[1-아세톡시메틸옥시카보닐-1-클로로메틸]-아제티딘-2-온이 용해된 용액을 50℃중에서 철야 교반시킨다. 생성된 포스프란을 70 : 30 디클로로메탄-에틸아세테이트를 용출제로 실리카겔상에서 칼럼 크로마토그 라피에 의해 정제하면 0.400g의 표제화합물이 수득된다.0.430 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-in 5 ml of dioxane containing 5 ml of tetrahydrofuran, 0.520 g of triphenylphosphine and 0.08 ml of pyridine The solution in which acetoxymethyloxycarbonyl-1-chloromethyl] -azetidin-2-one is dissolved is stirred overnight at 50 ° C. The resulting phosphane was purified by column chromatography on silica gel with 70:30 dichloromethane-ethyl acetate as eluent to afford 0.400 g of the title compound.
[실시예 12]Example 12
반응 (10)-(11)Reaction (10)-(11)
0.7g의 4β-비닐티오-[1,2-디아세톡시메틸]-1-[1-아세톡시메틸옥시 카보닐-1-트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 40ml의 디클로로메탄에 용해시킨다음-20℃에서 냉각시킨 후 디클로로 메탄중 10% 트리플루오로아세트산 용액 50ml를 가한다. 수 분후산소중의 오존을 -20℃의 용객에 약간 푸른색이 나타날때까지 통해준다. 이때, 반응을 중단시키고, 수적의 트리메틸포스파이트를 가한다.유기용액을 Na2SO4포화용액으로 세척한다음 NaHCO3로 건조시키면 0.550g의 표제화합물이 수득된다.40 ml of 0.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-acetoxymethyloxy carbonyl-1-triphenylphosphoranylidenemethyl] -azetidin-2-one In dichloromethane and then cooled to -20 ° C, then 50 ml of a 10% trifluoroacetic acid solution in dichloromethane is added. After a few minutes, oxygen in oxygen is passed through the solution at -20 ° C until it is slightly blue. At this time, the reaction is stopped and a few drops of trimethylphosphite are added. The organic solution is washed with saturated Na 2 SO 4 solution and dried over NaHCO 3 to give 0.550 g of the title compound.
[실시예 13]Example 13
반응 (11)-(1)Reaction (11)-(1)
0.7g의 4β-아세틸글리콜릴티오-1-[1-아세톡시메틸옥시카보닐-1-트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 30ml의 무수 톨루엔에 용해시킨다음 환류온도에서 2시간동안 가열시킨다. 표제화합물 및 트리페닐포스핀옥사이드로 구성된 반응 혼합물을 97 : 3 디클로로메탄-에틸아세테이트를 용출제로 실리카겔 상에서 단 칼럼 크로마토그라피에 의해 정제하여 0.250g의 아세톡시메틸-2-아세톡시메틸 2-페넴-3-카복실레이트를 수득한다.0.7 g of 4β-acetylglycolylthio-1- [1-acetoxymethyloxycarbonyl-1-triphenylphosphoranilidenemethyl] -azetidin-2-one is dissolved in 30 ml of anhydrous toluene and then reflux temperature. Heat at for 2 hours. The reaction mixture consisting of the title compound and triphenylphosphine oxide was purified by single column chromatography on silica gel with 97: 3 dichloromethane-ethyl acetate as eluent to yield 0.250 g of acetoxymethyl-2-acetoxymethyl 2-penem-. 3-carboxylate is obtained.
[실시예 14]Example 14
반응 (6)-(7)Reaction (6)-(7)
-니트로벤질푸마레이트를 가오존 분해하여 새로 제조한-니트로벤질 글리옥실레이트를 사용하여 실시예 9와 동일한 방법에 따라 표제 화합물을 수득한다. -Newly prepared by ozone decomposing nitrobenzyl fumarate Nitrobenzyl glyoxylate is used to obtain the title compound following the same method as in Example 9.
정량적 수율.Quantitative yield.
[실시예 15]Example 15
반응 (7)-(8)Reaction (7)-(8)
실시예 10에서 기술된 방법에 따라 표제화합물을 수득한다.The title compound is obtained according to the method described in Example 10.
[실시예 16]Example 16
반응 (8)-(9)Reaction (8)-(9)
표제 화합물은 실시예 11의 방법에 따라 수득한다.The title compound is obtained according to the method of Example 11.
[실시예 17]Example 17
반응 (9)-(11)Reaction (9)-(11)
표제 화합물은 실시예 12의 방법에 따라 수득한다.The title compound is obtained according to the method of Example 12.
[실시예 18]Example 18
반응 (11)-(1)Reaction (11)-(1)
표제화합물은 실시예 13의 방법에 따라 수득한다The title compound is obtained according to the method of Example 13.
[실시예 19]Example 19
반응(1)Reaction (1)
실시예 18에서 기술된 바와 같이 제조된 200mg의 (5R)--니트로벤질-2-아세톡시메틸-2-페넴-3-카복실레이트를 12ml의 에틸아세테이트에 용해시킨다. 다음에 8ml의 0.2 M NaHCO3용액 및 10% Pd/C 400mg을 가하여 생성된 2상 혼합물을 수소압하아에서 60분간 진탕시킨다. 촉매를 여과한 후 수층을 5%구연산용액 20ml로 산성화 한다음 메틸렌 클로라이드로 3회 추출한다. 유기층을 Na2SO4로 건조시킨다음 증발시켜 60mg의 표제화합물을 수득한다.200 mg of (5R)-prepared as described in Example 18. Nitrobenzyl-2-acetoxymethyl-2-phenem-3-carboxylate is dissolved in 12 ml of ethyl acetate. Then, 8 ml of 0.2 M NaHCO 3 solution and 400 mg of 10% Pd / C are added, and the resulting biphasic mixture is shaken under hydrogen pressure for 60 minutes. After filtering the catalyst, the aqueous layer was acidified with 20 ml of 5% citric acid solution and extracted three times with methylene chloride. The organic layer is dried over Na 2 S0 4 and evaporated to afford 60 mg of the title compound.
IR(CHCl3) : 1790(β락탐), 1735 및 1700cm-1 IR (CHCl 3 ): 1790 (β lactam), 1735 and 1700 cm -1
U.V(EtOH) : 300nmU.V (EtOH): 300nm
[실시예 20]Example 20
반응 (2)-(3)Reaction (2)-(3)
4g의 페니실란산 메틸 에스테르 s-옥사이드를 15ml의 톨루엔에 용해시킨 다음 15ml의 프로파질알콜과 함께 8시간 동안 환류시킨다. 진공하에서 증발시킨후, 잔사를 디클로로메탄-에틸 아세테이트 1 : 1을 용출제로 실리카겔상 단 칼럼 크로마토그라피하여 정제한다. 2.8g의 표제 화합물이 수득된다.4 g of peniclanic acid methyl ester s-oxide is dissolved in 15 ml of toluene and then refluxed with 15 ml of propazyl alcohol for 8 hours. After evaporation in vacuo, the residue is purified by single column chromatography on silica gel with dichloromethane-ethyl acetate 1: 1. 2.8 g of the title compound are obtained.
[실시예 21]Example 21
반응 (3)-(4)Reaction (3)-(4)
3.0g의 4β-(1-하이드록시메틸)-비닐티오-1-[메톡시카보닐-2-메틸-2-프로페닐]-아제티딘-2-온-s-옥사이드를 100ml의 디클로로메탄에 용해시켜 실온에서 수시간 방치한다. 용매를 증발시킨 후 정량적 수율로 순수한 표제 화합물로 이루어진 잔류물을 수득한다.3.0 g of 4β- (1-hydroxymethyl) -vinylthio-1- [methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-s-oxide in 100 ml of dichloromethane It is dissolved and left for several hours at room temperature. After evaporation of the solvent, a residue consisting of the pure title compound in quantitative yield is obtained.
[실시예 22]Example 22
반응 (4)-(12)Reaction (4)-(12)
1.8g의 4β-(1-하이드록시메틸)비닐티오-1-[1-메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-s-옥사이드를 40ml의 디메틸포름아마이드에 용해시킨 다음 20℃에서 냉각시킨다. 다음에 0.7ml의 피리딘 및 3.0ml의 PBr3를 가한 다음 혼합물을 교반하면서 15분간 방치시킨다. 에틸아세테이트를 가한 다음 유기층을 NaHCO3포화용액과 함께 진탕시켜 물로 세척한뒤 Na2SO4로 건조시켜 용매를 증발시키면 1.6g의 표제화합물이 수득된다.1.8 g of 4β- (1-hydroxymethyl) vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide in 40 ml of dimethylform It is dissolved in amide and then cooled at 20 ° C. 0.7 ml of pyridine and 3.0 ml of PBr3 are then added and the mixture is left for 15 minutes with stirring. Ethyl acetate was added and the organic layer was shaken with saturated NaHCO 3 solution, washed with water, dried over Na 2 SO 4 and evaporated to give 1.6 g of the title compound.
[실시예 23]Example 23
반응 (12)Reaction (12)
1.4g의 4β-(1-브로모메틸)-비닐티오-1-[1-메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온을 25ml의 테트라하이드로푸란에 용해시킨 다음0℃에서 냉각시킨다. 0.8g의 1-메틸-5-티올-테트라졸 나트륨염을 가한 다음 실온에서 3시간동안 교반시킨다. 불용물을 여과시킨 후 혼합물을 에틸아세테이트로 희석시키고 물로 세척해서 Na2SO4로 건조시켜 증발시킨다. 잔류물은 2.0g의 순수한 표제 화합물로 이루어져 있다.1.4 g of 4β- (1-bromomethyl) -vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one are dissolved in 25 ml of tetrahydrofuran Then cooled to 0 ° C. 0.8 g of 1-methyl-5-thiol-tetrazole sodium salt is added and then stirred at room temperature for 3 hours. After filtering off the insolubles, the mixture was diluted with ethyl acetate, washed with water, dried over Na 2 SO 4 and evaporated. The residue consists of 2.0 g of pure title compound.
[실시예 24]Example 24
반응 (12)-(13)Reaction (12)-(13)
1.8g의 4β-[1-(1-메틸-1-H-테트라졸-5-일)-티오메틸]-비닐티오-1-[1-메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온을 200ml의 디클로로메탄에 용해시키고 -78℃에서 냉각시킨다.1.8g 4β- [1- (1-methyl-1-H-tetrazol-5-yl) -thiomethyl] -vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl ] -Azetidin-2-one is dissolved in 200 ml of dichloromethane and cooled at -78 ° C.
푸른색이 나타날때까지 오존화된 산소를 용액에 통해준다. 수적의 P(OCH3)3를 가한 다음 이 혼합물의 온도를 실온까지 상승시킨후 증발시키면 1.3g의 표제 화합물이 수득된다.Pass ozoneized oxygen through the solution until blue color appears. A drop of P (OCH 3 ) 3 was added followed by raising the temperature of the mixture to room temperature and evaporating to yield 1.3 g of the title compound.
[실시예 25]Example 25
1.2g의 4β-(1-메틸-1-H-테트라졸-5-일)-티오아세틸티오-1-메톡시옥살로일-아제티딘-2-온을 1 : 1 에틸아세테이트 / 메탄을 혼합물에 용해시킨 다음 격렬히 교반하면서 수 g의 실리카겔을 가한다.1.2 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1-methoxyoxaloyl-azetidin-2-one 1: 1 ethylacetate / methane mixture It is dissolved in and then several g of silica gel is added with vigorous stirring.
1시간후 불용성물질을 여과 제거한 다음 용액을 진공하에서 증발시킨다.메탄올-에틸 에테르로부터 결정화하면 0.6g의 표제화합물이 수득된다.After 1 hour the insolubles are filtered off and the solution is evaporated in vacuo. Crystallization from methanol-ethyl ether gives 0.6 g of the title compound.
[실시예 26]Example 26
1.5g의 4β-(1-메틸-1-H-테트라졸-5-일)-티오아세틸티오아제티딘-2-온을 1.2g의 아세톡시메틸글리옥실레이트(디아세톡시메틸푸마레이트를 오존 분해하여 새로 제조한 것)와 함께 50ml의 벤젠중에서 환류시킨다. 3시간후 반응이 완결된다. 용매를 증발시켜 얻은 조오일을 다음 단계에서 더 정제하지 않고 사용할 수 있다. 스펙트로 스코피 데이타 수득용 시료를 TLC상에서 정제한다.1.5 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthioazetidin-2-one and 1.2 g of acetoxymethylglyoxylate (diacetoxymethylfumarate ozone And reflux in 50 ml of benzene with freshly prepared). After 3 hours the reaction is complete. The crude oil obtained by evaporating the solvent can be used without further purification in the next step. Spectroscopy data obtained samples are purified on TLC.
[실시예 27]Example 27
반응 (15)-(16)Reaction (15)-(16)
조 4β-(1-메틸-1-H-테트라졸-5-일)-티오아세틸티오-1-(1-아세톡시메틸옥시카보닐-1-하이드록시메틸)-아제티딘-2-온으로 구성된 실시예 26에서 수득된 오일을 무수 테트라하이드로푸란(20ml)에 용해시킨 다음 출발물질이 없어질때까지 동몰량의 피리딘 및 티오닐 클로라이드로 0oC에서 처리한다.Crude 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one The oil obtained in configured Example 26 was dissolved in anhydrous tetrahydrofuran (20 ml) and then treated with an equimolar amount of pyridine and thionyl chloride at 0 ° C. until the starting material disappeared.
불용성 물질을 여과한후 여액을 다음 단게에서 직접 사용한다.After filtering the insoluble material, the filtrate is used directly in the next step.
[실시예 28]Example 28
반응 (16)-(11)Reaction (16)-(11)
조 4β-(1-메틸-1-H-테트라졸-5-일)-티오아세틸티오-1-(1-아세톡시메틸옥시카보닐-1-클로로메틸)-아제티딘-2-온을 함유하는 용액에 800mg의 트리페닐포스핀 및 0.4ml의 피리딘을 가하여 생성된 혼합물을 60° 내지 70℃에서 수시간 동안 가열시킨다. 포스포란을 실리카겔상에서 디클로로메탄-에틸아세테이트(1:)로 용출시켜 정제한다.Crude 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one To the solution was added 800 mg of triphenylphosphine and 0.4 ml of pyridine to heat the resulting mixture at 60 ° to 70 ° C. for several hours. Phosphoran is purified by eluting with dichloromethane-ethyl acetate (1 :) on silica gel.
[실시예 29]Example 29
반응 (11)-(1)Reaction (11)-(1)
0.500g의 4β-(1-메틸-1-H-테트라졸-5-일)-티오아세틸티오-1-(1-아세톡시메틸옥시카보닐)-1-트리페닐포스포라닐리덴메틸)-아제티딘-2-온을 30ml의 톨루엔에 용해시킨 다음 100℃에서 2시간동안 가열시킨다. 표제 화합물을 실리카겔상 단 칼럼을 사용하여 디클로로메탄-에틸아세테이트(8:2)를 용출제 PPh3O로부터 정제한다.0.500 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl) -1-triphenylphosphoranylidenemethyl)- Azetidin-2-one is dissolved in 30 ml of toluene and then heated at 100 ° C. for 2 hours. The title compound is purified using eluent PPh 3 O with dichloromethane-ethylacetate (8: 2) using a single column on silica gel.
[실시예 30]Example 30
반응 (1)Reaction (1)
표제 화합물은 실시예 19에서 기술된 공정에 따라 수득된다. (5R)--니트로벤조일-2-(1-메틸-1-H-테트라졸-5-일)-티오메틸-2-페넴-3-카복실레이트는 전술된 실시예들어서 설명된 공정과 유사한 방법에 의해 수득된다.The title compound is obtained following the process described in Example 19. (5R)- -Nitrobenzoyl-2- (1-methyl-1-H-tetrazol-5-yl) -thiomethyl-2-phenem-3-carboxylate is obtained by a method similar to the process described in the above-described examples. .
I.R.(CHCl3) : 1800(β락탐), 1750 및 1720.I.R. (CHCl 3): 1800 (β lactam), 1750 and 1720.
[실시예 31]Example 31
반응 (17)-(2)Reaction (17)-(2)
50ml의 무수 테트라하이드로푸란중 2.3g의 메틸페니실리네이트가 용해된 용액을 -78℃에서 냉각시킨다. 무수 테트라하이드로푸란중에 용해시킨 리튬 디이소프로필아마이드(5ml의 디이소프로필아미과 20ml의 1.6M 부틸리륨 헥산용액으로부터 새로 제조된 것)를 가한 다음 이 혼합물을 -78℃에서 10분간 방치시킨다. 5ml의 아세트알데하이드를 계속해서 가하고 용액을 15분간 교반시킨다. 다음에 NH4Cl 포화수용액을 가하여 반응을 중단시키고 에틸아세테이트로 추출해서 물로 2회 세ㅊ거한 다음 Na2SO4로 건조시킨다.A solution of 2.3 g of methylphenicylinate dissolved in 50 ml of anhydrous tetrahydrofuran is cooled at -78 ° C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamid and 20 ml of 1.6M butyllilium hexane solution) dissolved in anhydrous tetrahydrofuran is added and the mixture is left at -78 ° C for 10 minutes. 5 ml of acetaldehyde is added continuously and the solution is stirred for 15 minutes. Subsequently, the reaction was quenched by addition of saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, washed twice with water, and dried over Na 2 SO 4 .
용매를 증발시킨 후 잔류물을 디클로로메탄-에틸아세테이트( 1: 1)를 용출제로 실리카겔상에서 칼럼크로마토그라피로 속히 정제한다. 1.5g의 생성물이 수득된다. 표제 화합물은 PMR에 근거할때 하이드록실을 함유하는 탄소에 대한 애피머 2: 3 혼합물로 구성되며, 이는 사용되는 조건에서 반응의 입체특이성 때문에 α-위치에만 새로운 C6-C8결합이 존재한다.After evaporation of the solvent, the residue is quickly purified by column chromatography on silica gel with dichloromethane-ethylacetate (1: 1) as eluent. 1.5 g of product are obtained. The title compound consists of an apimer 2: 3 mixture for hydroxyl-containing carbon based on PMR, which has new C 6 -C 8 bonds only at the α-position due to the stereospecificity of the reaction under the conditions used. .
[실시예 32]Example 32
반응 (17)-(2)Reaction (17)-(2)
30ml의 무수테트라하이드로푸란 중 2.2g의 메틸페니실리네이트가 용해된 용액에 약간 과량의 리튬 디이소프로필아마이드를 질소대기하 -78℃에서 가한다. 과량의 아세트알데히드를 가하고 혼합물을 5분간 교반시킨 다음 미량의 아세트산으로 반응을 중단시켜 물속에 주가하여 메틸렌 클로라이드로 추출한다. 유기층을 Na2SO4로 건조시킨 다음 진공하에서 증발시켜 0.8g의 표제 화합물을 수득한다.To a solution of 2.2 g of methylphenicylinate dissolved in 30 ml of anhydrous tetrahydrofuran is added a slight excess of lithium diisopropylamide at -78 ° C under nitrogen atmosphere. Excess acetaldehyde is added and the mixture is stirred for 5 minutes, then the reaction is stopped with a small amount of acetic acid and added to the mixture in water to extract with methylene chloride. The organic layer is dried over Na 2 SO 4 and then evaporated in vacuo to yield 0.8 g of the title compound.
[실시예 33]Example 33
반응(2)Reaction (2)
1.2g의 메틸-6-[1-하이드록시에틸]-3-페니실라네이트를 40ml의 테트라하이드로푸란에 용해시켜 -78℃에서 냉각시킨 다음 1당량의 부틸리튬으로 처리한다. 1.2당량의-니트로벤질옥시카보닐클로라이드를 상기 혼합물에 가하고 -78℃에서 30분후 반응 혼합물을 실온에서 60분간 방치시켜 물속에 주가한 다음 메틸렌 클로라이드로 추출한다. Na2SO4로 건조시킨후 증발시켜 1.4g의 표제 화합물을 수득한다.1.2 g of methyl-6- [1-hydroxyethyl] -3-penicilanate are dissolved in 40 ml of tetrahydrofuran, cooled at -78 ° C and treated with 1 equivalent of butyllithium. 1.2 equivalents Nitrobenzyloxycarbonylchloride was added to the mixture, and after 30 minutes at -78 ° C, the reaction mixture was left at room temperature for 60 minutes, added to water, and extracted with methylene chloride. Dry over Na 2 S0 4 and evaporate to afford 1.4 g of the title compound.
[실시예 34]Example 34
반응 (17)-(2)Reaction (17)-(2)
1.8g의 메틸-6-[1--니트로벤질옥시카보닐옥시에틸]-3-페니실라네이트를 50ml의메틸렌클로라이드에 용해시킨 다음 0℃에서 1.5당량의 m-클로로퍼벤조산으로 처리한다. 유기층을 NaHCO3포화용액으로 진탕시켜 추출하고 Na2SO4로 건조시킨 다음 증발시키면 1.4g의 기대된 설폭사이드가 수득된다.1.8 g of methyl-6- [1- Nitrobenzyloxycarbonyloxyethyl] -3-penicilanate is dissolved in 50 ml of methylene chloride and then treated with 1.5 equivalents of m-chloroperbenzoic acid at 0 < 0 > C. The organic layer was extracted by shaking with saturated NaHCO 3 solution, dried over Na 2 SO 4 and evaporated to yield 1.4 g of the expected sulfoxide.
[실시예 35]Example 35
반응 (2)-(3)Reaction (2)-(3)
50ml의 톨루엔중 2.0g의 메틸-6-[1--니트로벤질옥시카보닐옥시에틸]-3-페니실라네이트-s-옥사이드 및 2.4g의 부틴디올 디아세테이트가 용해된 용액을 24시간동안 환류시킨다. 방취장치를 한 화합물을 9 : 1 디클로로메틴-에틸 아세테이트를 용출제로 실리카겔 칼럼 크로마토그라피에 의해 정제시킨다.2.0 g methyl-6- [1- in 50 ml toluene -A solution of nitrobenzyloxycarbonyloxyethyl] -3-phenylanate-s-oxide and 2.4 g butynediol diacetate was refluxed for 24 hours. The deodorant compound is purified by silica gel column chromatography with 9: 1 dichloromethine-ethyl acetate as eluent.
1.1g의 표제 화합물이 수득된다.1.1 g of the title compound are obtained.
[실시예 36]Example 36
반응 (3)-(4)Reaction (3)-(4)
1.3g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-2-프로페닐]-아제티딘-2-은-s-옥사이드를 80ml의 디클로로메탄중에 용해시키고 0.3ml의 트리에틸아민을 가한 다음 실온에서 2시간 동안 방치시킨다. 용매를 증발시킨 후 순수한 표제 화합물이 정략적으로 수득된다.1.3 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-2-propenyl] -azetidine-2-silver-s-oxide in 80 ml of dichloromethane and 0.3 ml of tri Ethylamine is added and left for 2 hours at room temperature. Pure evaporation of the title compound is obtained after evaporation of the solvent.
[실시예 37]Example 37
반응 (4)-(5)Reaction (4)-(5)
100ml의 디클로로메탄중 1.1g의 4β-비닐티오-[1,2-디아세톡시메틸)-3-1.1g의 4β-비닐티오-[1,2-디아세톡시메틸)-3-[1--니트로벤질옥시 카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-s-옥사이드가 용해된 용액을 -78℃에서 냉각시킨다. 이 용액이 푸른색을 띨 때까지 산소 중 오존을 통해준다. 용액을 Na2S2O5수용액과 함께 진탕시켜 Na2SO4로 건조시킨다. 증발시키면 0.5g의 표제화합물이 수득된다.1.1 g of 4β-vinylthio- [1,2-diacetoxymethyl) -3-1.1 g of 4β-vinylthio- [1,2-diacetoxymethyl) -3- [1- in 100 ml of dichloromethane The solution in which nitrobenzyloxy carbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide is dissolved is cooled at -78 deg. Give ozone in oxygen until the solution turns blue. The solution is shaken with an aqueous Na 2 S 2 O 5 solution and dried over Na 2 SO 4 . Evaporation yields 0.5 g of the title compound.
[실시예 38]Example 38
반응 (5)Reaction (5)
15ml의 무수 디메틸포름아미드 중 0.8g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-메톡시옥살로일-아제티딘-2-온 이 용해된 용액을 -20℃에서 냉각시킨 다음 0.6ml의 3브롬화인을 가한다. 10분후 반응물을 에틸아세테이트로 희석하고 NaHCO3용액으로 2회 세척한다. 유기층을 Na2SO4로 건조시킨 다음 증발시켜 0.4g의 환원된 화합물을 수득한다.0.8 g 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 15 ml anhydrous dimethylformamide -A solution of nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxaloyl-azetidin-2-one is cooled at -20 ° C and then 0.6 ml of phosphorus tribromide is added. After 10 minutes the reaction is diluted with ethyl acetate and washed twice with NaHCO 3 solution. The organic layer is dried over Na 2 SO 4 and then evaporated to yield 0.4 g of reduced compound.
[실시예 39]Example 39
반응 (5)-(6)Reaction (5)-(6)
1.2g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-메톡시옥살로일-아제티딘-2-온을 메탄올중에 용해시킨 다음 2g의 실리카겔을 가한다. 60분 후 불용물을 여과하고 유기층을 증발시킨다. 단 칼럼크로마토그라피하면 0.4g의 표제 화합물이 수득된다.1.2 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- Nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxaloyl-azetidin-2-one is dissolved in methanol and then 2 g of silica gel is added. After 60 minutes the insolubles are filtered off and the organic layer is evaporated. Column chromatography gives 0.4 g of the title compound.
[실시예 40]Example 40
반응 (6)-(7)Reaction (6)-(7)
30ml의 벤젠중에 용해시킨 0.6g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-아제티딘-2-온 및 0.6g의 아세톡시메틸 글리옥실레이트(디아세톡시메틸 푸마레이트를 가오존분해시켜 새로 제조한 것)를 환류시킨다. 반응은 2시간후 완결된다. 축합 생성물은 더 정제하지 않고 다음 단계에 사용될 수 있다.0.6 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- dissolved in 30 ml of benzene Nitrobenzyloxycarbonyloxyethyl] -azetidin-2-one and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozone decomposing diacetoxymethyl fumarate) are refluxed. The reaction is complete after 2 hours. The condensation product can be used in the next step without further purification.
[실시예 41]Example 41
반응(7)-(8)Reaction (7)-(8)
0.5g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온을 12ml의 무수 테트라하이드로푸란에 용해시킨 다음 0℃에서 냉각시킨 후 1.1당량의 피리딘 미치 1.1당량의 티오닐 클로라이드를 가한다. 혼합물을 10분간 교반시킨다. 불용성 물질을 여과하고 용액을 실온에서 증발시키면 포제호합물이 거의 정량적인 수율로 수득된다.0.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- -Nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one is dissolved in 12 ml of anhydrous tetrahydrofuran and cooled at 0 ° C. 1.1 equivalents of pyridine methion and 1.1 equivalents of thionyl chloride are then added. The mixture is stirred for 10 minutes. Filtration of the insoluble material and evaporation of the solution at room temperature gave the foam formulation in near quantitative yield.
생성물은 더이상 정제하지 않고 다음단계에서 사용도리 수 있다.The product can be used in the next step without further purification.
[실시예 42]Example 42
반응 (8)-(9)Reaction (8)-(9)
10ml의 테트라하이드로푸란 및 10ml의 디옥산중 0.760g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤조일옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온이 용해된용액을 2당량의 트리페닐 포스피 및 1.1 당량의 피리딘과 함께 +50℃에서 철야 교반한다. 포스포란은 70:30디클로로메탄-에틸아세테이트를 용출제로 실리카겔 칼럼크로마토그라피로 정제한다. 0.480g의 표제 화합물이 수득된다.0.760 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 10 ml of tetrahydrofuran and 10 ml of dioxane 2-nitrobenzoyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one in 2 equivalents of triphenyl phosphine and 1.1 equivalents It is stirred overnight at + 50 ° C with pyridine. Phosphoran is purified by silica gel column chromatography using 70:30 dichloromethane-ethyl acetate as eluent. 0.480 g of the title compound are obtained.
[실시예 43]Example 43
반응 (9)-(11)Reaction (9)-(11)
0.45g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시에틸]-1-[아세톡시메틸옥시카보닐-1--트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 50ml의 디클로로메탄에 용해시킨 다음 -20℃에서 냉각시킨 후, 디클로로메탄 중 트리플루오로아세트산 용액 30ml를 가한다. 수 분후 산소중 오존을 약간 푸른색이 나타날때가지 용액에 통해준다. 반응을 중단시키고 수적의 트리메틸포스파이트를 가한다. 유기층을 NaHCO3의 포화용액으로 세척해서 Na2SO4로 건조시키면 0.26g의 표제 화합물이 수득된다.0.45 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- -Nitrobenzyloxyethyl] -1- [acetoxymethyloxycarbonyl-1--triphenylphosphoranylidenemethyl] -azetidin-2-one was dissolved in 50 ml of dichloromethane and cooled at -20 ° C. Then 30 ml of trifluoroacetic acid solution in dichloromethane are added. After a few minutes, ozone in oxygen is passed through the solution until a little blue color appears. The reaction is stopped and a few drops of trimethylphosphite are added. The organic layer was washed with saturated solution of NaHCO 3 and dried over Na 2 SO 4 to afford 0.26 g of the title compound.
[실시예 44]Example 44
반응(4)-(12)Reaction (4)-(12)
1.5g의 비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-s-옥사이드를 10ml의 무수 디메틸포름아마이드에 용해시킨 다음 -20℃에서 냉각시켜 0.8ml의 3브롬화 인을 가한다. 혼합물을 10시간 동안 교반시켜 에틸아세테이트로 희석하고 NaHCO3포화용액으로 2회 세척한다.유기층을 NaSO4로 건조시켜 증발 시키면 1.1g의 표제 화합물이 수득된다.1.5 g of vinylthio- [1,2-diacetoxymethyl] -3- [1- Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide in 10 ml of anhydrous dimethylformamide, and Cool at 20 ° C. and add 0.8 ml of phosphorus tribromide. The mixture is stirred for 10 hours, diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. The organic layer is dried over NaSO 4 and evaporated to give 1.1 g of the title compound.
[실시예 45]Example 45
반응 (12)-(13)Reaction (12)-(13)
120ml의 디클로로 메탄중 1.4g의 4β-비닐티오-[1,2-디아세톡시메틸]-3-[1--니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온을 -78℃ㄹ까지 냉각시킨다. 다음에 오존함유 산소를 푸른색이 나타날때까지 용액에 통해준다. 이 용액을 Na2S2O5의 수용액과 함께 진탕하고 Na2SO4로 건조시킨다. 용액을 증발시키면 0.8g의 표제 화합물이 수득된다.1.4 g 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 120 ml dichloromethane Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one is cooled to -78 ° C. Next, ozone-containing oxygen is passed through the solution until a blue color appears. This solution is shaken with an aqueous solution of Na 2 S 2 O 5 and dried over Na 2 SO 4 . Evaporation of the solution yields 0.8 g of the title compound.
[실시예 46]Example 46
반응 (13)-(14)Reaction (13)-(14)
0.800g의 4β-아세틸글리콜릴티오-3-[1--니트로벤질옥시카보닐옥시에틸 ]-1-메톡시옥살릴-아제티딘-2-온을 50ml의 메탄올에 용해시킨 다음 수 g의 실리카겔을 가한다. 혼합물을 실온에서 60분간 방치한다. 불용성물질을 여과하고 여액을 증발시키면 0.30g의 표제화합물이 수득된다.0.800 g of 4β-acetylglycolylthio-3- [1- Nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxalyl-azetidin-2-one is dissolved in 50 ml of methanol and then several grams of silica gel are added. The mixture is left at room temperature for 60 minutes. Filtration of the insolubles and evaporation of the filtrate gave 0.30 g of the title compound.
[실시예 47]Example 47
반응(14)-(15)Reaction (14)-(15)
30ml의 벤젠중 0.5g의 4β-아세틸글리콜릴티오-3-[1-p-니트로벤질옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온 및 0.5g의 아세톡시메틸글리옥실레이트를 반응이 완결될때까지(2시간)환류시킨다.수득된 표제 화합물을 더 정제하지 않고 다음 단계에서 사용될 수 있다.0.5 g 4β-acetylglycolylthio-3- [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -agent in 30 ml of benzene Tidin-2-one and 0.5 g of acetoxymethylglyoxylate are refluxed until the reaction is complete (2 hours). The title compound obtained can be used in the next step without further purification.
[실시예 48]Example 48
반응 (15)-(16)Reaction (15)-(16)
0.35g의 4β-아세틸글리콜릴티오-3-[1--니트로벤질옥시카보닐 옥시에틸] -1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온을 0℃에서 10m l의 무수 테트라 하이드로푸란에 용해시킨다. 다음에 1.1당량의 피리딘과 1.1 당량의 티오닐클로라이드를 가한 다음 혼합물을 10분간 교반시킨다. 침전물을 여과하고 여액을 증발시키면 표제 화합물이 정량적인 수율로 수득된다. 조생성물은 다음 단계에서 그대로 사용된다.0.35 g of 4β-acetylglycolylthio-3- [1- Nitrobenzyloxycarbonyl oxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one is dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C. Then 1.1 equivalents of pyridine and 1.1 equivalents of thionylchloride are added and the mixture is stirred for 10 minutes. Filtration of the precipitate and evaporation of the filtrate gave the title compound in quantitative yield. The crude product is used as is in the next step.
[실시예 49]Example 49
반응 (16)-(11)Reaction (16)-(11)
0.400g의 4β-아세틸글리콜릴티오-3-[1--니트로벤질옥시카보닐옥시에틸 ]-1-[1-아세톡시메틸옥시카보닐-1-클로로메틸]-아제티딘-2-온을 테트라하이드로푸란 및 디옥산(1: 1)의; 혼합물 20ml에 용해시킨다. 그후 2당량의 트리페닐포스핀과 1.1당량의 피리딘을 가하고 혼합물을 50℃에서 철야 교반시킨다. 표제 화합물을 70 : 30 디클로로메탄-에틸아세테이트를 용출제로하여 실리카겔 칼럼 크로마토그라피를 정제한다. 0.280g의 포스포란이 수득된다.0.400 g of 4β-acetylglycolylthio-3- [1- -Nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-chloromethyl] -azetidin-2-one of tetrahydrofuran and dioxane (1: 1); Dissolve in 20 ml of the mixture. Then 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine are added and the mixture is stirred overnight at 50 ° C. The title compound was purified by silica gel column chromatography using 70:30 dichloromethane-ethyl acetate as the eluent. 0.280 g of phosphorane is obtained.
[실시예 50]Example 50
반응 (11)-(1)Reaction (11)-(1)
0.210g의 4β-아세틸글리콜릴티오-3-[1--1-니트로벤질옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 7ml의 톨루엔에 용해시킨 다음2시간동안 환류시킨다. 95:5 디클로로메탄-에틸아세테이트를 용출제로 단 칼럼크로마토그라피로 정제하면 0.05g의 표제 화합물이 수득된다.0.210 g of 4β-acetyl glycolylthio-3- [1- -1-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl] -azetidin-2-one in 7 ml of toluene Reflux over time. Purification of 95: 5 dichloromethane-ethylacetate with eluent to sweet column chromatography afforded 0.05 g of the title compound.
[실시예 51]Example 51
반응(1)Reaction (1)
0.060g의 5R-아세톡시메틸-6-[1--니트로벤질옥시카보닐옥시에틸]-2-아세톡시메틸-2-페넴-4-카복실레이트를 물-에탄올-K2HPO4혼합물에 주가한 다음 % Pd/C로 가소분해시킨다. 실리카겔 칼럼크로마토그라피로 신속히 정제하면 0.015g의 표제 화합물이 수득된다.0.060 g of 5R-acetoxymethyl-6- [1- Nitrobenzyloxycarbonyloxyethyl] -2-acetoxymethyl-2-penem-4-carboxylate is added to the water-ethanol-K 2 HPO 4 mixture and then plasticized to% Pd / C. Rapid purification with silica gel column chromatography yields 0.015 g of the title compound.
전술된 실시예에서 설명된 바와 같이 조작하나 1-메틸-5-티올-테트라졸 대신 5-메틸-2-티올-1,3,4-티아디아졸, 5-티올=1,2,3-트리아졸 또는 티올피라진을 사용하면(5R)-2-[(5'-메틸-1',3,4'-티아디아졸-2'-일)-티오메틸]-2-페넴-3-카복실산, (5R)-2-[(1',2',3'-트리아졸-5-일)-티오메틸]-2-페넴-3-카복실산, (5R)-2-(피라지닐)-티오메틸-2-페넴-3-카복실산, (5R)-6-[1'-하이드록시에틸-2-[5"-메틸-1",3",4"-티아디아졸-2"-일)티오메틸]2-페넴-3-카복실산, (5R)-6-[1'-하이드록시에틸]-2-[(1",2",3"-트리아졸-5"-일) 티오메틸]-2-페넴-3-카복실산,(5R)-6-[1'-하이드록시에틸]-2-(피라지닐) 티오메틸-2-페넴-3-카복실산이 각각 제조된다.Manipulation as described in the above examples but with 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thiol = 1,2,3- instead of 1-methyl-5-thiol-tetrazole When triazole or thiolpyrazine is used, (5R) -2-[(5'-methyl-1 ', 3,4'-thiadiazol-2'-yl) -thiomethyl] -2-phenem-3-carboxylic acid , (5R) -2-[(1 ', 2', 3'-triazol-5-yl) -thiomethyl] -2-phenem-3-carboxylic acid, (5R) -2- (pyrazinyl) -thio Methyl-2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl-2- [5′-methyl-1 ′, 3 ′, 4′-thiadiazol-2′-yl) Thiomethyl] 2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl] -2-[(1 ', 2', 3'-triazol-5'-yl) thiomethyl] 2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl] -2- (pyrazinyl) thiomethyl-2-phenem-3-carboxylic acid, is prepared, respectively.
전술한 바와 같이 조작하나 공지된 방법에 따라서 메틸-6-[1'-하이드록시에틸]-3-페니실리네이트를 환원하면 상응하는 6-에틸-유도체가 수득된다.Operation as described above, but reduction of methyl-6- [1'-hydroxyethyl] -3-phenylinate according to known methods yields the corresponding 6-ethyl-derivatives.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB7906634 | 1979-02-24 | ||
GB7906634 | 1979-02-24 |
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KR830001945A KR830001945A (en) | 1983-05-19 |
KR840000865B1 true KR840000865B1 (en) | 1984-06-20 |
Family
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KR1019800000767A KR840000865B1 (en) | 1979-02-24 | 1980-02-25 | Process for preparing -lactam-containing antibacterial agents |
Country Status (4)
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JP (1) | JPS55136288A (en) |
KR (1) | KR840000865B1 (en) |
BE (1) | BE881862A (en) |
ZA (1) | ZA80993B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS5625110A (en) * | 1978-12-18 | 1981-03-10 | Bristol Myers Co | Antibacterial |
NO831160L (en) * | 1982-04-08 | 1983-10-10 | Erba Farmitalia | PREPARATION OF SUBSTITUTED PENEM DERIVATIVES |
GB8300295D0 (en) * | 1983-01-06 | 1983-02-09 | Erba Farmitalia | Penem esters |
GB8416651D0 (en) * | 1984-06-29 | 1984-08-01 | Erba Farmitalia | Penem derivatives |
DE69329939T2 (en) | 1992-04-28 | 2001-06-28 | Tanabe Seiyaku Co., Ltd. | Process for the elimination of silyl protective groups from protected HO groups |
DE69805975T2 (en) | 1997-12-29 | 2002-12-19 | Research Corp. Technologies, Inc. | 2-BETA-SUBSTITUTED-6-ALKYLIDENPENICILIC ACID DERIVATIVES AS BETA LACTAMASE INHIBITORS |
US6407091B1 (en) | 1999-04-15 | 2002-06-18 | Research Corporation Technologies, Inc. | β-lactamase inhibiting compounds |
CA2454413A1 (en) | 2001-07-24 | 2003-03-13 | Alamx, L.L.C. | 7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors |
AU2003224874A1 (en) | 2002-04-04 | 2003-10-27 | Alamx, L.L.C. | INHIBITORS OF SERINE AND METALLO-ss-LACTAMASES |
-
1980
- 1980-02-21 ZA ZA00800993A patent/ZA80993B/en unknown
- 1980-02-22 BE BE0/199502A patent/BE881862A/en not_active IP Right Cessation
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- 1980-02-25 KR KR1019800000767A patent/KR840000865B1/en active
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JPH03396B2 (en) | 1991-01-07 |
KR830001945A (en) | 1983-05-19 |
JPS55136288A (en) | 1980-10-23 |
ZA80993B (en) | 1981-02-25 |
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