JPH01211589A - (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative - Google Patents
(5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivativeInfo
- Publication number
- JPH01211589A JPH01211589A JP63035135A JP3513588A JPH01211589A JP H01211589 A JPH01211589 A JP H01211589A JP 63035135 A JP63035135 A JP 63035135A JP 3513588 A JP3513588 A JP 3513588A JP H01211589 A JPH01211589 A JP H01211589A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- group
- compound expressed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical class CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000002252 acyl group Chemical group 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 2
- UXCLFZKNWIVWEA-UHFFFAOYSA-N 1-(2-sulfanylidene-1,3-thiazol-3-yl)ethanone Chemical class CC(=O)N1C=CSC1=S UXCLFZKNWIVWEA-UHFFFAOYSA-N 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 150000002690 malonic acid derivatives Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 abstract 1
- -1 γ-lactam compound Chemical class 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000005837 enolization reaction Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 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
- 238000001816 cooling Methods 0.000 description 3
- 150000008049 diazo compounds Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BMOBFBQWISCVKX-UHFFFAOYSA-N 1-(2-sulfanylidene-1,3-thiazolidin-3-yl)ethanone Chemical class CC(=O)N1CCSC1=S BMOBFBQWISCVKX-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 102100040996 Cochlin Human genes 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 101000748988 Homo sapiens Cochlin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- YJMNLPRMBFMFDL-UHFFFAOYSA-N n-diazo-2-methylbenzenesulfonamide Chemical compound CC1=CC=CC=C1S(=O)(=O)N=[N+]=[N-] YJMNLPRMBFMFDL-UHFFFAOYSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-YZRHJBSPSA-N pyrrolidin-2-one Chemical class O=C1CC[14CH2]N1 HNJBEVLQSNELDL-YZRHJBSPSA-N 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 150000003952 β-lactams Chemical group 0.000 description 2
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- KUQSHRXUEGEMBF-UHFFFAOYSA-N (4-nitrophenyl)sulfonyl 4-nitrobenzenesulfonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 KUQSHRXUEGEMBF-UHFFFAOYSA-N 0.000 description 1
- ZCRVPHKAQIHANY-UHFFFAOYSA-N (ne)-n-diazo-2-dodecylbenzenesulfonamide Chemical compound CCCCCCCCCCCCC1=CC=CC=C1S(=O)(=O)N=[N+]=[N-] ZCRVPHKAQIHANY-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- XTJQPJAUFNYHRW-UHFFFAOYSA-N 2-(1,4-dioxan-2-yl)ethanol;hydrate Chemical compound O.OCCC1COCCO1 XTJQPJAUFNYHRW-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- OWULJVXJAZBQLL-UHFFFAOYSA-N 4-azidosulfonylbenzoic acid Chemical compound OC(=O)C1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 OWULJVXJAZBQLL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical class C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 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
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 description 1
- 150000001782 cephems Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- BHQIGUWUNPQBJY-UHFFFAOYSA-N n-diazomethanesulfonamide Chemical compound CS(=O)(=O)N=[N+]=[N-] BHQIGUWUNPQBJY-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HDKCVDHYIIKWFM-UHFFFAOYSA-K octanoate;rhodium(3+) Chemical compound [Rh+3].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O HDKCVDHYIIKWFM-UHFFFAOYSA-K 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 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 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- HIAIVILTZQDDNY-UHFFFAOYSA-J tin(4+);trifluoromethanesulfonate Chemical compound [Sn+4].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HIAIVILTZQDDNY-UHFFFAOYSA-J 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003953 γ-lactams Chemical group 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は新規なγ−ラクタム系化合物に関し、さらに詳
細には次式(I):
式中
R1は水素原子、アルカリ金属またはカルボキシル保護
基を表わし、
R1は非置換もしくは置換アルキル基または複素環式基
を表わす、
で示される(5S)−3−置換チオー8−オキソ−1−
アザビシクロ[3,3,01オクタ−2−エン−2−カ
ルボン酸誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel γ-lactam compound, more specifically, the following formula (I): In the formula, R1 represents a hydrogen atom, an alkali metal or a carboxyl protecting group, and R1 is unsubstituted or (5S)-3-substituted thio-8-oxo-1-, which represents a substituted alkyl group or a heterocyclic group;
The present invention relates to azabicyclo[3,3,01 oct-2-ene-2-carboxylic acid derivatives.
これまでに抗菌活性を目的とした抗生物質の検索が種々
検討されてきており、ペニシリン骨格またはセフェム骨
格を有するペニシリン化合物またはセフェム化合物等の
抗生物質が数多く提供されており、すでにいくつかの化
合物については実用的抗生剤として医療上の使用に供さ
れている。これらペニシリン化合物およびセフェム化合
物は基本的には次式:
で示されるβ−ラクタム骨格を有するものであり、β−
ラクタム系抗生物質の範−に分類される。Up to now, various studies have been conducted to search for antibiotics with the aim of antibacterial activity, and many antibiotics such as penicillin compounds or cephem compounds having a penicillin skeleton or cephem skeleton have been provided, and some compounds have already been investigated. is used medically as a practical antibiotic. These penicillin compounds and cephem compounds basically have a β-lactam skeleton represented by the following formula:
It is classified as a lactam antibiotic.
ところで、上述のβ−ラクタム系抗生物質の開発検討は
その後著るしい進歩をみせており、最近はセフェム系抗
生剤に続く化合物として次式:で示されるカルパー2−
ペネム−3−カルボン酸を基本骨格とするカルバペネム
抗生物質が数多く提案されており、そのなかで次式:
で示されるイミペネム(imipenew : I N
N )が実用的抗菌剤として登場するに至っている。By the way, research into the development of the above-mentioned β-lactam antibiotics has since shown remarkable progress, and recently Calper 2-, which is represented by the following formula:
Many carbapenem antibiotics having penem-3-carboxylic acid as the basic skeleton have been proposed, and among them, imipenem (imipenew: I N
N) has now appeared as a practical antibacterial agent.
また、上記β−ラクタム系化合物の開発検討に加え、更
にβ−ラクタム骨格とは異なる骨格を有する抗生物質の
検討もなされてきている。例えば次式:
式中、Xは一〇Nまたは−So 、 CH、を表わす、
で示されるビシクロピラゾリジオン化合物が提案されて
おり、この化合物にもある程度の抗菌活性の存在するこ
とが報告されている(第27回ICAAC11987年
9月、N ew Y ork)。In addition to the development studies of the above-mentioned β-lactam compounds, studies have also been carried out on antibiotics having a skeleton different from the β-lactam skeleton. For example, the following formula: where X represents 10N or -So, CH,
A bicyclopyrazolidione compound represented by the following has been proposed, and it has been reported that this compound also has a certain degree of antibacterial activity (27th ICAAC, September 1987, New York).
このビシクロピラゾリジオン化合物の骨格を考察した場
合、該化合物は基本的に次式:で示されるγ−ラクタム
系化合物の誘導体を判断することができ、γ−ラクタム
系化合物にも優れた抗菌活性の存在することが期待され
るものの、この系列の化合物についてはこれまであまり
精力的に検討されていないのが実情である。When considering the skeleton of this bicyclopyrazolidione compound, it can be determined that the compound is basically a derivative of a γ-lactam compound represented by the following formula: It has excellent antibacterial activity even in γ-lactam compounds. Although it is expected that this series of compounds exists, the reality is that this series of compounds has not been studied very vigorously to date.
そこで本発明者らはγ−ラクタム骨格を有する化合物の
合成検討を行い、その結果、前記式!で示される(5S
)−3−置換チオー8−オキソ−1−アザビシクロ[3
,3,0] オクタ−2−エン−2−カルボン酸誘導体
に抗菌活性が認められることを確認し、本発明を完成す
るに至った。Therefore, the present inventors investigated the synthesis of a compound having a γ-lactam skeleton, and as a result, the above formula! (5S
)-3-substituted thio8-oxo-1-azabicyclo[3
, 3, 0] It was confirmed that oct-2-ene-2-carboxylic acid derivatives have antibacterial activity, and the present invention was completed.
したがって、本発明は抗菌活性を有する前記式(1)で
示される従来の文献に未載の新規なγ−ラクタム系化合
物を提供するものである。Therefore, the present invention provides a novel γ-lactam compound having antibacterial activity and having the above formula (1), which has not been described in the conventional literature.
本発明が提供する前記式(I)で示される化合物におい
て R1によって表わされうる「アルカリ金属」として
は、ナトリウム、カリウム等が包含され、またFカルボ
キシル保護基jは、抗生物質系化合物の分野で知られて
いる任意のカルボキシル保護基であることができ、エス
テル残基を例示することができる。かかるエステル残基
としては、例えば、メチル、エチル、n−プロピル、イ
ソプロピル、n−1iso−1sec−もしくはter
t −ブチル、n−ヘキシルエステル等の低級アルキル
エステル残基;ベンジル、p−ニトロベンジル、0−ニ
トロベンジル、p−メトキシベンジル等のアラルアルキ
ルエステル残基:アセトキシメチル、プロピオニルオキ
シメチル、n−1IsO−もしくはtert−ブチリル
オキシメチル、ピバロイルオキシメチル等の低級脂肪族
アシルオキシメチル残基等が挙げられる。In the compound represented by the formula (I) provided by the present invention, the "alkali metal" that can be represented by R1 includes sodium, potassium, etc., and the F carboxyl protecting group It can be any carboxyl protecting group known in the art, and examples thereof include ester residues. Such ester residues include, for example, methyl, ethyl, n-propyl, isopropyl, n-1iso-1sec- or ter
Lower alkyl ester residues such as t-butyl and n-hexyl esters; aral alkyl ester residues such as benzyl, p-nitrobenzyl, 0-nitrobenzyl, and p-methoxybenzyl: acetoxymethyl, propionyloxymethyl, n-1IsO - or tert-butyryloxymethyl, lower aliphatic acyloxymethyl residues such as pivaloyloxymethyl, and the like.
また、Rzによって表わされうる「アルキル基」は直鎖
状または分岐鎖状のいずれであってもよく、好ましくは
1〜6個の炭素原子を有する低級アルキルであることが
でき、例えば、メチル、エチル、n−プロピル、イソプ
ロピル、n−ブチル、イソブチル、5ee−ブチル、t
ert−ブチル、n−ペンチル、イソペンチル、n−ヘ
キシル、イソヘキシル基等が包含される。In addition, the "alkyl group" that can be represented by Rz may be linear or branched, and is preferably a lower alkyl group having 1 to 6 carbon atoms, such as methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ee-butyl, t
Included are ert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups, and the like.
「置換アルキル基」は上記の「アルキル基」の任意の位
置が1個もしくはそれ以上の種々の置換基で置換された
アルキル基を意味し、そのような置換基の例としては、
アミノ、置換アミノ、アミジノ、イミノ、グアニジノ、
グアニジニウム、スルファモイル、ウレイド、アミド、
メルカプト、アルキルチオ、アリールチオ等を上げるこ
とができる。"Substituted alkyl group" means an alkyl group in which any position of the above "alkyl group" is substituted with one or more various substituents; examples of such substituents include:
Amino, substituted amino, amidino, imino, guanidino,
Guanidinium, sulfamoyl, ureido, amide,
Examples include mercapto, alkylthio, and arylthio.
更に上記の置換アルキル基には、次にの説明する「複素
環式基」で置換されたアルキル基も包含される。Furthermore, the above-mentioned substituted alkyl group also includes an alkyl group substituted with a "heterocyclic group" described below.
「複素環式基」はへテロ原子として酸素、窒素、硫黄原
子の少なくとも1個を含有する、好ましくは4〜8員の
芳香族系または脂肪族系の環式基であり、例えばアゼチ
ジニル、フリル、フルフリノ呟チエニル、ピリジル、ピ
リミジル、ピロリジニル、ピペリジル、オキサゾリジニ
ル、チアゾリジニル、チアゾリル、オキサシリル、チア
ジアゾリル、トリアゾリル、テトラゾリル等を挙げるこ
とができ、これらのものは前記した如くメチレン鎖を介
して結合していても良い。更に環炭素原子は置換アルキ
ル基について前述した置換基で置換されていてもよい。A "heterocyclic group" is a preferably 4- to 8-membered aromatic or aliphatic cyclic group containing at least one of oxygen, nitrogen, or sulfur atoms as a heteroatom, such as azetidinyl, furyl, etc. , furfurinothienyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidyl, oxazolidinyl, thiazolidinyl, thiazolyl, oxasilyl, thiadiazolyl, triazolyl, tetrazolyl, etc., and these may be bonded via a methylene chain as described above. good. Additionally, ring carbon atoms may be substituted with the substituents described above for substituted alkyl groups.
好ましいR2の具体例としてはアミノエチル基、3−ア
ゼチジン−3−イル基を挙げることができる。Preferred specific examples of R2 include aminoethyl group and 3-azetidin-3-yl group.
本発明の前記式(I)で示される化合物は、基本的には
下記反応式Aに示す工程に従って製造することができる
。The compound represented by the formula (I) of the present invention can be basically produced according to the steps shown in Reaction Formula A below.
反応丸A
(II) (DI)
(V) (Vl)(■
) (■)
([) (X)上記反応式中、
Lはアシル基等の脱離基を表わし、R3はカルボキシル
保護基を表わし、R’は水素原子またはアルキル基を表
わし Raはアシル基を表わす。またカッコ内は各工程
を示す。Reaction circle A (II) (DI) (V) (Vl) (■
) (■) ([) (X) In the above reaction formula,
L represents a leaving group such as an acyl group, R3 represents a carboxyl protecting group, R' represents a hydrogen atom or an alkyl group, and Ra represents an acyl group. Each step is shown in parentheses.
なお、上記式中のしおよびR1で示される「アシル基」
には、単に有機カルボン酸のカルボキシル基からOHを
除いた残りの原子団のみならず、広義に、有機スルホン
酸や有機リン酸から誘導されるアシル基をも包含され、
例えば、アセチル、プロピオニル、ブチリル等の低級ア
ルカノイル基:メタンスルホニル、トリフルオロメタン
スルホニル基等の(ハロ)低級アルキルスルホニル基:
ベンゼンスルホニル、p−ニトロベンゼンスルホニル、
p−ブロモベンゼンスルホニル、トルエンスルホニル、
2.4.6−トリイソプロビルベンゼンスルホニル等の
置換もしくは未置換のアリールスルホニル基;ジフェニ
ルホスホリル基等が挙げられる。In addition, the "acyl group" represented by and R1 in the above formula
includes not only the atomic group remaining after removing OH from the carboxyl group of an organic carboxylic acid, but also, in a broad sense, acyl groups derived from organic sulfonic acids and organic phosphoric acids.
For example, lower alkanoyl groups such as acetyl, propionyl, butyryl; (halo)lower alkylsulfonyl groups such as methanesulfonyl and trifluoromethanesulfonyl groups:
Benzenesulfonyl, p-nitrobenzenesulfonyl,
p-bromobenzenesulfonyl, toluenesulfonyl,
2.4. Substituted or unsubstituted arylsulfonyl groups such as 6-triisopropylbenzenesulfonyl; diphenylphosphoryl groups, and the like.
以下上記反応の各工程を更に詳細に説明する。Each step of the above reaction will be explained in more detail below.
工程(a)は、式(1)のN−アセチル−1,3−チア
ゾリジン−2−チオン誘導体を、塩基の存在下にスズ(
■)トリフレートと反応させて二ル−トを生成させ、次
いでこれに式(I[)の化合物を反応させて、式(IV
)のピロリジン−2−オン誘導体を製造することからな
る。In step (a), the N-acetyl-1,3-thiazolidine-2-thione derivative of formula (1) is reacted with tin (
■) React with triflate to produce a di-root, which is then reacted with a compound of formula (I[) to form a compound of formula (IV
) of pyrrolidin-2-one derivatives.
上記の式([[)のN−アセチル−1,3−チアゾリジ
ン−2−チオン誘導体のスズ(■)トリフレートによる
エノール化反応は、通常反応に不活性な溶媒中、例えば
、ジエチルエーテル、テトラヒドロ7ラン等のエーテル
類;トルエン、キシレン、シクロヘキサン等の炭化水素
類;ジクロルメタン、クロロホルム等のハロゲン化炭化
水素類など、特にテトラヒドロフラン中で好適に実施す
ることができる。The enolization reaction of the N-acetyl-1,3-thiazolidine-2-thione derivative of the above formula ([[) with tin (■) triflate is usually carried out in a solvent inert to the reaction, such as diethyl ether, Ethers such as 7ran; hydrocarbons such as toluene, xylene, and cyclohexane; halogenated hydrocarbons such as dichloromethane and chloroform; and particularly, the reaction can be suitably carried out in tetrahydrofuran.
反応温度は厳密に制限されるものではなく、使用する出
発原料等に応じて広範に変えることができるが、一般に
は約−100℃ないしほぼ室温程度、好ましくは約−7
8°C〜約O℃の比較的低温が使用される。The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but is generally about -100°C to about room temperature, preferably about -7°C.
Relatively low temperatures of 8°C to about 0°C are used.
式(I[I)の化合物に対するスズ(■)トリフレート
の使用量は臨界的なものではないが、通常、式(II[
)の化合物1モルに対するスズ(■)トリフレートは約
1〜約2モル、好ましくは1〜1゜5モルの割合で使用
することができる。Although the amount of tin (■) triflate used relative to the compound of formula (I[I) is not critical, it is usually
The tin (■) triflate can be used in a ratio of about 1 to about 2 mol, preferably 1 to 1.5 mol, per mol of the compound ().
上記エノール化反応は塩基の条件下に実施され、使用し
うる塩基としては、例えば、トリエチルアミン、ジイソ
プロピルエチルアミン
アザビシクロ[2.2.2]オクタン、N−メチルモル
ホリン、N−エチルピペリジン、ピリジン等の第三級ア
ミン等が挙げられ、中でもN−エチルピペリジンが有利
に用いられる。これらの塩基は一般に式(m)の化合物
1モル当り約り.o〜約3当量、好ましくは1.0〜2
.0当量の割合で使用することができる。The above enolization reaction is carried out under basic conditions, and examples of bases that can be used include triethylamine, diisopropylethylamine azabicyclo[2.2.2]octane, N-methylmorpholine, N-ethylpiperidine, and pyridine. Examples include tertiary amines, among which N-ethylpiperidine is advantageously used. These bases are generally used in amounts of about . o to about 3 equivalents, preferably 1.0 to 2
.. It can be used in a proportion of 0 equivalents.
上記エノール化反応は一般に約5分〜約4時間で終らせ
ることができ、これによってエルレートが得られる。The enolization reaction can generally be completed in about 5 minutes to about 4 hours, thereby yielding erulate.
このエノール化反応に引続いてそのまま、生成するエル
レートに前記式(II)の化合物を反応せしめることが
できる。Following this enolization reaction, the resulting erulate can be directly reacted with the compound of formula (II).
前記エルレートと式(…)の化合物との間のアルキル化
反応は一般に、約−100℃ないしほぼ室温、好ましく
は約−78℃〜約lo℃の温度において実施することが
できる。その際の式(III)の化合物の使用量は臨界
的ではなく適宜変更することができるが、通常、前記エ
ノール化反応に用いた式(III)の化合物1モル当り
約0.5〜約5モル、好ましくは0.5〜2モルの割合
で用いるのが適当である。The alkylation reaction between the erulate and the compound of formula (...) can generally be carried out at a temperature of about -100<0>C to about room temperature, preferably about -78<0>C to about lo<0>C. The amount of the compound of formula (III) used in this case is not critical and can be changed as appropriate, but is usually about 0.5 to about 5 It is appropriate to use it in a molar ratio, preferably 0.5 to 2 molar.
かかる条件下に反応は一般に約5分〜約5時間、より一
般には5分〜約2時間程度で終了させることができる。Under such conditions, the reaction can generally be completed in about 5 minutes to about 5 hours, more generally about 5 minutes to about 2 hours.
前述のエノール化反応及び上記アルキル化反応は、必須
ではないが、不活性雰囲気下、例えば窒素ガス、アルゴ
ンガス雰囲気下に実施するのが望ましい。The enolization reaction and the alkylation reaction described above are preferably, but not necessarily, carried out under an inert atmosphere, such as a nitrogen gas or argon gas atmosphere.
最後に反応生成物は水で剋理される。例えば、反応終了
後、pH7付近の燐酸緩衝液を加え撹拌し、不溶物を濾
別したのち、式(IV)の化合物を常法により、例えば
抽出、再結晶、クロマトグラフィー等により分離精製す
ることができる。Finally, the reaction product is washed with water. For example, after the reaction is completed, a phosphate buffer solution with a pH around 7 is added and stirred, insoluble matter is filtered off, and then the compound of formula (IV) is separated and purified by conventional methods such as extraction, recrystallization, chromatography, etc. Can be done.
工程(b)は、前記工程(a)で製造される式(IV)
で示されるピロリジン−2−オン誘導体を、イミダゾー
ルノ存在下に式(R300CCH,Goり2Mgテ表わ
されるマグネシウムマロネート化合物と反応させ、式(
V)で表わされる化合物を得る工程である。Step (b) is the formula (IV) produced in step (a).
A pyrrolidin-2-one derivative represented by the above formula is reacted with a magnesium malonate compound represented by the formula (R300CCH, Go2Mg) in the presence of imidazol to form the formula (
This is a step of obtaining a compound represented by V).
反応は好ましくは不活性有機溶媒中で行なわれ、例えば
エーテル、テトラヒドロフラン、ジオキサン等のエーテ
ル系溶媒;トルエン、キシレン、シクロヘキサン等の炭
化水素系溶媒;ジクロルメタン、クロロホルム等のハロ
ゲン化炭化水素系溶媒ニアセトニトリル等などを挙げる
ことができるが、特にアセトニトリルが好適に使用され
る。The reaction is preferably carried out in an inert organic solvent, such as ether solvents such as ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as toluene, xylene and cyclohexane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; niacetonitrile; Among them, acetonitrile is particularly preferably used.
反応温度は厳密に制限されるものではなく、使用する出
発原料等に応じて広範に変えるこきができるが、一般に
約0℃ないしほぼ100°C程度、好ましくは室温付近
の比較的低温が使用される。The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but generally a relatively low temperature of about 0°C to about 100°C, preferably around room temperature, is used. Ru.
式(IV)の化合物に対するマグネシウムマロネート化
合物の使用量はほぼ等モル量が使用され、反応は50時
間程度、好ましくは20時間程度で完了する。The amount of magnesium malonate compound used is approximately equimolar to the compound of formula (IV), and the reaction is completed in about 50 hours, preferably about 20 hours.
なお、使用するマグネシウムマロネート化合物としては
、例えば、バラニトロベンジルマグネシウムマロネート
、ベンジルマグネシウムマロネート、メチルマグネシウ
ムマロネート等を挙げることができるが、なかでもパラ
ニトロベンジルマグネシウムマロネートを用いるのが好
ましい。In addition, examples of the magnesium malonate compound to be used include paranitrobenzylmagnesium malonate, benzylmagnesium malonate, methylmagnesium malonate, etc. Among them, it is preferable to use paranitrobenzylmagnesium malonate. .
工程(C)では、工程(b)で得られる式(V)で示さ
れる化合物を、塩基の存在下に、前記工程(b)で述べ
たと同様の不活性有機溶媒中でアジド化合物で処理し、
目的とする式(Vl)のジアゾ化合物を得る。In step (C), the compound represented by formula (V) obtained in step (b) is treated with an azide compound in the same inert organic solvent as described in step (b) in the presence of a base. ,
The desired diazo compound of formula (Vl) is obtained.
使用されるアジド化合物としては、例えば、p−カルボ
キシベンゼンスルホニルアシト、トルエンスルホニルア
ジド、メタンスルホニルアジド、ドデシルベンゼンスル
ホニルアジドなどを挙げることができ、また、塩基とし
ては、トリエチルアミン、ピリジン、ジエチルアミンな
どの塩基を例示することができる。Examples of the azide compound to be used include p-carboxybenzenesulfonyl azide, toluenesulfonyl azide, methanesulfonyl azide, dodecylbenzenesulfonyl azide, and bases such as triethylamine, pyridine, and diethylamine. can be exemplified.
反応は、好ましくはトリエチルアミンの存在下アセトニ
トリル中で、p−トルエンスルホニルアジドを加え、0
〜100°C1好ましくは室温で1〜50時間旭理する
ことにより行なうことができ、これによって高収率で目
的とする式(Vl)のジアゾ化合物を得ることができる
。The reaction is preferably carried out in acetonitrile in the presence of triethylamine by adding p-toluenesulfonyl azide and
This can be carried out by heating at ~100°C, preferably at room temperature, for 1 to 50 hours, and thereby the desired diazo compound of formula (Vl) can be obtained in high yield.
工程(d)は、工程(C)で得られる式(Vl)のジア
ゾ化合物を環化し、式(■)で示される化合物とする工
程である。本工程は好適には、例えば式(Vl)の化合
物を、ベンゼン、トルエン、テトラヒドロフラン、シク
ロヘキサン、酢酸エチル、ジクロルメタンなどのような
不活性溶媒中、好ましくはトルエン中で、25〜110
℃の温度において1〜5時間、ビス(アセチルアセトナ
ト)Cu(II) 、Cu5Oa、銅粉末、Rh2(O
COCHs)いロジウムオクタノエートまたはPb(O
COCH,)、のような金属カルボキシレート化合物な
どの金属触媒の存在下で地理することにより実施される
。−万態の方法として、上記環化工程はまた式(Vl)
の化合物を、ベンゼン、ジエチルエーテルなどのような
溶媒中で、0〜250℃の温度において0.5〜2時間
、バイレックスフィルター(波長は300nmより大)
を通して光を照射することにより実施することもできる
。Step (d) is a step in which the diazo compound of formula (Vl) obtained in step (C) is cyclized to form a compound represented by formula (■). This step suitably comprises, for example, preparing a compound of formula (Vl) in an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane, etc., preferably in toluene, at 25 to 110%
Bis(acetylacetonato)Cu(II), CuOa, copper powder, Rh2(O
COCHs) rhodium octanoate or Pb(O
It is carried out in the presence of a metal catalyst such as a metal carboxylate compound such as COCH, ). - As a universal method, the above cyclization step also includes formula (Vl)
of the compound in a solvent such as benzene, diethyl ether, etc. at a temperature of 0 to 250°C for 0.5 to 2 hours using a Virex filter (wavelength greater than 300 nm).
It can also be carried out by irradiating light through.
ついで、工程(e)において、工程(d)で得られる式
(■)の化合物をR@OHで示される酸の反応性誘導体
(例えば、酸無水物、ハライドなど)と反応させること
により、式(■)で示される化合物が得られる。Then, in step (e), the compound of formula (■) obtained in step (d) is reacted with a reactive derivative of the acid represented by R@OH (e.g., acid anhydride, halide, etc.) to obtain the compound of formula (■). A compound indicated by (■) is obtained.
かかる酸の反応性誘導体としては、例えば、無水酢酸、
アセチルクロリド、プロピオニルクロリド、p−トルエ
ンスルホン酸無水物、p−ニトロベンゼンスルホン酸無
水物、2,4.6−1−リイソプロビルベンゼンスルホ
ン酸無水物、メタンスルホン酸無水物、トリフルオロメ
タンスルホン酸無水物、ジフェニルリン酸クロリド、ト
ルエンスルホニルアジドF、p−7’ロモベンゼンスル
ホニルクロリドなどが挙げられ、特にジフェニルリン酸
クロリド(R1=ジフェニルホスホリル基)が好適であ
る。Reactive derivatives of such acids include, for example, acetic anhydride,
Acetyl chloride, propionyl chloride, p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4.6-1-lyisoprobylbenzenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride Diphenylphosphoryl chloride, diphenylphosphoryl chloride, toluenesulfonyl azide F, p-7' lomobenzenesulfonyl chloride and the like are particularly preferred, with diphenylphosphoryl chloride (R1=diphenylphosphoryl group) being particularly preferred.
式(■)の化合物と上記酸の反応性誘導体との反応は、
通常のアシル化法と同様にして行なうことができ、例え
ば、メチレンクロリド、アセトニトリル、ジメチルホル
ムアミド等の不活性溶媒中で、適宜ジイソプロピルエチ
ルアミン、トリエチルアミン、4−ジメチルアミノピリ
ジン等の塩基の存在下に、−20〜40°Cの温度で約
30分〜約24時間処理することにより行なうことがで
きる。The reaction between the compound of formula (■) and the reactive derivative of the above acid is
It can be carried out in the same manner as the usual acylation method, for example, in an inert solvent such as methylene chloride, acetonitrile, dimethylformamide, etc., in the presence of an appropriate base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc. This can be carried out by treating at a temperature of -20 to 40°C for about 30 minutes to about 24 hours.
次いで工程(f)は、工程(e)で得られる式(■)で
示される化合物Iこ、メルカプト試薬:H3−R”を反
応させ、式(II)で示される化合物を得る工程である
。Next, step (f) is a step of reacting the compound I represented by formula (■) obtained in step (e) with a mercapto reagent: H3-R'' to obtain a compound represented by formula (II).
式(■)の化合物とメルカプト試薬との反応は、例えば
、式(■)で示される化合物を、テトラヒドロ7ラン、
ジクロルメタン、ジオキサン、ジメチルホルムアミド、
ジメチルスルホキシド、アセトニトリル、ヘキサメチル
ホスホラミドなど等の適当な溶媒中で、はぼ等モル量乃
至約1.5倍モル量の過剰量のメルカプト試薬と、好ま
しくは炭酸水素ナトリウム、炭酸カリウム、トリエチル
アミン、ジイソプロピルエチルアミンなどの塩基の存在
下に約−40〜約25°Cの範囲内の温度で約30分〜
約24時間反応させることにより行なうことができる。The reaction between the compound of formula (■) and a mercapto reagent can be carried out, for example, by reacting the compound of formula (■) with tetrahydro7rane,
dichloromethane, dioxane, dimethylformamide,
In a suitable solvent such as dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., an approximately equimolar to about 1.5 times molar excess of the mercapto reagent and preferably sodium bicarbonate, potassium carbonate, triethylamine, etc. in the presence of a base such as diisopropylethylamine at a temperature within the range of about -40 to about 25°C for about 30 minutes to
This can be carried out by reacting for about 24 hours.
以上の反応により式(ff)で示される化合物を得るこ
とができるが、該化合物においては2位のカルボン酸が
カルボキシル保護基Hsで保護されている。この保護基
R3の除去(工程g)は、ソルボリシスまたは水素添加
分解のようなそれ自体既知の脱保護基反応により行なう
ことができる。典型的には、式(Iりで示される化合物
を例えばpH7のモルホリノプロパンスルホン酸−水酸
化ナトリウム緩衝液、pH7のリン酸塩緩衝液、リン酸
二カリウム、重炭酸ナトリウムなどを含むテトラヒドロ
フラン−水、テトラヒドロ7ランーエタノールー水、ジ
オキサン−水、ジオキサン−エタノール−水、n−ブタ
ノール−などのような混合溶媒中で、1〜4気圧の水素
を用い、酸化白金、パラジウム−活性炭、水酸化パラジ
ウム−活性炭などの水添触媒の存在下に、約O〜約50
℃の範囲内の温度で約0.25〜約4時間処理すること
により行なうことができる。A compound represented by formula (ff) can be obtained by the above reaction, and in this compound, the carboxylic acid at the 2-position is protected with a carboxyl protecting group Hs. Removal of this protecting group R3 (step g) can be carried out by deprotecting group reactions known per se, such as solvolysis or hydrogenolysis. Typically, a compound of formula Platinum oxide, palladium-activated carbon, hydroxide using hydrogen at 1 to 4 atmospheres in a mixed solvent such as , tetrahydro7rane-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-, etc. In the presence of a hydrogenation catalyst such as palladium on activated carbon, from about O to about 50
This can be done by treatment at a temperature within the range of 0.25 to about 4 hours.
かくして本発明の式Iで示される目的化合物中R1が水
素原子で表わされる式(X)の化合物を得ることができ
る。In this way, a compound of formula (X) in which R1 in the target compound of formula I of the present invention is represented by a hydrogen atom can be obtained.
なお、該化合物はそれ自体既知の方法に従い、ナトリウ
ム塩、カリウム塩等の塩に導くことができる。Incidentally, the compound can be converted into salts such as sodium salts and potassium salts according to methods known per se.
以上の如くして製造される式■の化合物は優れた抗菌活
性を有しており、抗菌剤として使用することが期待され
る。The compound of formula (2) produced as described above has excellent antibacterial activity and is expected to be used as an antibacterial agent.
以下、本発明を実施例により更に説明する。The present invention will be further explained below with reference to Examples.
スズトリフレート697mg(1,67m、u)を窒素
気流下、無水テトラヒドロフラン2.5m12に懸濁さ
せ、−40〜−50℃に冷却後、N−エチルピペリジン
0.26m12および化合物(2)243mgの無水テ
トラヒドロフラン1.5mQ溶液を加え、同温度にて3
.5時間撹拌した。その後、化合物(1)239mgの
無水テトラヒドロフラン1.5mQ溶液を加え、0°C
にて2時間撹拌した。反応液に10%クエン酸水溶液お
よびクロロホルムを加え、セライト濾過を行ない、濾液
を飽和食塩水で洗浄後、Na25o、で乾燥した。溶媒
を留去し、残留物をシリカゲルカラムクロマトで精製し
、化合物(3)を黄色油状物として302mg(86%
)得 Iこ 。697 mg (1,67 m, u) of tin triflate was suspended in 2.5 m12 of anhydrous tetrahydrofuran under a nitrogen stream, and after cooling to -40 to -50°C, 0.26 m12 of N-ethylpiperidine and 243 mg of compound (2) were suspended. Add 1.5 mQ of anhydrous tetrahydrofuran solution and stir at the same temperature for 3
.. Stirred for 5 hours. Then, a solution of 239 mg of compound (1) in 1.5 mQ of anhydrous tetrahydrofuran was added, and the mixture was heated to 0°C.
The mixture was stirred for 2 hours. A 10% aqueous citric acid solution and chloroform were added to the reaction solution, which was then filtered through Celite. The filtrate was washed with saturated brine and dried over Na25O. The solvent was distilled off, the residue was purified by silica gel column chromatography, and 302 mg (86%) of compound (3) was obtained as a yellow oil.
) I got it.
NMR(δ 、 CD C(2s) : l
、02(3H,t−y=7Hz)、1.6〜2.6(
6HS m)、 2.9〜3.3(2H1m)、
3.4〜3.9(2HS m)、 3,95〜4
.25(LH,m)、 5.0〜5.3(IHSm)
、 6゜33(IH,bs)。NMR(δ, CDC(2s): l
, 02 (3H, t-y=7Hz), 1.6-2.6 (
6HS m), 2.9-3.3 (2H1m),
3.4-3.9 (2HS m), 3,95-4
.. 25 (LH, m), 5.0-5.3 (IHSm)
, 6°33 (IH, bs).
物4)
実施例1で得た化合物(3)326mgの無水アセトニ
トリル12mff溶液に、窒素気流下イミダゾール20
4mgを加え、室温で5.5時間撹拌後、M g (0
2CCH! COOP N B ) 2899 mgを
加え、更に窒素気流下60°Cで18時間撹拌した。反
応終了後、反応液に酢酸エチルを加え、lN塩酸、5%
炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、
Na25Oaにて乾燥した。溶媒を減圧下に留去し、得
られた残留物をシリカゲルクロマトにて精製し、化合物
(4)を白色固体として214mg(56% ) 得
Iこ 。Product 4) To a solution of 326 mg of the compound (3) obtained in Example 1 in 12 mff of anhydrous acetonitrile was added 20 ml of imidazole under a nitrogen stream.
After adding 4 mg and stirring at room temperature for 5.5 hours, M g (0
2CCH! 2899 mg of COOP N B ) was added thereto, and the mixture was further stirred at 60°C for 18 hours under a nitrogen stream. After the reaction was completed, ethyl acetate was added to the reaction solution, and 1N hydrochloric acid, 5%
Wash sequentially with sodium bicarbonate aqueous solution and saturated saline,
It was dried with Na25Oa. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 214 mg (56%) of compound (4) as a white solid.
NMR(δ、CD CQs): 2.2〜2.5(4H
,m)、2.8〜3.0(2H,m)、3.60(2H
,S)、3.9〜4.2(LH,m)、5.3(2H,
s)、6.53(IH,bs)、7.53(2H,d、
J= 8.8Hz)、8.22(2H,d、J = 8
.8Hz)。NMR (δ, CD CQs): 2.2-2.5 (4H
, m), 2.8-3.0 (2H, m), 3.60 (2H
, S), 3.9-4.2 (LH, m), 5.3 (2H,
s), 6.53 (IH, bs), 7.53 (2H, d,
J = 8.8Hz), 8.22 (2H, d, J = 8
.. 8Hz).
実施例3 : (5S)−5−(3−ジアゾ−3−p
−ニトロベンジルオキシカルボニル−2−化合物(4)
214mgの無水アセトニトリル3゜5m12溶液に、
パラトルコンスルホニルアジド170mgおよびトリコ
チルアミン0.121mffを加え、室温で20分間撹
拌した。反応終了後、溶媒を減圧上留去し、残留物をシ
リカゲルクロマトで精製し、化合物(5)を淡黄色状物
として230mg(定量的)得た。Example 3: (5S)-5-(3-diazo-3-p
-nitrobenzyloxycarbonyl-2-compound (4)
214 mg of anhydrous acetonitrile in 3゜5ml solution,
170 mg of paraturcosulfonyl azide and 0.121 mff of tricotylamine were added, and the mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 230 mg (quantitative) of Compound (5) as a pale yellow substance.
NMR(δ、CD CQ3) : 2.2−2.5(
4H1m)、3.0−3.2(2H,m)、4.0−4
.3(IH,m)、5.38(2H1s)、6.50(
IH,bs)、7.56(2H,d、 J=8.8Hz
)、8.26(2H。NMR (δ, CD CQ3): 2.2-2.5(
4H1m), 3.0-3.2 (2H,m), 4.0-4
.. 3 (IH, m), 5.38 (2H1s), 6.50 (
IH, bs), 7.56 (2H, d, J=8.8Hz
), 8.26 (2H.
d、 J=8.8Hz)。d, J=8.8Hz).
実施例4:(5S)−1−アザ−2,7−シオキソー8
−p−ニトロベンジルオキシカ
ルボニル−ビシクロ[3,3,0] オフ化合物(5)
88mgの酢酸エチル溶液に、ロジウム(n)アセテー
ト1mgを加え、窒素気流下80°C″r15分間撹拌
した。溶媒を減圧上留去し、残留物をシリカゲルクロマ
トで精製し、化合物(6)を淡黄色油状物として70m
g(87%)得た。Example 4: (5S)-1-aza-2,7-thioxo 8
-p-nitrobenzyloxycarbonyl-bicyclo[3,3,0]off compound (5)
1 mg of rhodium (n) acetate was added to a solution of 88 mg of ethyl acetate, and the mixture was stirred at 80°C for 15 minutes under a nitrogen stream. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound (6). 70m as pale yellow oil
g (87%) was obtained.
NMR(δ、CD CQs): 2.1”’3.0(6
H,m)、4.2〜4−6(LH,m)、4.85(I
H,bs)、5.23および5.50(2H,ABq、
J=13Hz)、7.55(2H,、d、 J=
8.8Hz)、8.28(2H,d、 J−8,8Hz
)。NMR (δ, CD CQs): 2.1"'3.0 (6
H, m), 4.2-4-6 (LH, m), 4.85 (I
H, bs), 5.23 and 5.50 (2H, ABq,
J=13Hz), 7.55(2H,,d, J=
8.8Hz), 8.28(2H,d, J-8,8Hz
).
ン(化合物7)
実施例4で得た化合物(6)80mgの無水アセトニト
リル1m+2溶液に、水冷下ジフェニルリン酸りロルド
0.06m+2およびジイソプロピルエチルアミンQ、
Q5m12を加え、窒素気流下1時間撹拌した。反応終
了後、反応液を減圧上留去し、残留物をシリカゲルクロ
マトにて精製し、化合物(7)を黄色油状物としてl1
6mg(80%)得た。(Compound 7) To a solution of 80 mg of the compound (6) obtained in Example 4 in 1 m+2 of anhydrous acetonitrile, 0.06 m+2 of diphenylphosphoric acid salt and diisopropylethylamine Q,
Q5m12 was added and stirred for 1 hour under a nitrogen stream. After the reaction was completed, the reaction solution was distilled off under reduced pressure, and the residue was purified using silica gel chromatography to obtain compound (7) as a yellow oil.
6 mg (80%) was obtained.
NMR(δ、CD CQ3): 2.3〜3.1(6H
,m)、4.3−4.7(IHSm)、5.15および
5.39(2H,ABq、 J−10Hz)、7.1−
7.4(IOH,m)、7.53(2H,d、 J−8
,8Hz)、8.12(2H,d、 J=8.8Hz)
。NMR (δ, CD CQ3): 2.3-3.1 (6H
, m), 4.3-4.7 (IHSm), 5.15 and 5.39 (2H, ABq, J-10Hz), 7.1-
7.4 (IOH, m), 7.53 (2H, d, J-8
, 8Hz), 8.12 (2H, d, J=8.8Hz)
.
実施例6:
化合物(7)304mgの無水アセトニトリル溶液に、
4オ一ル化合物(8)169mgおよびジイソプロピル
エチルアミンO,l1mQを氷冷下に加え、窒素気流下
1時間撹拌した。反応液を減圧留去し、得られた残留物
をシリカゲルクロマトで精製し、化合物(9)を黄色状
物として290mg(97%)得た。Example 6: To a solution of 304 mg of compound (7) in anhydrous acetonitrile,
169 mg of 4-ol compound (8) and 1 mQ of diisopropylethylamine were added under ice cooling, and the mixture was stirred for 1 hour under a nitrogen stream. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 290 mg (97%) of compound (9) as a yellow substance.
NMR(δ、CD CQs) : 2.2−3.0(6
H,m)、3.8〜4.7(6H,m)、5.19(2
8%s)、5.25および5.52(2H。NMR (δ, CD CQs): 2.2-3.0 (6
H, m), 3.8-4.7 (6H, m), 5.19 (2
8%s), 5.25 and 5.52 (2H.
ABQ、 J=13H2)、7.4〜8.3(8H,m
)。ABQ, J=13H2), 7.4~8.3(8H, m
).
実施例7:
■
化合物(7)320mgの無水アセトニトリル溶液にメ
ルカプト化合物(10)170mgおよびジイソプロピ
ルエチルアミン0.12m12を水冷下に加え、窒素気
流下2時間撹拌した。反応液を減圧留去し、得られた残
留物をシリカゲルクロマトで精製し、化合物(11)を
黄色状物として309mg(定量的)得る。Example 7: (1) To a solution of 320 mg of compound (7) in anhydrous acetonitrile were added 170 mg of mercapto compound (10) and 0.12 ml of diisopropylethylamine under water cooling, and the mixture was stirred for 2 hours under a nitrogen stream. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 309 mg (quantitative) of compound (11) as a yellow substance.
NMR(δ、CD CQs”) : 1.6〜2−1(
2H,m)、2.3〜3.6(8B、 m)、4.4〜
4.8(IH,m)、5.2(2H,s)、5゜52お
よび5.25(2H1ABq、 J = 13Hz)、
7.4〜8.3 (8H。NMR (δ, CD CQs”): 1.6 to 2-1 (
2H, m), 2.3~3.6 (8B, m), 4.4~
4.8 (IH, m), 5.2 (2H, s), 5°52 and 5.25 (2H1ABq, J = 13Hz),
7.4-8.3 (8H.
m)。m).
実施例8 : (5S)−3−(3−アゼチジニル)チ
オ−8−オキソ−■−アザビシクロ
実施例6で得た化合物(9)232mgのテトラヒドロ
7ランー水(l二l)混合液に、酸化白金40mgを加
え、水素気流下(3気圧)室温にて1時間水素添加を行
なった。反応終了後、反応液をセライト濾過し、セライ
トをエーテル洗浄後、有機層を減圧留去し、次いで凍結
乾燥し、化合物(12)を白色粉末として84mg(8
0%)得た。Example 8: (5S)-3-(3-azetidinyl)thio-8-oxo-■-azabicyclo A mixture of 232 mg of the compound (9) obtained in Example 6 in tetrahydro7rane and water (121) was oxidized. 40 mg of platinum was added, and hydrogenation was carried out at room temperature under a hydrogen stream (3 atm) for 1 hour. After the reaction was completed, the reaction solution was filtered through Celite, and after washing the Celite with ether, the organic layer was distilled off under reduced pressure and then freeze-dried to give 84 mg (84 mg) of Compound (12) as a white powder.
0%) obtained.
NMR(δ、Dgo ) : 1.8〜2.8(lOH
−m)、3.9〜4−5(2H,m)
カルボン酸(化合物13)
実施例7で得た化合物(11)205mgを用い、実施
例8と同様酸化白金40mgを用いた水素添加を行ない
、凍結乾燥し、化合物(13)を白色粉末として53m
g(59%)得た。NMR (δ, Dgo): 1.8-2.8 (lOH
-m), 3.9 to 4-5 (2H, m) Carboxylic acid (compound 13) Using 205 mg of compound (11) obtained in Example 7, hydrogenation using 40 mg of platinum oxide was carried out in the same manner as in Example 8. The compound (13) was prepared as a white powder and lyophilized to give 53 m
g (59%) was obtained.
NMR(δ、CD C12s) : L、8〜3.0(
IIH,m)。NMR (δ, CD C12s): L, 8-3.0 (
IIH, m).
Claims (1)
護基を表わし、 R^2は非置換もしくは置換アルキル基または複素環基
式を表わす、 で示される(5S)−3−置換チオ−8−オキソ−1−
アザビシクロ[3.3.0]オクタ−2−エン−2−カ
ルボン酸誘導体。 2、R^2がアミノエチル基またはアゼチジン−3−イ
ル基である特許請求の範囲第1項に記載の化合物。[Claims] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 represents a hydrogen atom, an alkali metal, or a carboxyl protecting group, and R^2 is (5S)-3-substituted thio-8-oxo-1-, which represents an unsubstituted or substituted alkyl group or a heterocyclic group formula;
Azabicyclo[3.3.0]oct-2-ene-2-carboxylic acid derivative. 2. The compound according to claim 1, wherein R^2 is an aminoethyl group or an azetidin-3-yl group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63035135A JPH01211589A (en) | 1988-02-19 | 1988-02-19 | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63035135A JPH01211589A (en) | 1988-02-19 | 1988-02-19 | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH01211589A true JPH01211589A (en) | 1989-08-24 |
Family
ID=12433479
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63035135A Pending JPH01211589A (en) | 1988-02-19 | 1988-02-19 | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH01211589A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107629061A (en) * | 2017-10-31 | 2018-01-26 | 江西师范大学 | A kind of fluoro (±) PenibrugiueramineA and its synthesis and the application as antibacterials |
-
1988
- 1988-02-19 JP JP63035135A patent/JPH01211589A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107629061A (en) * | 2017-10-31 | 2018-01-26 | 江西师范大学 | A kind of fluoro (±) PenibrugiueramineA and its synthesis and the application as antibacterials |
CN107629061B (en) * | 2017-10-31 | 2019-11-08 | 江西师范大学 | A kind of fluoro (±)-PenibrugiueramineA and its synthesis and the application as antibacterials |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SU1508959A3 (en) | Method of producing carbapenem derivatives | |
WO1999057121A1 (en) | Carbapenem derivatives, utilization thereof and intermediate compounds of the same | |
PL152381B1 (en) | 6-(Substituted methylene) penems. | |
EP0557122B1 (en) | A production method for sulfamide | |
FR2585704A1 (en) | ALKYLCARBAMOYLOXYMETHYLCEPHEMES | |
JPH01211589A (en) | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative | |
JPS63284176A (en) | Highly stereoselective production of (1r,5r,6s)-6-((1r)-1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid derivative | |
JPS58208292A (en) | Novel beta-lactam derivative | |
JPH0463076B2 (en) | ||
JPS588085A (en) | Manufacture of optically active trans-6- substituted-5(r)-2-penem-3-carboxylic acid derivatives, manufacture and compounds obtained thereby | |
WO2004043973A1 (en) | Novel intermediate for carbapenem compound for oral administration and process for producing the same | |
JPS61243088A (en) | Heterocyclyl-penem compound | |
JPS6363680A (en) | (1r)-1-methylcarbapenem-3-carboxylic acid derivative | |
JPH06192273A (en) | Carbapenem-3-carboxylic ester derivative | |
JPS6363681A (en) | (1r)-1-methylcarbapenem-3-carboxylic acid derivative | |
JPS63310890A (en) | 6-amino-substituted-1-methylcarbapenem derivative | |
JPS62212388A (en) | (1r)-1-substituted carbapenem-3-carboxylic acid derivative | |
JPH0713058B2 (en) | Process for producing 4-substituted azetidinone derivative | |
JP3238512B2 (en) | Method for producing sulfamides | |
Branch et al. | Direct incorporation of a 6α (7α)-formamido group into penicillin and cephalosporin sulphides and sulphoxides | |
EP0041813A1 (en) | Penicillin derivatives, processes for their preparation and compositions containing them | |
JPH0288578A (en) | Production or carbapenem compound | |
JPS58116418A (en) | Antimicrobial pharmaceutical composition | |
JPS63310889A (en) | 6-alkylthio-carbapenem derivative | |
JPH0224834B2 (en) |