JPH0261478B2 - - Google Patents
Info
- Publication number
- JPH0261478B2 JPH0261478B2 JP56103695A JP10369581A JPH0261478B2 JP H0261478 B2 JPH0261478 B2 JP H0261478B2 JP 56103695 A JP56103695 A JP 56103695A JP 10369581 A JP10369581 A JP 10369581A JP H0261478 B2 JPH0261478 B2 JP H0261478B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- acid
- general formula
- dioxide
- methylpenam
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 21
- 238000001727 in vivo Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical class O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- -1 alkali metal salts Chemical class 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000000862 absorption spectrum Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 7
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000002132 β-lactam antibiotic Substances 0.000 description 6
- 229940124586 β-lactam antibiotics Drugs 0.000 description 6
- 102000006635 beta-lactamase Human genes 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 150000008049 diazo compounds Chemical class 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 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 3
- 229960000723 ampicillin Drugs 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000003460 beta-lactamyl group Chemical group 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000007257 deesterification reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229940116108 lactase Drugs 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910001509 metal bromide Inorganic materials 0.000 description 2
- 229910001510 metal chloride Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229940049954 penicillin Drugs 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical class C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910000497 Amalgam Inorganic materials 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 108010059881 Lactase Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- QYCSNMDOZNUZIT-UHFFFAOYSA-N benzhydrylidenehydrazine Chemical compound C=1C=CC=CC=1C(=NN)C1=CC=CC=C1 QYCSNMDOZNUZIT-UHFFFAOYSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical class O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- WYYQVWLEPYFFLP-UHFFFAOYSA-K chromium(3+);triacetate Chemical compound [Cr+3].CC([O-])=O.CC([O-])=O.CC([O-])=O WYYQVWLEPYFFLP-UHFFFAOYSA-K 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 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
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はペニシラン酸１，１−ジオキシド誘導
体、その医薬として許容される塩及び生体内で加
水分解されるエステルに関する。
本発明のペニシラン酸１，１−ジオキシド誘導
体は下記一般式（）で表わされる。
K0704
（式中R1は水素原子、塩素原子または臭素原子
を示し、R2は塩素原子または臭素原子を示す。
但し、R1が水素原子又は臭素原子であり、且つ
R2が塩素原子である場合を除く。）
本発明のペニシラン酸１，１−ジオキシド誘導
体、その医薬として許容される塩及び生体内で加
水分解されるエステルは新規化合物であり、β−
ラクタマーゼ阻害作用を有し、β−ラクタマーゼ
阻害剤として有用である。
市販抗生物質の中でβ−ラクタム環を有するβ
−ラクタム系抗生物質即ちペニシリン類及びセフ
アロスポリン類は、最もよく知られ、且つ繁用さ
れている。これらβ−ラクタム系抗生物質は、有
用な化学療法剤として広く用いられているにもか
かわらず、ある種の微生物に対しては、その耐生
のため十分な効果が得られない。これらのある種
の微生物のβ−ラクタム系抗生物質に対する耐性
は、通常該微生物によつて産出されたβ−ラクタ
マーゼによるものである。β−ラクタマーゼとは
β−ラクタム系抗生物質のβ−ラクタム環を開裂
し、抗菌活性を有さない生成物とする酵素であ
る。従つて前記β−ラクタム系抗生物質が十分効
力を現わすためには、β−ラクタマーゼの作用を
なくするかまたはその作用を最小に抑えることが
必要である。このβ−ラクタマーゼの作用の消失
乃至抑制はβ−ラクタマーゼ阻害剤により達成さ
れ、そのようなβ−ラクタマーゼ阻害剤は、これ
をβ−ラクタム系抗生物質と共に使用することに
より、該抗生物質の抗菌活性を上昇させることが
できる。本発明者らは種々の化合物を合成し研究
した結果、本発明の一般式（）で示されるペニ
シラン酸１，１−ジオキシド誘導体、その医薬と
して許容される塩及び生体内で加水分解され上記
誘導体を与えるエステルがβ−ラクタマーゼに対
してすぐれた阻害効果を有することを見い出し、
本発明を完成するに至つた。
本発明のペニシラン酸１，１−ジオキシド誘導
体（）のうちには、６位において２種類（α
型、β型）の異性体をとるものもあるが本発明は
これらのいずれをも包含する。
本発明により得られる前記一般式（）で表わ
される誘導体のうち、医薬として許容される塩と
しては、たとえばナトリウム、カリウム、リチウ
ム等のアルカリ金属塩、カルシウム、マグネシウ
ム等のアルカリ土類金属塩、シクロヘキシルアミ
ン、トリメチルアミン、ジエタノールアミン等の
有機アミン塩、アルギニン、リジン等の塩基性ア
ミノ酸塩、アンモニウム塩等が例示される。また
本発明の前記一般式（）で表わされる誘導体の
生体内で加水分解されるエステルとしては、生体
内で容易に加水分解されて対応する遊離の酸即ち
一般式（）で表わされる誘導体に変換され、且
つ医薬として許容される各種のエステルを包含す
る。之等エステルを構成するエステル残渣は、β
−ラクタム系抗生物質において生体内で容易に加
水分解されることの知られている通常のエステル
残渣と同様であり、その代表例としては、例えば
メチル基、エチル基、プロピル基、ブチル基、
tert−ブチル基等の直鎖あるいは分枝状のアルキ
ル基、アセトキシメチル基、アセトキシエチル
基、プロピオニルオキシブチル基、ピバロイルオ
キシメチル基、ピバロイルオキシプロピル基、ベ
ンゾイツオキシエチル基、ベンジルカルボニルオ
キシメチル基、シクロヘキシルカルボニルオキシ
メチル基等のアシルオキシアルキル基、メトキシ
メチル基、エトキシメチル基、ベンジルオキシメ
チル基等のアルコキシアルキル基、３−フタリジ
ル基、４−クロトノラクトニル基、γ−ブチロラ
クトン−４−イル基等のラクトン及び置換又は非
置換フエニル基等が例示される。これらのエステ
ル残渣のうちでは、ピバロイルオキシメチル基、
３−フタリジル基、４−クロトノラクトニル基及
びγ−ブチロラクトン−４−イル基等が好まし
い。
本発明の具体的な化合物は以下のもの及びこれ
らの医薬として許容される塩及び生体内で加水分
解されるエステルである。
(1) 6α−または6β−クロロ−2β−クロロメチル
−2α−メチルペナム−3α−カルボン酸−１，
１−ジオキシド
(2) 2β−ブロモメチル−2α−メチルペナム−3α
−カルボン酸−１，１−ジオキシド
(3) 6α−または6β−クロロ−2β−ブロモメチル
−2α−メチルペナム−3α−カルボン酸−１，
１−ジオキシド
(4) 6α−または6β−ブロモ−2β−ブロモメチル
−2α−メチルペナム−3α−カルボン酸−１，
１−ジオキシド
本発明のペニシラン酸１，１−ジオキシド誘導
体（）は例えば以下の反応工程式に示す方法で
製造することができる。
K0705
（式中R1及びR2は前記に同じ、R3はペニシリン
カルボキシ保護基を示す。）
上記においてR3で示されるペニシリンカルボ
キシ保護基は、通常公知のものでよく、その代表
例は特開昭49−81380号公報及びエツチ・イー・
フライン編セフアロスポリン アンド ペニシリ
ンズ、ケミストリー アンド バイオロジー
（1972年アカデミツクプレス発行）に記載されて
いる。具体的には、例えばエチル、プロピル、
tert−ブチル、トリクロロエチル等の置換又は非
置換アルキル基、ベンジル、ジフエニルメチル、
β−ニトロベンジル等の置換又は非置換アラルキ
ル基、アセトキシメチル、ベンゾイルオキシメチ
ル等のアシルオキシアルキル基、メトキシメチル
等のアルコキシアルキル基、その他テトラヒドロ
ピラニル、ジメチルアミノエチル、ジメチルクロ
ロシラン、トリクロロシラン等が例示される。
Ａ工程
一般式（）で示されるスルフイドを酸化する
ことにより一般式（−ａ）で示されるジオキシ
ドを得る。上記反応において酸化剤としては過マ
ンガン酸、過ヨウソ酸、過酢酸、過蟻酸、トリフ
ルオロ過酢酸、過安臭香酸、ｍ−クロル過安臭香
酸、過酸化水素等が例示できるが、これらに限定
されるものではない。酸化反応は通常、溶媒中で
行なわれ、溶媒としてはクロロホルム、ピリジ
ン、テトラヒドロフラン、ジオキサン、メチレン
クロライド、四塩化炭素、酢酸、蟻酸、ジメチル
ホルムアミド、水等の本反応に影響しないものは
すべて使用することができる。反応温度は特に限
定されないが通常は室温ないしは冷却下に行なわ
れる。
かくして得られる一般式（−ａ）の化合物
は、そのR3で示される保護基の種類により、そ
のままの形態で本発明の目的物、即ち一般式
（）で表わされるジオキシド誘導体の生体内で
加水分解されるエステルである場合もあるが、よ
り好ましくは通常Ｂ工程に示す如き脱エステル反
応を行なつて、本発明の一般式（）で表わされ
るジオキシド誘導体とし、次いで必要に応じ常法
に従い医薬として許容される塩又は生体内で加水
分解されるエステルに変換される。また上記一般
式（−ａ）の化合物は、これを直接常法に従い
エステル交換反応又は塩形成反応に供することに
より、生体内で加水分解されるエステル又は医薬
として許容される塩とすることもできる。
Ｂ工程
得られた酸化生成物〔一般式（−ａ）の化合
物〕をＡ工程の反応系より単離するか或いは単離
しないで、脱エステル反応に供し、一般式（）
で示されるジオキサイドを得る。脱エステルの方
法としては、カルボキシ保護基をカルボキシ基に
導く所の還元、加水分解等のすべての脱離方法が
適用できる。例えばカルボキシ保護基が活性エス
テルである場合には通常の加水分解条件下ではも
ちろん水と接触させる程度の緩和な加水分解条件
で反応が進行する場合が多い。カルボキシ保護基
がトリクロロエチルベンジル、ｐ−ニトロベンジ
ル、ジフエニルメチル等のときには還元による方
法が、またカルボキシ保護基が４−メトキシベン
ジル、tert−ブチル、トリチルジフエニルメチ
ル、メトキシメチル、テトラヒドロピラニル等の
ときには酸による方法が採用される。
ここで還元による方法としてはまず亜鉛、亜鉛
アマルガム等の金属及び（または）塩化クロム、
酢酸クロム等のクロム塩と蟻酸、酢酸等の酸とを
用いる方法あるいは接触還元による方法がその代
表例としてあげられる。ここで接触還元の触媒と
してはたとえば白金、酸化白金、パラジウム、酸
化パラジウム、パラジウム硫酸バリウム、パラジ
ウム炭酸カルシウム、パラジウム炭素、酸化ニツ
ケル、ラネーニツケル等があげられる。溶媒とし
ては本反応に関与しないものであれば特に限定は
ないがメタノール、エタノール等のアルコール
類、テトラヒドロフラン、ジオキサン等のエーテ
ル類、酢酸エチル等のエステル類、酢酸等の脂肪
酸及びこれら有機溶剤と水との混合溶媒が好適で
ある。
また、酸による方法の際に使用される酸として
は、蟻酸、酢酸等の低級脂肪酸、トリクロロ酢
酸、トリフロオロ酢酸等のトリハロ酢酸、塩酸、
弗化水素酸等のハロゲン化水素酸、ｐ−トルエン
スルホン酸、トリフロオロメタンスルホン酸等の
有機スルホン酸、またはこれらの混合物等が例示
される。
この反応は液体の酸を使用するときには特に他
の溶媒を必要としないがジメチルホルムアミド、
ジクロロメタン、クロロホルム、テトラヒドロフ
ラン、アセトン等のこの反応に悪影響を与えない
ものは使用してもよい。
かくして得られる一般式（）で示されるジオ
キシドを生体内で加水分解されるエステルとする
には、通常の当分野で慣用されるエステル化反応
を利用することができる。
エステル残基が、たとえば３−フタリジル、４
−クロトノラクトニル、γ−ブチロラクトン−４
−イル基等の場合は、一般式（）で示されるジ
オキシドを３−ハロゲン化フタリド、４−ハロゲ
ン化クロトノラクトン、４−ハロゲン化−γ−ブ
チロラクトンでアルキル化することができる。こ
こで上記ハロゲン化物におけるハロゲンとしては
塩素、臭素及びヨウ素が使用できる。
反応は一般式（）で示されるジオキシドの塩
をＮ，Ｎ−ジメチルホルムアミドのような適当な
極性有機溶媒中に溶解させて、約当モル量のハロ
ゲン化物を加えることによつて行なわれる。反応
温度は０〜100℃で、好ましくは15〜35℃とする
のが良い。本エステル化反応で用いられるジオキ
シドの塩としてはナトリウム、カリウム等のアル
カリ金属塩及びトリエチルアミン、エチルジイソ
プロピルアミン、Ｎ−エチルピペリジン、Ｎ，Ｎ
−ジメチルアニリン、Ｎ−メチルモルホリン等の
第３アミン塩を用いることができる。反応完了
後、従来公知の方法により、目的物を容易に単離
することができる。
前記反応行程式１において出発原料とする一般
式（）で表わされる化合物は、公知の化合物を
原料として下記反応工程式２及び３に示す如き各
種の方法により製造することができる。
K0706
（式中R1、R2及びR3は前記に同じ。）
Ｃ工程
一般式（）で示されるＳ−オキシドと１〜
1.5倍モルの２−メルカプトベンゾチアゾールを
反応させることにより一般式（）で示されるジ
スルフイドを得る。溶媒としては本反応に関与し
ないものであれば特に限定はないが、ジオキサン
等のエーテル類、ベンゼン、トルエン、キシレ
ン、クロロベンゼン、ジクロロベンゼン等の芳香
族炭化水素またはこれらの混合溶媒が好適に用い
られる。反応温度は50〜180℃で好ましくは80〜
150℃である。本反応は必要ならば脱水装置を使
用して行う。
Ｄ工程
一般式（）で示されるジスルフイドに塩素、
臭素、塩化水素、臭化水素、金属塩化物または金
属臭化物を作用させることにより一般式（）で
示されるスルフイドと得る。金属塩化物、金属臭
化物としては銅（Cu2+）、亜鉛、水銀（Hg2+）等
の塩化物及び臭化物が代表例として挙げられる。
本反応は通常溶媒中で行なわれ、溶媒としてはク
ロロホルム、メチレンクロライド、四塩化炭素、
アセトン、アセトニトリル、アルコール、酢酸等
の本反応に悪影響を及ぼさない溶媒はいずれも用
いることができる。反応温度は特に限定されない
が、用いられたハロゲン化剤の種類に応じて適宜
選択される。
一般式（）の化合物中R1がα−Clまたはα
−Brのもの〔一般式（）′〕は、下記反応工程
式３によつても製造することができる。
K0707
（式中R2及びR3は前記に同じ。R4はアシルアミ
ノ基、R5は塩素原子または臭素原子を示す。）
Ｅ工程
一般式（）で示されるスルフイドを酢酸エチ
ルあるいはメチレンクロライド等の本反応に影響
しない溶媒中、無水酢酸ナトリウムの存在下でジ
ナイトロジエンテトラオキサイドと反応させ、次
いで酢酸エチルあるいはメチレンクロライド等の
本反応に影響しない溶媒中でピリジン等の塩基を
加え、加熱する。加熱温度は30〜50℃である。本
反応において一般式（）で表わされるスルフイ
ドの６位のアシルアミノ基としては、通常入手容
易なフエニルアセチルアミノ、フエノキシアセチ
ルアミノ基等が好ましい。
Ｆ工程
一般式（）で示されるジアゾ化合物を本反応
に影響しない溶媒中、塩化水素または臭化水素と
反応させることにより、一般式（）′で示され
るスルフイド化合物が得られる。反応温度は特に
限定されないが室温または冷却下で行なうのが好
ましい。本反応は、通常触媒の存在なしで進行す
るが、必要ならば触媒として、三フツ化ホウ素あ
るいは硫酸銅、酢酸銅、ハロゲン化銅等の銅塩を
用いることができる。
Ｇ工程
一般式（）で示される６−アミノ化合物を塩
酸あるいは臭化水素酸中で亜硝酸ナトリウムと反
応することにより、一般式（）′で示されるス
ルフイドが得られる。本反応においてはメチレン
クロライド、クロロホルム、酢酸エチル等の本反
応に影響しない有機溶媒を添加することにより、
生成物は有機溶媒層に溶解し、後処理に好都合で
ある。反応温度は特に限定されないが、室温以下
の温度で行うのが好ましい。
更に、一般式（−ａ）の化合物のうちR1が
α−Clまたはα−Brのもの〔一般式（ａ
−）′〕は、下記反応工程式４によつても製造す
ることができる。
K0708
K0709
（式中R2、R3、R4及びR5は前記と同じ。）
Ｈ工程
一般式（）で示されるスルフイドをＡ工程と
同じ方法で酸化することにより、一般式（）で
示されるジオキシドが得られる。
Ｉ工程
一般式（）で示されるジオキシドをＥ工程と
同じ方法でジアゾ化して、一般式（）で示され
るジアゾ化合物が得られる。
Ｊ工程
一般式（）で示されるジアゾ化合物をＦ工程
と同じ方法でハロゲン化して、一般式（−
ａ）′で示されるジオキシドが得られる。
かくして得られるジオキシド（）は、所望に
より医薬として許容される塩あるいは生体内で加
水分解されるエステルに変換することができる。
このようにして得られた目的化合物は、必要なら
ば再結晶法、薄層クロマトグラフイー、カラムク
ロマトグラフイーなどにより精製することができ
る。
次に実施例をあげて本発明を具体的に説明す
る。
実施例 １
6α−クロルペニシラン酸−１−スルホキシド
ベンツヒドリルエステル
6αクロルペニシラン酸（54ｇ）をクロロホル
ム（346ml）、水（290ml）及びアセトン（18.5ml）
の混合溶媒に溶解した溶液に過酢酸（32％溶液、
52.6ｇ）を氷冷下で30分を要して加えた。さらに
15分間撹拌後ベンゾフエノンヒドラゾン（47.2
ｇ）、ヨウ化カリ（１％溶液、13.8ml）を加え、
その後過酢酸（32％溶液、59.8ｇ）および10％硫
酸（74ml）を氷冷下で30分を要して加えた。０℃
で45分撹拌後、30分を要して12℃まで加温した。
クロロホルム層を分取し、水（150ml）、重炭酸ソ
ーダ水（200ml）で各２回洗浄した後、硫酸マグ
ネシウムで乾燥し、クロロホルムを留去した。留
去残渣をシリカゲルカラムクロマトグラフイーに
付し、ベンゼン−酢酸エチルの流分より6α−ク
ロルペニシラン酸−１−スルホキシドベンツヒド
リルエステル（30.4ｇ）を得た。
実施例 ２
３−クロル−２−オキソ−４−（ベンゾチアゾ
ール−２−イル）ジチオ−α−イソプロペニル
−１−アゼチジン酢酸ベンツヒドリルエステル
6α−クロルペニシラン酸−１−スルホキシド
ベンツヒドリルエステル（10.43ｇ）および２−
メルカプトベンゾチアゾール（4.18ｇ）のトルエ
ン（250ml）溶液をデイーン・スタークトラツプ
を用いて1.5時間還流した後、重炭酸ソーダ水お
よび水で洗浄し、硫酸マグネシウムで乾燥後、ト
ルエンを留去し、粗目的物（13.9ｇ）を得た。本
物質は精製することなしに次の反応に用いた。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1790 1735
核磁気共鳴スペクトル（CDCl3）δ；
1.85（3H、ｓ）、5.0（4H、ｍ）、
5.25（1H、ｍ）、6.89（1H、ｓ）、
7.2（14H、ｍ）
実施例 ３
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエス
テル
実施例２で得られた粗生成物（13.9ｇ）および
塩化第二銅（3.25ｇ）を塩化メチレン（240ml）
中で室温にて1.5時間撹拌した。反応混合物をセ
ライトろ過し、重炭酸ソーダ水、重亜硫酸ソーダ
水および水で洗浄し、硫酸マグネシウムで乾燥
後、溶媒を留去し、6α−クロル−2β−クロルメ
チル−2α−メチルペナム−3α−カルボン酸ベン
ツヒドリルエステル（10.9ｇ）を得た。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1800 1750
核磁気共鳴スペクトル（CDCl3）δ；
1.29（3H、ｓ）、3.45（2H、broads）
4.68（1H、ｓ）、5.1（1H、ｄ、Ｊ＝2Hz）、
5.33（1H、ｄ、Ｊ＝2Hz）、6.87（1H、ｓ）、
7.28（1OH、ｍ）
実施例 ４
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸−１，１−ジオキシ
ドベンツヒドリルエステル
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエステ
ル（10.9ｇ）を酢酸（440ml）−水（58ml）混合溶
媒に溶解した溶液に過マンガン酸カリウム（8.29
ｇ）を室温で1.5時間を要して加えた。さらに３
時間撹拌後、氷冷し、氷と水（500ml）を加えて
生成した白色沈澱物をろ過し、氷水で洗浄後、酢
酸エチルに溶解し、硫酸マグネシウムで乾燥後、
溶媒を留去し、6α−クロル−2β−クロルメチル
−2α−メチルペナム−3α−カルボン酸−１，１
−ジオキシドベンツヒドリルエステル（7.63ｇ）
を得た。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1800 1750
核磁気共鳴スペクトル（CDCl3）δ；
1.0（3H、ｓ）、4.0（2H、ｑ）、
4.6（1H、ｓ）、4.92（1H、ｄ、Ｊ＝2Hz）、
5.09（1H、ｄ、Ｊ＝2Hz）、6.97（1H、ｓ）、
7.2（10H、ｍ）
実施例 ５
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸−１，１−ジオキシ
ドナトリウム塩
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸−１，１−ジオキシド
ベンツヒドリルエステル（4.17ｇ）を蟻酸（50
ml）中、室温下５時間撹拌した後、反応混合物を
凍結乾燥処理し、得られた残留物を重炭酸ソーダ
（0.756ｇ）および水（40ml）と撹拌し、水溶液を
酢酸エチル（40ml）で２回洗浄した。活性炭処
理、セライトろ過したろ液を凍結乾燥し、6α−
クロル−2β−クロルメチル−2α−メチルペナム
−3α−カルボン酸−１，１−ジオキシドナトリ
ウム塩（2.5ｇ）を得た。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1790 1635
核磁気共鳴スペクトル（D2O）δ；
表１に示す（化合物２）
実施例 ６
２−オキソ−４−（ベンゾチアゾール−２−イ
ル）ジチオ−α−イソプロペニル−１−アゼチ
ジン酢酸ベンツヒドリルエステル
２−ジメチルペナム−3α−カルボン酸−１−
スルホキシドベンツヒドリルエステル（1.5ｇ）
および２−メルカプトベンゾチアゾール（0.7ｇ）
のトルエン（50ml）溶液をデイーン・スタークト
ラツプを用いて還流下撹拌、加熱した。反応は薄
層クロマトグラフイーで追跡し、４時間で終了し
た。反応混合物は重炭酸ソーダ水、水で洗浄し、
硫酸マグネシウムで乾燥した後溶媒を留去し、目
的物（２ｇ）を得た。本生成物は精製することな
しに次の反応に用いた。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1785 1745
核磁気共鳴スペクトル（CDCl3）δ；
1.82（3H、ｓ）、3.22（2H、ｔ）、
4.82（1H、ｓ）、4.92〜5.02（2H、ｍ）、
5.24（1H、ｍ）、6.82（1H、ｓ）、
7.12（14H、ｍ）
実施例 ７
6α−ジアゾ−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエス
テル
ジナイトロジエンテトラオキサイド（56.0ｇ）
を無水酢酸エチル（500ml）に０℃で溶解させた。
6β−フエノキシアセトアミド−2β−クロルメチ
ル−2α−メチルペナム−3α−カルボン酸ベンツ
ヒドリルエステル（28.5ｇ）の酢酸エチル（20
ml）溶液を酢酸ソーダ（46.0ｇ）上記ジナイトロ
ジエンテトラオキサイドの溶液（200ml）および
酢酸エチル（200ml）の混合物中に65℃で撹拌下
20分を要して加えた。その後上記ジナイトロジエ
ンテトラオキサイドの酢酸エチル溶液（60ml）を
さらに加えた。30分後残りの上記ジナイトロジエ
ンテトラオキサイドの酢酸エチル溶液（200ml）
を加え、−５℃で２時間撹拌した。反応混合物を
ろ過した後、飽和重炭酸ソーダ水で処理し、酢酸
エチル層を硫酸マグネシウムで乾燥後、100mlま
で濃縮して、ピリジン（3.3ml）を加え、３時間
40℃に加温した。反応混合物を水（100ml）、食塩
水（100ml）および飽和重炭酸ソーダ水（100ml）
で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を
留去して目的物を得、精製することなしに次の反
応に用いた。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
2100 1800 1750
実施例 ８
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエス
テル
実施例７で得られた６−ジアゾ−2β−クロル
メチル−2α−メチルペナム−3α−カルボン酸ベ
ンツヒドリルエステルの塩化メチレン（100ml）
溶液に塩化水素（４ｇ）を含有するメタノール
（10ml）および塩化メチレン（40ml）の混合溶液
を０℃で窒素ガスが発生しなくなるまで滴下し
た。さらに０℃で１時間撹拌後、重炭酸ソーダ
水、水で洗浄し、硫酸マグネシウムで乾燥溶媒を
留去した。得られた残渣物をシリカゲルカラムク
ロマトグラフイーに付し、酢酸エチル−ヘキサン
の流分から6α−クロル−2β−クロルメチル−2α
−メチルペナム−3α−カルボン酸ベンツヒドリ
ルエステル（8.55ｇ）を得た。本品は実施例３で
得られたものとIR、NMRともに同一であつた。
実施例 ９
6β−フエノキシアセトアミド−2β−クロルメ
チル−2α−メチルペナム−3α−カルボン酸−
１，１−ジオキシドベンツヒドリルエステル
6β−フエノキシアセトアミド−2β−クロルメ
チル−2α−メチルペナム−3α−カルボン酸ベン
ツヒドリルエステル（19.3ｇ）の90％酢酸（300
ml）を０℃に冷却し、過マンガン酸カリウム
（12.6ｇ）を加えた。反応混合液を０℃で15分撹
拌後室温に戻して２時間撹拌した。反応混合液を
10％過酸化水素で脱色し、氷水（700ml）を加え
て白色沈澱を得た。この白色沈澱を酢酸エチルに
溶解後、重亜硫酸ソーダ水で洗浄し、硫酸マグネ
シウムで乾燥後濃縮して6β−フエノキシアセト
アミド−2β−クロルメチル−2α−メチルペナム
−3α−カルボン酸−１，１−ジオキシドベンツ
ヒドリルエステル（14.2ｇ）を得た。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1800 1750 1700
核磁気共鳴スペクトル（CDCl3）δ；
1.18（3H、ｓ）、4.0（2H、ｑ）、
4.45（2H、ｓ）、4.8（2H、ｍ）、
6.2（1H、ｑ）、6.95（1H、ｓ）、
7.32（15H、ｍ）、8.22（1H、ｄ）
実施例 10
６−ジアゾ−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸−１，１−ジオキシ
ドベンツヒドリルエステル
ジナイトロジエンテトラオキサイド（26ｇ）を
氷冷下無水酢酸エチル（250ml）に溶解し、水溶
液を以下の反応に用いた。6β−フエノキシアセ
トアミド−2β−クロルメチル−2α−メチルペナ
ム−3α−カルボン酸−１，１−ジオキシドベン
ツヒドリルエステル（14.0ｇ）の酢酸エチル
（100ml）溶液を酢酸ナトリウム（21.3ｇ）、ジナ
イトロジエンテトラオキサイド酢酸エチル溶液
（100ml）および酢酸エチル（100ml）の混合物中
に撹拌下−５℃で20分を要して加えた。さらにジ
ナイトロジエンテトラオキサイド酢酸エチル溶液
（30ml）を加えた。30分後残りのジナイトロジエ
ンテトラオキサイド酢酸エチル溶液（100ml）を
加え、ろ過し、飽和重炭酸ソーダ水で処理後、酢
酸エチル層をマグネシウムで乾燥し、250mlまで
濃縮して、ピリジン（7.0ml）を加え３時間40℃
に加温した。反応混合物は水（200ml）、食塩水
（200ml）、飽和重炭酸ソーダ水（200ml）で洗浄
し、硫酸ナトリウムで乾燥した後に溶媒を留去
し、目的物を得た。本目的物は精製することなし
に次の反応に用いた。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
2080 1780 1750
核磁気共鳴スペクトル（CDCl3）δ；
1.32（3H、ｓ）、3.66（2H、ｓ）、
5.10（1H、ｓ）、6.24（1H、ｓ）、
7.0（1H、ｓ）、7.44（10H、ｍ）
実施例 11
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸−１，１−ジオキシ
ドベンツヒドリルエステル
実施例10で得られた2β−クロルメチル−2α−
メチルペナム−3α−カルボン酸−１，１−ジオ
キシドベンツヒドリルエステルの塩化メチレン
（50ml）溶液に塩化水素（1.8ｇ）を含むメタノー
ル（５ml）を氷冷下窒素ガスが発生しなくなるま
で加えた。氷冷下１時間撹拌した後、食塩水、重
炭酸ソーダ水、水で洗浄し、硫酸ナトリウムで乾
燥して溶媒を留去した。得られた粗生成物をシリ
カゲルクロマトグラフイーで精製し、6α−クロ
ル−2β−クロルメチル−2α−メチルペナム−3α
−カルボン酸−１，１−ジオキシドベンツヒドリ
ルエステル（3.9ｇ）を得た。本生成物は実施例
４で得られた目的物とIR、NMRは同一であつ
た。
実施例 12
6α−クロル−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエス
テル
６−アミノ−2β−クロルメチル−2α−メチル
ペナム−3α−カルボン酸ベンツヒドリルエステ
ル塩酸塩（4.2ｇ）を濃塩酸（50ml）−水（50ml）
−メタノール（200ml）混合溶媒に溶解した溶液
を氷冷下撹拌して、亜硝酸ナトリウム（１ｇ）を
少量ずつ加えた。2.5時間撹拌後、室温で濃縮し、
酢酸エチル50mlで３回抽出した。抽出層を合わ
せ、硫酸マグネシウムで乾燥後濃縮して6α−ク
ロル−2β−クロルメチル−2α−メチルペナム−
3α−カルボン酸ベンツヒドリルエステル（1.5ｇ）
を得た。本生成物のIR、NMRは実施例３で得ら
れた生成物のそれと同一であつた。
実施例 13
実施例１〜５と同様にして得られた2β−ブロ
ムメチル−2α−メチルペナム−3α−カルボン酸
−１，１−ジオキシドベンツヒドリルエステル
（200mg）及び炭酸水素ナトリウム（35mg）を、テ
トラヒドロフラン（100ml）と水（100ml）との混
合溶媒に溶解し、10％パラジウム炭素（100mg）
を加え、常圧下、室温にて水素添加を行なつた。
水素の吸収が認められなくなつた後、反応液を
過し、液からテトラヒドロフランを減圧下留去
した。残渣をクロロホルムにて洗浄後、水溶液を
減圧濃縮し、MCIゲルCHP20P（三菱化成社製）
を用いたカラムクロマトグラフイーに付し、水−
10％アセトン水にてグラジエント展開した。β−
ラクターゼ阻害活性フラクシヨンを合せて凍結乾
燥し、白色粉末として2β−ブロムメチル−2α−
メチルペナム−3α−カルボン酸−１，１−ジオ
キシドナトリウム塩（32mg）を得た。
赤外吸収スペクトル（ヌジヨール）νnaxcm-1；
1785 1630
核磁気共鳴スペクトル（D2O）δ；
第１表に示す。（化合物１）
次に実施例によりまたは実施例と同様にして得
られた本発明の化合物を表１に示す。表１に示し
た化合物のうち、１、２、３、４、５及び７はそ
れぞれ実施例１〜５によりまたはそれらと同様に
して得られたものである。また６の化合物は、実
施例９、10、11、５と同様にして得られたもので
ある。
The present invention relates to penicillanic acid 1,1-dioxide derivatives, their pharmaceutically acceptable salts and in vivo hydrolysable esters. The penicillanic acid 1,1-dioxide derivative of the present invention is represented by the following general formula (). K0704 (In the formula, R 1 represents a hydrogen atom, a chlorine atom, or a bromine atom, and R 2 represents a chlorine atom or a bromine atom.
However, R 1 is a hydrogen atom or a bromine atom, and
Except when R 2 is a chlorine atom. ) The penicillanic acid 1,1-dioxide derivatives, their pharmaceutically acceptable salts and in vivo hydrolyzable esters of the present invention are novel compounds, and the β-
It has a lactamase inhibitory effect and is useful as a β-lactamase inhibitor. Among commercially available antibiotics, β-lactam ring-containing β
- Lactam antibiotics, ie penicillins and cephalosporins, are the best known and most frequently used. Although these β-lactam antibiotics are widely used as useful chemotherapeutic agents, they are not sufficiently effective against certain microorganisms due to their resistance. The resistance of certain microorganisms to β-lactam antibiotics is usually due to the β-lactamases produced by the microorganisms. β-lactamase is an enzyme that cleaves the β-lactam ring of β-lactam antibiotics to produce a product without antibacterial activity. Therefore, in order for the β-lactam antibiotics to exhibit sufficient efficacy, it is necessary to eliminate or minimize the action of β-lactamase. Eliminating or suppressing the action of β-lactamase can be achieved by using a β-lactamase inhibitor, and when used together with a β-lactam antibiotic, such a β-lactamase inhibitor can improve the antibacterial activity of the antibiotic. can be raised. As a result of synthesizing and researching various compounds, the present inventors found that the penicillanic acid 1,1-dioxide derivative represented by the general formula () of the present invention, its pharmaceutically acceptable salt, and the above-mentioned derivative that is hydrolyzed in vivo. It was discovered that an ester that gives
The present invention has now been completed. Among the penicillanic acid 1,1-dioxide derivatives () of the present invention, there are two types (α
Some of them take isomers of type (type, β type), and the present invention includes all of these isomers. Among the derivatives represented by the general formula () obtained by the present invention, pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium, potassium, and lithium, alkaline earth metal salts such as calcium and magnesium, and cyclohexyl salts. Examples include organic amine salts such as amine, trimethylamine, and diethanolamine, basic amino acid salts such as arginine and lysine, and ammonium salts. Furthermore, the in vivo hydrolyzable ester of the derivative represented by the general formula () of the present invention is easily hydrolyzed in the living body and converted into the corresponding free acid, that is, the derivative represented by the general formula (). and includes various pharmaceutically acceptable esters. The ester residue constituting the isoester is β
- It is similar to the usual ester residues that are known to be easily hydrolyzed in vivo in lactam antibiotics, and typical examples thereof include methyl group, ethyl group, propyl group, butyl group,
Straight chain or branched alkyl groups such as tert-butyl group, acetoxymethyl group, acetoxyethyl group, propionyloxybutyl group, pivaloyloxymethyl group, pivaloyloxypropyl group, benzoitoxyethyl group, benzyl Acyloxyalkyl groups such as carbonyloxymethyl group and cyclohexylcarbonyloxymethyl group, alkoxyalkyl groups such as methoxymethyl group, ethoxymethyl group and benzyloxymethyl group, 3-phthalidyl group, 4-crotonolactonyl group, γ-butyrolactone Examples include lactones such as -4-yl groups, substituted or unsubstituted phenyl groups, and the like. Among these ester residues, pivaloyloxymethyl group,
3-phthalidyl group, 4-crotonolactonyl group, γ-butyrolactone-4-yl group, etc. are preferred. Specific compounds of the invention are the following and their pharmaceutically acceptable salts and in vivo hydrolysable esters. (1) 6α- or 6β-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,
1-dioxide (2) 2β-bromomethyl-2α-methylpenam-3α
-Carboxylic acid-1,1-dioxide (3) 6α- or 6β-chloro-2β-bromomethyl-2α-methylpenam-3α-carboxylic acid-1,
1-dioxide (4) 6α- or 6β-bromo-2β-bromomethyl-2α-methylpenam-3α-carboxylic acid-1,
1-Dioxide The penicillanic acid 1,1-dioxide derivative () of the present invention can be produced, for example, by the method shown in the following reaction scheme. K0705 (In the formula, R 1 and R 2 are the same as above, and R 3 represents a penicillin carboxy-protecting group.) The penicillin carboxy-protecting group represented by R 3 above may be a commonly known one, and typical examples thereof are Publication No. 49-81380 and H.E.
Described in Cephalosporins and Penicillins, Chemistry and Biology, edited by Frein (Academic Press, 1972). Specifically, for example, ethyl, propyl,
Substituted or unsubstituted alkyl groups such as tert-butyl, trichloroethyl, benzyl, diphenylmethyl,
Examples include substituted or unsubstituted aralkyl groups such as β-nitrobenzyl, acyloxyalkyl groups such as acetoxymethyl and benzoyloxymethyl, alkoxyalkyl groups such as methoxymethyl, and other tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilane, and trichlorosilane. be done. Step A: A sulfide represented by the general formula () is oxidized to obtain a dioxide represented by the general formula (-a). Examples of the oxidizing agent in the above reaction include permanganic acid, periodic acid, peracetic acid, performic acid, trifluoroperacetic acid, perbenbrozoic acid, m-chloroperbenzoic acid, hydrogen peroxide, etc. It is not limited to these. The oxidation reaction is usually carried out in a solvent, and any solvent that does not affect the reaction, such as chloroform, pyridine, tetrahydrofuran, dioxane, methylene chloride, carbon tetrachloride, acetic acid, formic acid, dimethylformamide, and water, should be used as the solvent. Can be done. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or under cooling. The compound of the general formula (-a) obtained in this way can be used as it is to hydrate the object of the present invention, that is, the dioxide derivative represented by the general formula () in vivo, depending on the type of protecting group represented by R3. Although it may be an ester that is decomposed, more preferably it is usually subjected to a deesterification reaction as shown in Step B to obtain a dioxide derivative represented by the general formula ( It is converted into an acceptable salt or an ester that is hydrolyzed in vivo. Further, the compound of the above general formula (-a) can be directly subjected to a transesterification reaction or a salt formation reaction according to a conventional method to form an ester that is hydrolyzed in vivo or a pharmaceutically acceptable salt. . Step B: The obtained oxidation product [compound of general formula (-a)] is isolated from the reaction system of Step A, or is not isolated, and subjected to deesterification reaction to obtain the compound of general formula (-a).
Obtain the dioxide shown in As the de-esterification method, all elimination methods such as reduction and hydrolysis that lead a carboxy protecting group to a carboxy group can be applied. For example, when the carboxy protecting group is an active ester, the reaction often proceeds not only under normal hydrolysis conditions but also under mild hydrolysis conditions such as contact with water. When the carboxy-protecting group is trichloroethylbenzyl, p-nitrobenzyl, diphenylmethyl, etc., a reduction method is used, and when the carboxy-protecting group is 4-methoxybenzyl, tert-butyl, trityldiphenylmethyl, methoxymethyl, tetrahydropyranyl, etc. An acid method is used. Here, as a reduction method, metals such as zinc and zinc amalgam and/or chromium chloride,
Typical examples include a method using a chromium salt such as chromium acetate and an acid such as formic acid or acetic acid, or a method using catalytic reduction. Examples of catalysts for catalytic reduction include platinum, platinum oxide, palladium, palladium oxide, palladium barium sulfate, palladium calcium carbonate, palladium on carbon, nickel oxide, and Raney nickel. The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, fatty acids such as acetic acid, and these organic solvents and water A mixed solvent with is suitable. In addition, acids used in the acid method include lower fatty acids such as formic acid and acetic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrochloric acid,
Examples include hydrohalic acids such as hydrofluoric acid, organic sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid, and mixtures thereof. This reaction does not require any other solvent when using a liquid acid, but dimethylformamide,
Those that do not adversely affect this reaction, such as dichloromethane, chloroform, tetrahydrofuran, and acetone, may be used. In order to convert the thus obtained dioxide represented by the general formula () into an ester that is hydrolyzed in vivo, an esterification reaction commonly used in the art can be used. If the ester residue is, for example, 3-phthalidyl, 4
-Crotonolactonil, γ-butyrolactone-4
In the case of -yl group, etc., the dioxide represented by the general formula () can be alkylated with 3-halogenated phthalide, 4-halogenated crotonolactone, or 4-halogenated-γ-butyrolactone. Here, as the halogen in the above-mentioned halide, chlorine, bromine and iodine can be used. The reaction is carried out by dissolving the salt of the dioxide of general formula () in a suitable polar organic solvent such as N,N-dimethylformamide and adding about an equimolar amount of the halide. The reaction temperature is 0 to 100°C, preferably 15 to 35°C. Dioxide salts used in this esterification reaction include alkali metal salts such as sodium and potassium salts, triethylamine, ethyldiisopropylamine, N-ethylpiperidine, N,N
Tertiary amine salts such as -dimethylaniline and N-methylmorpholine can be used. After the reaction is completed, the target product can be easily isolated by a conventionally known method. The compound represented by the general formula () used as the starting material in Reaction Scheme 1 can be produced by various methods as shown in Reaction Schemes 2 and 3 below using known compounds as raw materials. K0706 (In the formula, R 1 , R 2 and R 3 are the same as above.) C step S-oxide represented by the general formula () and 1 to
A disulfide represented by the general formula () is obtained by reacting with 1.5 times the mole of 2-mercaptobenzothiazole. The solvent is not particularly limited as long as it does not participate in this reaction, but ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, or a mixed solvent thereof are preferably used. . The reaction temperature is 50~180℃, preferably 80~
The temperature is 150℃. This reaction is carried out using a dehydrator if necessary. Step D Chlorine is added to the disulfide represented by the general formula ().
A sulfide represented by the general formula () is obtained by reacting with bromine, hydrogen chloride, hydrogen bromide, metal chloride or metal bromide. Typical examples of metal chlorides and metal bromides include chlorides and bromides of copper (Cu 2+ ), zinc, mercury (Hg 2+ ), and the like.
This reaction is usually carried out in a solvent, such as chloroform, methylene chloride, carbon tetrachloride,
Any solvent that does not adversely affect this reaction, such as acetone, acetonitrile, alcohol, and acetic acid, can be used. The reaction temperature is not particularly limited, but is appropriately selected depending on the type of halogenating agent used. In the compound of general formula (), R 1 is α-Cl or α
-Br [general formula ()'] can also be produced by the following reaction scheme 3. K0707 (In the formula, R 2 and R 3 are the same as above. R 4 is an acylamino group, and R 5 is a chlorine atom or a bromine atom.) It is reacted with dinitrodiene tetraoxide in the presence of anhydrous sodium acetate in a solvent that does not affect the main reaction, and then a base such as pyridine is added in a solvent that does not affect the main reaction, such as ethyl acetate or methylene chloride, and heated. Heating temperature is 30-50°C. In this reaction, the acylamino group at the 6-position of the sulfide represented by the general formula () is preferably a phenylacetylamino group, a phenoxyacetylamino group, etc., which are usually easily available. Step F A sulfide compound represented by the general formula ()' is obtained by reacting the diazo compound represented by the general formula () with hydrogen chloride or hydrogen bromide in a solvent that does not affect the main reaction. The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or under cooling. This reaction usually proceeds without the presence of a catalyst, but if necessary, boron trifluoride or a copper salt such as copper sulfate, copper acetate, or copper halide can be used as a catalyst. Step G A sulfide represented by the general formula ()' is obtained by reacting the 6-amino compound represented by the general formula () with sodium nitrite in hydrochloric acid or hydrobromic acid. In this reaction, by adding organic solvents that do not affect the reaction, such as methylene chloride, chloroform, and ethyl acetate,
The product dissolves in the organic solvent layer and is convenient for work-up. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction at a temperature below room temperature. Furthermore, among the compounds of general formula (-a), those in which R 1 is α-Cl or α-Br [general formula (a
-)'] can also be produced by the following reaction scheme 4. K0708 K0709 (In the formula, R 2 , R 3 , R 4 and R 5 are the same as above.) Step H: By oxidizing the sulfide represented by the general formula () in the same manner as in the A process, Dioxide is obtained. Step I: The dioxide represented by the general formula () is diazotized in the same manner as in the E step to obtain a diazo compound represented by the general formula (). Step J: The diazo compound represented by the general formula () is halogenated in the same manner as in the F step, and the diazo compound represented by the general formula (-
The dioxide represented by a)' is obtained. The thus obtained dioxide () can be converted into a pharmaceutically acceptable salt or an ester that is hydrolyzed in vivo, if desired.
The target compound thus obtained can be purified by recrystallization, thin layer chromatography, column chromatography, etc., if necessary. Next, the present invention will be specifically explained with reference to Examples. Example 1 6α-chlorpenicillanic acid-1-sulfoxide benzhydryl ester 6α-chlorpenicillanic acid (54 g) was mixed with chloroform (346 ml), water (290 ml) and acetone (18.5 ml).
peracetic acid (32% solution,
52.6 g) was added over 30 minutes under ice cooling. moreover
After stirring for 15 minutes, add benzophenone hydrazone (47.2
g), add potassium iodide (1% solution, 13.8ml),
Thereafter, peracetic acid (32% solution, 59.8 g) and 10% sulfuric acid (74 ml) were added over 30 minutes under ice cooling. 0℃
After stirring for 45 minutes, the mixture was heated to 12°C over 30 minutes.
The chloroform layer was separated, washed twice each with water (150 ml) and sodium bicarbonate water (200 ml), dried over magnesium sulfate, and chloroform was distilled off. The distillation residue was subjected to silica gel column chromatography, and 6α-chlorpenicillanic acid-1-sulfoxide benzhydryl ester (30.4 g) was obtained from the benzene-ethyl acetate fraction. Example 2 3-chloro-2-oxo-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidine acetic acid benzhydryl ester 6α-chlorpenicilanic acid-1-sulfoxide benzhydryl ester (10.43 g) and 2-
A solution of mercaptobenzothiazole (4.18 g) in toluene (250 ml) was refluxed for 1.5 hours using a Dean-Stark trap, washed with sodium bicarbonate and water, dried over magnesium sulfate, and the toluene was distilled off to obtain the crude target product ( 13.9g) was obtained. This substance was used in the next reaction without purification. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 1790 1735 Nuclear magnetic resonance spectrum (CDCl 3 ) δ; 1.85 (3H, s), 5.0 (4H, m), 5.25 (1H, m), 6.89 (1H, s), 7.2 (14H, m) Example 3 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester Crude product obtained in Example 2 (13.9 g) and cupric chloride (3.25g) in methylene chloride (240ml)
The mixture was stirred for 1.5 hours at room temperature. The reaction mixture was filtered through Celite, washed with aqueous sodium bicarbonate, aqueous sodium bisulfite, and water, dried over magnesium sulfate, and then the solvent was distilled off to give 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydride. ester (10.9 g) was obtained. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 1800 1750 Nuclear magnetic resonance spectrum (CDCl 3 ) δ; 1.29 (3H, s), 3.45 (2H, broads) 4.68 (1H, s), 5.1 (1H, d , J=2Hz), 5.33 (1H, d, J=2Hz), 6.87 (1H, s), 7.28 (1OH, m) Example 4 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid- 1,1-Dioxide benzhydryl ester A solution of 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester (10.9 g) in a mixed solvent of acetic acid (440 ml) and water (58 ml) was filtered. Potassium manganate (8.29
g) was added over a period of 1.5 hours at room temperature. 3 more
After stirring for an hour, ice-cooling, adding ice and water (500 ml), filtering the resulting white precipitate, washing with ice water, dissolving in ethyl acetate, and drying with magnesium sulfate.
The solvent was distilled off and 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1
-Dioxide benzhydryl ester (7.63g)
I got it. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 1800 1750 Nuclear magnetic resonance spectrum (CDCl 3 ) δ; 1.0 (3H, s), 4.0 (2H, q), 4.6 (1H, s), 4.92 (1H, d, J=2Hz), 5.09 (1H, d, J=2Hz), 6.97 (1H, s), 7.2 (10H, m) Example 5 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid -1,1-dioxide sodium salt 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1-dioxide benzhydryl ester (4.17 g) was mixed with formic acid (50 g).
ml) at room temperature for 5 hours, the reaction mixture was lyophilized, the resulting residue was stirred with sodium bicarbonate (0.756 g) and water (40 ml), and the aqueous solution was diluted twice with ethyl acetate (40 ml). Washed. The activated carbon-treated, celite-filtered filtrate was freeze-dried and 6α-
Chlor-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1-dioxide sodium salt (2.5 g) was obtained. Infrared absorption spectrum (Nudiyol) ν nax cm -1 ; 1790 1635 Nuclear magnetic resonance spectrum (D 2 O) δ; Shown in Table 1 (Compound 2) Example 6 2-oxo-4-(benzothiazol-2-yl ) dithio-α-isopropenyl-1-azetidine acetic acid benzhydryl ester 2-dimethylpenam-3α-carboxylic acid-1-
Sulfoxide benzhydryl ester (1.5g)
and 2-mercaptobenzothiazole (0.7g)
A toluene (50 ml) solution was stirred and heated under reflux using a Dean-Stark trap. The reaction was monitored by thin layer chromatography and completed in 4 hours. The reaction mixture was washed with bicarbonate of soda, water,
After drying over magnesium sulfate, the solvent was distilled off to obtain the desired product (2 g). This product was used in the next reaction without purification. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 1785 1745 Nuclear magnetic resonance spectrum ( CDCl3 ) δ; 1.82 (3H, s), 3.22 (2H, t), 4.82 (1H, s), 4.92-5.02 ( 2H, m), 5.24 (1H, m), 6.82 (1H, s), 7.12 (14H, m) Example 7 6α-Diazo-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester dinitrodiene Tetraoxide (56.0g)
was dissolved in anhydrous ethyl acetate (500ml) at 0°C.
6β-Phenoxyacetamide-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester (28.5 g) in ethyl acetate (20
ml) solution in a mixture of sodium acetate (46.0 g) above solution of dinitrodiene tetraoxide (200 ml) and ethyl acetate (200 ml) at 65°C under stirring.
It took 20 minutes to add. Thereafter, an ethyl acetate solution (60 ml) of the above dinitrodientetraoxide was further added. After 30 minutes, add the remaining dinitrodiene tetraoxide to ethyl acetate solution (200 ml).
was added and stirred at -5°C for 2 hours. After filtering the reaction mixture, it was treated with saturated sodium bicarbonate water, the ethyl acetate layer was dried over magnesium sulfate, concentrated to 100 ml, pyridine (3.3 ml) was added, and the mixture was incubated for 3 hours.
Warmed to 40°C. The reaction mixture was diluted with water (100 ml), brine (100 ml) and saturated bicarbonate of soda (100 ml).
After washing with and drying with sodium sulfate, the solvent was distilled off to obtain the desired product, which was used in the next reaction without purification. Infrared absorption spectrum (Nudiyol) ν nax cm -1 ; 2100 1800 1750 Example 8 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester 6-diazo-2β obtained in Example 7 -chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester in methylene chloride (100ml)
A mixed solution of methanol (10 ml) and methylene chloride (40 ml) containing hydrogen chloride (4 g) was added dropwise to the solution at 0° C. until no nitrogen gas was generated. After further stirring at 0° C. for 1 hour, the mixture was washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and 6α-chloro-2β-chloromethyl-2α was extracted from the ethyl acetate-hexane stream.
-Methylpenam-3α-carboxylic acid benzhydryl ester (8.55 g) was obtained. This product was identical to that obtained in Example 3 in both IR and NMR. Example 9 6β-phenoxyacetamide-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-
1,1-dioxide benzhydryl ester 6β-phenoxyacetamide-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester (19.3 g) in 90% acetic acid (300 g)
ml) was cooled to 0°C and potassium permanganate (12.6g) was added. The reaction mixture was stirred at 0° C. for 15 minutes, then returned to room temperature and stirred for 2 hours. reaction mixture
The mixture was decolorized with 10% hydrogen peroxide, and ice water (700 ml) was added to obtain a white precipitate. This white precipitate was dissolved in ethyl acetate, washed with sodium bisulfite water, dried over magnesium sulfate, and concentrated to give 6β-phenoxyacetamide-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1- Dioxide benzhydryl ester (14.2g) was obtained. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 1800 1750 1700 Nuclear magnetic resonance spectrum (CDCl 3 ) δ; 1.18 (3H, s), 4.0 (2H, q), 4.45 (2H, s), 4.8 (2H , m), 6.2 (1H, q), 6.95 (1H, s), 7.32 (15H, m), 8.22 (1H, d) Example 10 6-Diazo-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid -1,1-Dioxide benzhydryl ester Dinitrodiene tetraoxide (26 g) was dissolved in anhydrous ethyl acetate (250 ml) under ice cooling, and the aqueous solution was used in the following reaction. A solution of 6β-phenoxyacetamide-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1-dioxide benzhydryl ester (14.0 g) in ethyl acetate (100 ml) was mixed with sodium acetate (21.3 g) and dinitrate. The dienetetraoxide was added to a mixture of ethyl acetate solution (100 ml) and ethyl acetate (100 ml) at -5°C with stirring over 20 minutes. Furthermore, dinitrodiene tetraoxide ethyl acetate solution (30 ml) was added. After 30 minutes, the remaining dinitrodiene tetraoxide ethyl acetate solution (100 ml) was added, filtered, and treated with saturated sodium bicarbonate water. The ethyl acetate layer was dried over magnesium, concentrated to 250 ml, and pyridine (7.0 ml) was added. Add 3 hours at 40℃
It was heated to The reaction mixture was washed with water (200 ml), brine (200 ml), and saturated sodium bicarbonate water (200 ml), dried over sodium sulfate, and then the solvent was distilled off to obtain the desired product. This target product was used in the next reaction without purification. Infrared absorption spectrum (nujiol) ν nax cm -1 ; 2080 1780 1750 Nuclear magnetic resonance spectrum (CDCl 3 ) δ; 1.32 (3H, s), 3.66 (2H, s), 5.10 (1H, s), 6.24 (1H , s), 7.0 (1H, s), 7.44 (10H, m) Example 11 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid-1,1-dioxide benzhydryl ester In Example 10 Obtained 2β-chloromethyl-2α-
Methanol (5 ml) containing hydrogen chloride (1.8 g) was added to a solution of methyl penam-3α-carboxylic acid-1,1-dioxide benzhydryl ester in methylene chloride (50 ml) under ice cooling until no nitrogen gas was generated. After stirring for 1 hour under ice-cooling, the mixture was washed with brine, sodium bicarbonate water, and water, dried over sodium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel chromatography to give 6α-chloro-2β-chloromethyl-2α-methylpenam-3α
-Carboxylic acid-1,1-dioxide benzhydryl ester (3.9 g) was obtained. This product had the same IR and NMR characteristics as the target product obtained in Example 4. Example 12 6α-chloro-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester 6-Amino-2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester hydrochloride (4.2 g) was dissolved in concentrated hydrochloric acid. (50ml) - water (50ml)
- A solution dissolved in a mixed solvent of methanol (200 ml) was stirred under ice cooling, and sodium nitrite (1 g) was added little by little. After stirring for 2.5 hours, concentrate at room temperature,
Extracted three times with 50 ml of ethyl acetate. The extracted layers were combined, dried over magnesium sulfate, and concentrated to give 6α-chloro-2β-chloromethyl-2α-methylpenam-
3α-carboxylic acid benzhydryl ester (1.5g)
I got it. The IR and NMR of this product were the same as those of the product obtained in Example 3. Example 13 2β-bromomethyl-2α-methylpenam-3α-carboxylic acid-1,1-dioxide benzhydryl ester (200 mg) obtained in the same manner as in Examples 1 to 5 and sodium hydrogen carbonate (35 mg) were added to tetrahydrofuran. 10% palladium on carbon (100 mg) dissolved in a mixed solvent of (100 ml) and water (100 ml)
was added, and hydrogenation was carried out at room temperature under normal pressure.
After hydrogen absorption was no longer observed, the reaction solution was filtered, and tetrahydrofuran was distilled off from the solution under reduced pressure. After washing the residue with chloroform, the aqueous solution was concentrated under reduced pressure, and MCI gel CHP20P (manufactured by Mitsubishi Kasei Corporation) was added.
Column chromatography using water-
A gradient was developed using 10% acetone water. β-
The lactase inhibitory activity fractions were combined and lyophilized to produce a white powder of 2β-bromomethyl-2α-
Methylpenam-3α-carboxylic acid-1,1-dioxide sodium salt (32 mg) was obtained. Infrared absorption spectrum (Nudyol) ν nax cm -1 ; 1785 1630 Nuclear magnetic resonance spectrum (D 2 O) δ; Shown in Table 1. (Compound 1) Next, Table 1 shows the compounds of the present invention obtained in Examples or in the same manner as in Examples. Among the compounds shown in Table 1, 1, 2, 3, 4, 5 and 7 were obtained by or in a similar manner to Examples 1 to 5, respectively. Compound 6 was obtained in the same manner as in Examples 9, 10, 11, and 5.
【表】【table】
【表】
β−ラクターゼ阻害活性
本発明化合物のバチルス属由来のペニシリナー
ゼ（β−ラクタマーゼ）に対する阻害活性を、ペ
ニシリンＧを基質としてpHスタツト法〔ジヤー
ナル フアーマシユウテイカル サイエンス、第
61巻、第10号、1954〜1958頁、1972年参照〕によ
り測定した。結果を表２に示す。[Table] β-lactase inhibitory activity The inhibitory activity of the compounds of the present invention against penicillinase (β-lactamase) derived from the genus Bacillus was determined using the pH stat method using penicillin G as a substrate [Journal Pharmaceutical Sciences, Vol.
61, No. 10, pp. 1954-1958, 1972]. The results are shown in Table 2.
【表】
抗菌活性（アンピシリンとの併用効果）
本発明の化合物及びアンピシリンの単独での各
種細菌に対する最小発育阻止濃度（MIC）と共
に、本発明化合物10μｇ／mlを併用した時のアン
ピシリンの各種細菌に対するMICを日本化学療
学会標準法に従つて測定した。増菌用培地として
はミユラーヒントンブロス（デイフコ社製）を用
い、また感受性測定用培地としては、ミユラーヒ
ントンメデイウム（デイフコ社製）を用いた。結
果を第３表に示す。
尚、ここに用いた細菌はすべて京都薬科大学微
生物学研究室から分譲されたものである。[Table] Antibacterial activity (effect in combination with ampicillin) The minimum inhibitory concentration (MIC) of the compound of the present invention and ampicillin against various bacteria alone, as well as the minimum inhibitory concentration (MIC) of ampicillin against various bacteria when the compound of the present invention is used in combination with 10 μg/ml. MIC was measured according to the standard method of the Japanese Society of Chemotherapy. Mueller-Hinton Broth (manufactured by Difco) was used as the culture medium for enrichment, and Mueller-Hinton Medium (manufactured by Difco) was used as the medium for sensitivity measurement. The results are shown in Table 3. All bacteria used here were provided by the Microbiology Laboratory of Kyoto Pharmaceutical University.
Claims (1)
示す。R2は塩素原子又は臭素原子を示す。但し、
R1が水素原子又は臭素原子であり、且つR2が塩
素原子である場合を除く。） で表わされるペニシラン酸１，１−ジオキシド誘
導体、その医薬として許容される塩及び生体内で
加水分解されるエステル。 ２ R1が水素原子である特許請求の範囲第１項
に記載の化合物。 ３ R1が塩素原子である特許請求の範囲第１項
に記載の化合物。 ４ R1が臭素原子である特許請求の範囲第１項
に記載の化合物。[Claims] 1 General formula K0703 (In the formula, R 1 represents a hydrogen atom, a chlorine atom, or a bromine atom. R 2 represents a chlorine atom or a bromine atom. However,
Except when R 1 is a hydrogen atom or a bromine atom and R 2 is a chlorine atom. Penicillanic acid 1,1-dioxide derivatives represented by ), pharmaceutically acceptable salts thereof, and esters hydrolyzed in vivo. 2. The compound according to claim 1, wherein R 1 is a hydrogen atom. 3. The compound according to claim 1, wherein R 1 is a chlorine atom. 4. The compound according to claim 1, wherein R 1 is a bromine atom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56103695A JPS584788A (en) | 1981-07-01 | 1981-07-01 | Penicillanic acid 1,1-dioxide derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56103695A JPS584788A (en) | 1981-07-01 | 1981-07-01 | Penicillanic acid 1,1-dioxide derivative and its preparation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62136521A Division JPS62294686A (en) | 1987-05-29 | 1987-05-29 | Penicillanic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS584788A JPS584788A (en) | 1983-01-11 |
| JPH0261478B2 true JPH0261478B2 (en) | 1990-12-20 |
Family
ID=14360908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56103695A Granted JPS584788A (en) | 1981-07-01 | 1981-07-01 | Penicillanic acid 1,1-dioxide derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS584788A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08296962A (en) * | 1993-04-27 | 1996-11-12 | T-P Kogyo Kk | Heating/drying apparatus using gas far infrared heater |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6061528A (en) * | 1983-09-09 | 1985-04-09 | ブリストル―マイヤーズ スクイブ カンパニー | Treatment of tolerated bacteria containing anaerobe |
-
1981
- 1981-07-01 JP JP56103695A patent/JPS584788A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08296962A (en) * | 1993-04-27 | 1996-11-12 | T-P Kogyo Kk | Heating/drying apparatus using gas far infrared heater |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS584788A (en) | 1983-01-11 |
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