JPS62198687A - 2beta-substituted thiomethylpenicillin derivative - Google Patents
2beta-substituted thiomethylpenicillin derivativeInfo
- Publication number
- JPS62198687A JPS62198687A JP61043763A JP4376386A JPS62198687A JP S62198687 A JPS62198687 A JP S62198687A JP 61043763 A JP61043763 A JP 61043763A JP 4376386 A JP4376386 A JP 4376386A JP S62198687 A JPS62198687 A JP S62198687A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- acid
- group
- reaction
- compound
- 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.)
- Granted
Links
- 150000002960 penicillins Chemical class 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 3
- 150000002148 esters Chemical class 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 12
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 1
- -1 mercapto compound Chemical class 0.000 abstract description 60
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 238000002360 preparation method Methods 0.000 abstract description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 abstract description 5
- 102000006635 beta-lactamase Human genes 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- WINXNKPZLFISPD-UHFFFAOYSA-N sodium;1,1-dioxo-1,2-benzothiazol-3-one Chemical compound [Na+].C1=CC=C2C(=O)NS(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 238000000862 absorption spectrum Methods 0.000 description 18
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000005973 Carvone Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 229930182555 Penicillin Natural products 0.000 description 9
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000002132 β-lactam antibiotic Substances 0.000 description 8
- 229940124586 β-lactam antibiotics Drugs 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 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 4
- 239000002024 ethyl acetate extract Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
- 229940106164 cephalexin Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000007257 deesterification reaction Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 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
- 239000007800 oxidant agent Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 125000006000 trichloroethyl group Chemical group 0.000 description 3
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 2
- JAAIPIWKKXCNOC-UHFFFAOYSA-N 1h-tetrazol-1-ium-5-thiolate Chemical compound SC1=NN=NN1 JAAIPIWKKXCNOC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000894006 Bacteria Species 0.000 description 2
- 108020004256 Beta-lactamase Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-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
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- NURYIUVWTWXGID-INYFRXACSA-N [N+](=O)([O-])C1=CC=C(COC(=O)[C@H]2C(S[C@H]3N2C(C3)=O)C)C=C1 Chemical compound [N+](=O)([O-])C1=CC=C(COC(=O)[C@H]2C(S[C@H]3N2C(C3)=O)C)C=C1 NURYIUVWTWXGID-INYFRXACSA-N 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 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 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl 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
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 2
- 229960003669 carbenicillin Drugs 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 229960000603 cefalotin Drugs 0.000 description 2
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 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 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 2
- 229940116357 potassium thiocyanate Drugs 0.000 description 2
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000004867 thiadiazoles Chemical group 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
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- GGZHVNZHFYCSEV-UHFFFAOYSA-N 1-Phenyl-5-mercaptotetrazole Chemical compound SC1=NN=NN1C1=CC=CC=C1 GGZHVNZHFYCSEV-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
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-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
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- OCVLSHAVSIYKLI-UHFFFAOYSA-N 3h-1,3-thiazole-2-thione Chemical compound SC1=NC=CS1 OCVLSHAVSIYKLI-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
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 description 1
- ZTLMHGOWADYAHM-UHFFFAOYSA-N 5-phenyl-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(S)=NN=C1C1=CC=CC=C1 ZTLMHGOWADYAHM-UHFFFAOYSA-N 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
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 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
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 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 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
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin 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=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin 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
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical class O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- DGAODIKUWGRDBO-UHFFFAOYSA-N butanethioic s-acid Chemical compound CCCC(O)=S DGAODIKUWGRDBO-UHFFFAOYSA-N 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
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 1
- 229950004030 cefaloglycin Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229960004350 cefapirin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 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
- 238000013329 compounding Methods 0.000 description 1
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 description 1
- 229960004244 cyclacillin Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-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
- 229950004394 ditiocarb Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MIHRVCSSMAGKNH-UHFFFAOYSA-N ethylcarbamodithioic acid Chemical compound CCNC(S)=S MIHRVCSSMAGKNH-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 description 1
- 229960003884 hetacillin Drugs 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JQQHKTPQFWSNBC-UHFFFAOYSA-J hydrogen carbonate thorium(4+) Chemical compound [Th+4].OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O JQQHKTPQFWSNBC-UHFFFAOYSA-J 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 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
- 229960000433 latamoxef Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HYVVJDQGXFXBRZ-UHFFFAOYSA-N metam Chemical compound CNC(S)=S HYVVJDQGXFXBRZ-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 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
- 159000000001 potassium salts Chemical class 0.000 description 1
- KOODSCBKXPPKHE-UHFFFAOYSA-N propanethioic s-acid Chemical compound CCC(S)=O KOODSCBKXPPKHE-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- TWIOETHNYAHVFS-UHFFFAOYSA-N propylcarbamodithioic acid Chemical compound CCCNC(S)=S TWIOETHNYAHVFS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000008028 secondary esters Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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)
Abstract
Description
【発明の詳細な説明】
髪泉上旦剋里方！
本発明のペニシリン誘導体、その医薬として許容される
塩及びそのエステルは、いずれも新規化合物であり、之
等は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。[Detailed Description of the Invention] Hair Spring Kamidan Riho! The penicillin derivatives, pharmaceutically acceptable salts thereof, and esters thereof of the present invention are all new compounds, and they have β-lactamase inhibitory activity and are useful as β-lactamase inhibitors.
来の ■ びその口 φ
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ァロスポリン類
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、その耐性のため十分な効果が得られない。これらの
おる種の微生物のβ−ラクタム系抗生物質に対する耐性
は、通常該微生物により生産されるβ−ラクタマ−ゼ、
即ちβ−ラクタム系抗生物質のβ−ラクタム環を開裂し
抗菌活性を有ざない生成物とする酵素、によるものであ
る。従って前記β−ラクタム系抗生物質が十分な効力を
現わすためには、β−ラクタマーゼの作用をなくするか
又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。Among commercially available antibiotics, β-lactam antibiotics having a β-lactam ring, namely penicillins and cephalosporins, are the most well-known and frequently used. These β−
Although lactam antibiotics are widely used as useful chemotherapeutic agents, they are not sufficiently effective against certain microorganisms due to their resistance. The resistance of these types of microorganisms to β-lactam antibiotics is usually due to the β-lactamases produced by the microorganisms,
That is, it uses an enzyme that cleaves the β-lactam ring of a β-lactam antibiotic to produce a product that has no 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. This β
- Eliminating or inhibiting the action of lactamases is achieved by β-lactamase inhibitors, and such β-lactamase inhibitors can be used together with β-lactam antibiotics to enhance the antibacterial activity of the antibiotics. can be raised.
族１１且
本発明者らは種々の化合物を合成し研究した結果、下記
一般式（Ｉ＞で示されるペニシリン誘導体、その医薬と
して許容される塩及びそのエステルが、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った。Group 11 As a result of synthesizing and studying various compounds, the present inventors found that penicillin derivatives represented by the following general formula (I>, their pharmaceutically acceptable salts, and their esters are excellent against β-lactamases. found that it has an inhibitory effect,
The present invention has now been completed.
及皿五皿ｊ
本発明は、新規なペニシリン誘導体、その塩及びそのエ
ステルに係る。The present invention relates to novel penicillin derivatives, salts thereof and esters thereof.
本発明のペニシリン誘導体は下記一般式（Ｉ＞で表わさ
れる。The penicillin derivative of the present invention is represented by the following general formula (I>).
（０）ｎ
〔式中、ｎはＯｌｌ又は２を、Ｙはシアノ基、低級アシ
ル基、低級アルキルチオカルバモイル基又は置換基とし
て低級アルキル基若しくは）工二ル基を有することのあ
るテトラゾリル基、ベンツチアゾール基若しくはチアジ
アゾール基を示す。〕
式中、Ｙで表される低級アシル基としては炭素数２〜６
のアセチル、プロピオニル、ブチリル、ペンタノイル、
ヘキサノイル基を、低級アルキルチオカルバモイル
の窒素原子上に炭素数１〜６の低級アルキル基が１又は
２個置換したメチルチオカルバモイル、エチルチオカル
バモイル
バモイル、ヘキシルチオカルバモイル、ジメチルチオカ
ルバモイル
ゾリル基、ベンツチアゾール基又はチアジアゾール基の
置換基としての低級アルキル基としては、メチル、エチ
ル、プロピル、ｉＳＯ−プロピル、ブチル、ｓｅｃ−ブ
チル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル等の直鎮
状又は分校状の炭素数１〜６のアルキル基を示す。(0)n [In the formula, n is Oll or 2, Y is a cyano group, a lower acyl group, a lower alkylthiocarbamoyl group, or a tetrazolyl group which may have a lower alkyl group or a) engineered group as a substituent, benzene Indicates a thiazole group or thiadiazole group. ] In the formula, the lower acyl group represented by Y has 2 to 6 carbon atoms.
acetyl, propionyl, butyryl, pentanoyl,
Methylthiocarbamoyl, ethylthiocarbamoylbamoyl, hexylthiocarbamoyl, dimethylthiocarbamoylzolyl group, benzthiazole, in which a hexanoyl group is substituted with one or two lower alkyl groups having 1 to 6 carbon atoms on the nitrogen atom of the lower alkylthiocarbamoyl group. The lower alkyl group as a substituent for the group or thiadiazole group is a straight or branched carbon number 1 group such as methyl, ethyl, propyl, iSO-propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. ~6 alkyl group is shown.
本発明ペニシリン誘導体（Ｉ＞のエステルとしては、通
常よく知られるペニシリンカルボキシル基の保護基によ
り保護されたエステル及び生体内で加水分解されるエス
テルを挙げることができる。Examples of the ester of the penicillin derivative (I>) of the present invention include esters protected by well-known penicillin carboxyl protecting groups and esters that are hydrolyzed in vivo.
２等エステル及び該エステルを形成する保護基としては
、例えば特開昭４９−８１３８０号公報やエッチ・イー
・フライン編セファロスポリン 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）に記載の、通常のβ−ラクタ
ム系抗生物質に慣用されるもののいずれであってもよい
。その代表的具体例としては、例えばメチル、エチル、
プロピル、ブチル、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、ジフェニ
ルメチル、ｐ−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、アセトキシエチル、プロ
ピオニルオキシエチル、ピバロイルオキシメチル、ピバ
ロイルオキシプロピル、ベンゾイルオキシメチル、ペン
ゾイルオキシエチル、ベンジルカルボニルオキシメチル
ロへキシルカルボニ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、エトキシメチル、ベンジル
オキシメチル等のアルコキシアルキル基：３−７タリジ
ル基、４−クロトノラクトニル基、γーブチロラクトン
ー４ーイル基等のラクトン及び置換又は非置換フェニル
基：その他（２−オキソ−１，３−ジオキソチン−４ー
イル）メチル基、（５−メチル−２−オキソ−１、３−
ジオキソチン−４ーイル）メチル基、（５−フェニル−
２−オキソ−１，３−ジオキソデン−４−イル）メチル
基、テトラヒドロピラニル基、ジメチルアミンエチル基
、ジメチルクロロシリル基、トリクロロシリル基等を例
示することができる。Examples of secondary esters and protective groups forming the esters include Japanese Patent Application Laid-Open No. 49-81380 and H.E. Flynn, Cephalosporins and Penicillins, Chemistry and Biology (1972).
It may be any of the commonly used β-lactam antibiotics described in ``Academic Press''. Typical examples include methyl, ethyl,
Substituted or unsubstituted alkyl groups such as propyl, butyl, tert-butyl, trichloroethyl; substituted or unsubstituted aralkyl groups such as benzyl, diphenylmethyl, p-nitrobenzyl; acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyl Acyloxyalkyl groups such as oxymethyl, pivaloyloxypropyl, benzoyloxymethyl, penzoyloxyethyl, benzylcarbonyloxymethylhexylcarbonyloxymethyl; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, and benzyloxymethyl: 3- 7 Lactones such as talidyl group, 4-crotonolactonyl group, γ-butyrolactone-4-yl group and substituted or unsubstituted phenyl group: Others (2-oxo-1,3-dioxotin-4-yl)methyl group, (5 -Methyl-2-oxo-1,3-
dioxotin-4-yl)methyl group, (5-phenyl-
Examples include a 2-oxo-1,3-dioxoden-4-yl)methyl group, a tetrahydropyranyl group, a dimethylamineethyl group, a dimethylchlorosilyl group, and a trichlorosilyl group.
また前記一般式（Ｉ＞で表わされる本発明化合物の塩と
しては、例えばナトリウム、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
、ジェ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。Examples of the salt of the compound of the present invention represented by the general formula (I>) include alkali metal salts such as sodium, potassium, and lithium, alkaline earth metal salts such as calcium and magnesium, cyclohexylamine, trimethylamine, jetanolamine, etc. organic amine salt, arginine,
Examples include basic amino acid salts such as lysine, ammonium salts, and the like.
本発明化合物と併用され、抗菌活性を上昇され得る抗生
物質としては、通常のペニシリン類例えばアンピシリン
、アモキシシリン、ヘタシリン、シクラシリン、メシリ
ナム、カルベニシリン、スルペニシリン、チカルシリン
、ピペラジリン、アンピシリン、メチシリン、メズロシ
リン等及び之等の塩類ヤバカンピシリン、カリンダシリ
ン、タランビシリン、カルベニシリン、ピブメシリナム
等のエステル類並びにセファロスポリン類例えばセファ
ロリジン、セファロチン、セファピリン、セフアセドリ
ル、セファゾリン、セファレキシン、セフラジン、セフ
オキシン、セファマンドール、セフオキシン、セフオキ
シン、セフメタゾール、セファロチン、セフオキシン、
セファレキシン、セファレキシン、セフメツキシム、ラ
タモキセフ、セファクロール、セフオキシン、セファト
リジン、セファドロキシル、セファログリシン等及びこ
れらの塩類等の各種グラム陰性菌及びグラム陰性菌に対
して抗菌作用を示すβ−ラクタム抗生物質を例示できる
。本発明化合物及びこれと併用されるβ−ラクタム抗生
物質の配合割合は、重量比にて通常に約０．１〜１０、
好ましくは１：約０、２〜５とするのが良い。Antibiotics that can be used in combination with the compound of the present invention to increase antibacterial activity include common penicillins such as ampicillin, amoxicillin, hetacillin, cyclacillin, mecillinum, carbenicillin, sulpenicillin, ticarcillin, piperagiline, ampicillin, methicillin, mezlocillin, etc. salts such as yabacampicillin, calindacillin, tarambicillin, carbenicillin, pibmecillinum, and esters, and cephalosporins such as cephalolidine, cephalothin, cephapirin, cefacedolyl, cefazolin, cephalexin, cefrazine, cefuoxin, cefamandole, cefuoxin, cefoxin, cefmetazole, cephalothin, cefoxin,
Examples include cephalexin, cephalexin, cefmetuxime, latamoxef, cefaclor, cefoxin, cefatridine, cefadroxil, cephaloglycin, and their salts, as well as β-lactam antibiotics that exhibit antibacterial activity against various Gram-negative bacteria and Gram-negative bacteria. The compounding ratio of the compound of the present invention and the β-lactam antibiotic used in combination with the compound is usually about 0.1 to 10,
Preferably, the ratio is 1:about 0, 2-5.
本発明のペニシリン誘導体（Ｉ＞は、下記反応工程式に
示す各種方法に従い製造することができる。The penicillin derivative (I>) of the present invention can be produced according to various methods shown in the following reaction scheme.
〈反応工程式〉
（Ｉ−ａ＞ （Ｉ’ ）（上記
各式中、Ｘは塩素原子又は臭素原子を示し、Ｙは前記に
同じである。また、Ｒはペニシリンカルボキシル保護基
を示す。）
上記においてＲで表わされるペニシリンカルボキシル保
ＩＩとしては、通常公知のものでよく、具体的には、例
えば前記特開昭４９−８１３８０号公報及びエッチ・イ
ー・フライン編セファロスポリン 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）に記載のものをいずれも使用
できる。好ましいＲ基としては、例えばメチル、エチル
、プロピル、ブチル、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、ジフェ
ニルメチル、ｐ−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、アセトキシエチル、プ
ロピオニルオキシエチル、ピバロイルオキシエチル、ピ
バロイルオキシプロビル、ベンゾイルオキシメチル、ベ
ンゾイルオキシエチル、ベンジルカルボニルオキシメチ
ルアシルオキシアルキル基：メトキシメチル、エトキシ
メチル、ベンジルオ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、ジメチルクロロシリル、トリクロロシリル基等が例
示される。<Reaction process formula>(I-a>(I') (In each of the above formulas, X represents a chlorine atom or a bromine atom, Y is the same as above. Also, R represents a penicillin carboxyl protecting group.) The penicillin carboxyl compound II represented by R in the above may be a commonly known one, and specifically, for example, in the above-mentioned Japanese Patent Application Laid-Open No. 49-81380 and in Cephalosporins and Penicillins, Chemistry, edited by H.E. and Biology (1972)
You can use any of the ones listed in Academic Press (Published by Academic Press). Preferred R groups include, for example, substituted or unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, tert-butyl, and trichloroethyl; substituted or unsubstituted aralkyl groups such as benzyl, diphenylmethyl, and p-nitrobenzyl; acetoxymethyl; , acetoxyethyl, propionyloxyethyl, pivaloyloxyethyl, pivaloyloxyprobyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethylacyloxyalkyl group: alkoxyalkyl such as methoxymethyl, ethoxymethyl, benzyloxymethyl, etc. Groups; Other examples include tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, trichlorosilyl groups, and the like.
上記反応工程式における各工程は、より詳細には以下の
如くして実施される。Each step in the above reaction scheme is carried out in more detail as follows.
くＡ工程〉
一般式（ＩＩ＞で表わされるペニシリン誘導体と一般式
（ＩＩ＞で表わされるメルカプト誘導体もしくはその塩
とを反応させることにより、一般式（Ｉ−Ｃ）で表わさ
れる化合物を得る。本反応は一般式（Ｉ［）で表わされ
る公知のペニシリン誘導体（特開昭５８−４７８８＠参
照）を、適当な溶媒中で該誘導体１モルに対して約１〜
１０倍モル当量、好ましくは約１〜５倍モル当量のメル
カプト誘導体（１）を塩基の存在下もしくはその塩を反
応させることにより行われる。用いられるメルカプト誘
導体（ＩＩＩ）としては、チオシアン酸及び、チオ酢酸
、チオプロピオン酸、チオブチリル酸、チオペンタノイ
ル酸、チオヘキサノイル酸等の炭素数２〜６の低級チオ
脂肪酸を、Ｎ−メチルジチオカルバミン酸、Ｎ，Ｎ−ジ
エチルジチオカルバミン酸、Ｎ−エチルジチオカルバミ
ン酸、Ｎ， Ｎ−ジエチルジチオカルバミン酸、Ｎ−プ
ロピルジチオカルバミン酸等の低級アルキルジチオカル
バミン酸を、５−メルカプトテトラゾール、５−メルカ
プト１−メチルテトラゾール、５−メルカ１１ー１ーフ
ェニルテ１ーラゾール、２−メルカプトベンゾチアゾー
ル、２−メルカプト−５−メチル１。Step A> A compound represented by the general formula (I-C) is obtained by reacting a penicillin derivative represented by the general formula (II> with a mercapto derivative represented by the general formula (II>) or a salt thereof. In the reaction, a known penicillin derivative represented by the general formula (I
This is carried out by reacting 10 times the molar equivalent, preferably about 1 to 5 times the molar equivalent, of the mercapto derivative (1) in the presence of a base or a salt thereof. The mercapto derivatives (III) used include thiocyanic acid and lower thio fatty acids having 2 to 6 carbon atoms such as thioacetic acid, thiopropionic acid, thiobutyric acid, thiopentanoic acid, and thiohexanoic acid, N-methyldithiocarbamic acid, N, Lower alkyl dithiocarbamic acids such as N-diethyldithiocarbamic acid, N-ethyldithiocarbamic acid, N, N-diethyldithiocarbamic acid, and N-propyldithiocarbamic acid are combined with 5-mercaptotetrazole, 5-mercapto-1-methyltetrazole, and 5-mercapto-11. -1-phenylterazole, 2-mercaptobenzothiazole, 2-mercapto-5-methyl 1.
３、４−チアジアゾール、２−メルカプト−５−フェニ
ル１，３．４−チアジアゾール等の買換基として炭素数
１〜６の低級アルキル基又はフェニル基を有することの
あるメルカプトテトラゾール、メルカプトベンゾチアゾ
ール、及びメルカプトチアゾールが例示できる。そして
、これらの塩とはカリウム、ナトリウム等のアルカリ金
属塩を示す。Mercaptotetrazole, mercaptobenzothiazole, which may have a lower alkyl group having 1 to 6 carbon atoms or a phenyl group as an exchange group such as 3,4-thiadiazole and 2-mercapto-5-phenyl 1,3,4-thiadiazole; and mercaptothiazole. These salts refer to alkali metal salts such as potassium and sodium.
また溶媒としては反応に影響を与えないものであれば特
に制限はなく、例えばジメチルホルムアミド、アセトン
、テトラハイドロフラン、ジオキサン、メタノール、エ
タノール等の各種有機溶媒が１種単独で又は２種以上混
合して、又は２等有機溶媒と水との混合溶媒が、いずれ
も使用できる。There are no particular restrictions on the solvent as long as it does not affect the reaction; for example, various organic solvents such as dimethylformamide, acetone, tetrahydrofuran, dioxane, methanol, and ethanol may be used singly or in combination of two or more. A mixed solvent of a secondary organic solvent and water can be used.
本反応は通常的Ｏ℃・−６０℃の温度条件下に進行する
。反応終了後、目的物は特に単離することなく、引き続
く反応に供してもよく、また通常公知の各種方法に従い
単離精製することもできる。This reaction normally proceeds under temperature conditions of 0°C/-60°C. After completion of the reaction, the target product may be subjected to subsequent reactions without being isolated, or may be isolated and purified according to various commonly known methods.
〈Ｂ工程〉
上記Ａ工程で得られる、一般式（Ｉ−Ｃ）で表わされる
化合物を、酸化することにより、一般式（Ｉ−ｂ）で表
わされるスルホキシドを中間体として経由して、一般式
（Ｉ−ａ＞で表わされるジオキシドを得る。上記酸化反
応は通常の酸化剤例えば過マンガン酸、過ヨウ素酸、過
酢酸、トリフルオロ過酢酸、過安息香酸、ｍ−クロル過
安息香酸、過酸化水素等を利用して実施される。之等の
酸化剤は大過剰用いてもよいが、通常好ましくは一般式
（Ｉ−ｃ）の化合物に対して等モル優〜４倍モル量程度
用いるのがよい。この時反応条件、酸化剤及び用いるモ
ル数を適当に選択することにより中間体である一般式（
Ｉ−ｂ）で表わされるスルホキシドを得ることができる
。また該反応は一般に適当な溶媒中で行われる。<Step B> By oxidizing the compound represented by the general formula (IC) obtained in the above step A, the compound represented by the general formula (I-C) is converted into the compound represented by the general formula (I-b) via the sulfoxide represented by the general formula (I-b) as an intermediate. (I-a> is obtained. The above oxidation reaction is carried out using ordinary oxidizing agents such as permanganic acid, periodic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, peroxidizing The oxidizing agent may be used in large excess, but is usually preferably used in an equimolar amount to approximately 4 times the molar amount of the compound of general formula (I-c). At this time, by appropriately selecting the reaction conditions, oxidizing agent, and number of moles used, the intermediate, general formula (
A sulfoxide of I-b) can be obtained. Moreover, the reaction is generally carried out in a suitable solvent.
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、アセトン、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を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空温ないしは冷
却下に行われる。As the solvent, any solvent that does not affect this reaction, such as chloroform, pyridine, tetrahydrofuran, dioxane, acetone, methylene chloride, carbon tetrachloride, acetic acid, formic acid, dimethylformamide, and water, can be used. Although the reaction temperature is not particularly limited, it is usually carried out at air temperature or under cooling.
上記Ａ工程及びＢ工程により得られる一般式（Ｉ−〇）
、（Ｉ−ｂ）乃至（Ｉ−ａ）で表わされる各化合物は、
それらの有するＲで示されるペニシリンカルボキシル保
護基の種類によって、本発明の目的物、即ち一般式（Ｉ
）で表わされるペニシリン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
引き続きＣ工程に示す如き脱エステル反応を行って、本
発明の一般式（工′）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。General formula (I-〇) obtained by the above steps A and B
, (I-b) to (I-a) are each compound represented by
Depending on the type of penicillin carboxyl protecting group represented by R they have, the object of the present invention, that is, the general formula (I
) may be an in vivo hydrolyzed ester of a penicillin derivative, but more preferably, it is usually followed by a deesterification reaction as shown in step C to obtain the penicillin derivative represented by the general formula (E) of the present invention. The compound is then converted into a pharmaceutically acceptable salt or an ester that can be hydrolyzed in vivo according to a conventional method, if necessary.
また上記一般式（Ｉ−ａ）、（Ｉ−ｂ）乃至（Ｉ−Ｃ）
の化合物は、これを直接常法に従いエステル交換反応に
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。In addition, the above general formulas (I-a), (I-b) to (I-C)
The compound can also be directly subjected to a transesterification reaction according to a conventional method to form an ester or a pharmaceutically acceptable salt that is hydrolyzed in vivo.
くＣ工程〉
一般式（Ｉ−ａ）で表わされる化合物を、Ｂ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（工′）で表わされるペニシリン誘導体
を得る。Step C> The compound represented by the general formula (I-a) is isolated from the reaction system of the B step, or is subjected to a deesterification reaction without being isolated, to produce a penicillin derivative represented by the general formula (I-a). get.
脱エステルの方法としては、カルボキシル保護基をカル
ボキシル基に導く通常の還元、加水分解等のすべての脱
離方法が適用できる。特にＲで表わされるペニシリンカ
ルボキシル保護基がトリクロロエチル、ペンシル、ｐ−
ニトロベンジル、ジフェニルメチル等である場合には、
還元による方法が、また該保護基が４−メトキシベンジ
ル、ｔｅｒｔ−ブチル、トリチル、ジフェニルメチル、
メトキシメチル、テトラヒドロピラニル等である場合に
は、酸による方法が夫々有利に採用される。As a method for deesterification, all the usual elimination methods such as reduction and hydrolysis that lead a carboxyl protecting group to a carboxyl group can be applied. In particular, the penicillin carboxyl protecting group represented by R is trichloroethyl, pencil, p-
In the case of nitrobenzyl, diphenylmethyl, etc.
The method by reduction is also used when the protecting group is 4-methoxybenzyl, tert-butyl, trityl, diphenylmethyl,
In the case of methoxymethyl, tetrahydropyranyl, etc., the method using an acid is advantageously employed.
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（又は）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。上記
接触還元による場合、触媒としては例えば白金、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
化ニッケル、ラネーニッケル等が例示される。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
の混合溶媒を好適に使用できる。Typical examples of reduction methods include a method using a metal such as zinc or zinc amalgam, and/or a chromium salt such as chromium chloride or chromium acetate, and an acid such as formic acid or acetic acid, or a method using catalytic reduction. can give. In the case of the above catalytic reduction, examples of the catalyst include platinum, platinum oxide, palladium, palladium oxide, palladium barium sulfate, palladium calcium carbonate, palladium carbon, nickel oxide, Raney nickel and the like. 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 can be suitably used.
また、酸による方法の際に使用される酸としては、１１
１酸、酢酸等の低級脂肪酸、トリクロロ酢酸、トリフル
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、トリフルオロ
メタンスルホン酸等の有懇スルホン酸、またはこれらの
混合物等が例示される。酸を用いる上記反応は液体の酸
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
えない溶媒を使用して実施することも可能である。In addition, the acid used in the acid method is 11
1 acid, lower fatty acids such as acetic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrohalic acids such as hydrochloric acid and hydrofluoric acid, amorphous sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid, Or a mixture thereof is exemplified. The above reaction using an acid does not require any other solvent when using a liquid acid, but it can also be carried out using a solvent that does not adversely affect the reaction, such as dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, acetone, etc. It is possible.
かくして得られる遊離酸形態の本発明の一般式（工′）
で表わされるペニシリン誘導体は、通常の当分野で慣用
される塩形成反応及び（又は）エステル化反応に従って
、医薬として許容される塩及びエステルに変換すること
ができる。The general formula (E) of the present invention in the free acid form thus obtained
Penicillin derivatives represented by can be converted into pharmaceutically acceptable salts and esters according to salt formation and/or esterification reactions commonly used in the art.
またエステル残塁が、例えば３−フタリジル、４−クロ
トノラクトニル、γ−ブチロラクトンー４−イル基等の
場合は、一般式（■′）で示されるペニシリン誘導体を
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−丁−ブチロラクトン等でアルキ
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される
。In addition, when the ester residue is, for example, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl group, etc., the penicillin derivative represented by the general formula (■') can be used as a 3-halogenated phthalide, 4- Alkylation can be performed with halogenated crotonolactone, 4-halogenated-di-butyrolactone, and the like. Here, chlorine, bromine and iodine are used as the halogen in the above-mentioned halide.
該反応は一般式（工′）で示されるペニシリン誘導体の
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、約等モルｌのハロゲン化物
を加えることによって行なわれる。反応温度は通常約Ｏ
〜１００’Ｃ１好ましくは約１５〜３５℃とするのが良
い。本エステル化反応で用いられるペニシリン誘導体の
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級アミン塩を例示すること
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。The reaction is carried out by dissolving a salt of a penicillin derivative represented by the general formula (E) in a suitable polar organic solvent such as N,N-dimethylformamide, and adding about an equimolar amount of a halide. It will be done. The reaction temperature is usually about O
~100'C1, preferably about 15-35°C. Salts of penicillin derivatives used in this esterification reaction include alkali metal salts such as sodium and potassium salts, triethylamine, ethyldiisopropylamine,
N-ethylpiperidine, N,N-dimethylaniline, N
- Tertiary amine salts such as methylmorpholine can be exemplified. After the reaction is completed, the target product can be easily isolated by a conventionally known method.
上記各工程により得られる目的化合物、並びに本発明ペ
ニシリン誘導体、その医薬として許容される塩及びエス
テルは、各工程での反応完了後に、常法に従い分離採取
され、また必要に応じて再結晶法、薄闇クロマトグラフ
ィー、カラムクロマトグラフィーなどにより精製するこ
とができる。The target compound obtained in each of the above steps, the penicillin derivative of the present invention, and its pharmaceutically acceptable salts and esters are separated and collected according to a conventional method after the completion of the reaction in each step, and if necessary, a recrystallization method, It can be purified by dark chromatography, column chromatography, etc.
！−厘−１ 次に実施例を示し、本発明を具体的に説明する。! -Rin-1 Next, examples will be shown to specifically explain the present invention.
実施例１
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 ｐ−ニトロベンジルエステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボン酸 ｐ−ニトロベンジルエステル１ ４８ｍｇ（０
． ４ｍｍｏｌ）及びチオシアン酸力’）ラム５ｓｍｇ
’（ｏ． ６ｍｍｏｌ）をアセトン３鵬及び水１鵬中に
加えて溶かし、２５°Ｃにて１２時間撹きまぜた。反応
混合物に酢酸エチル１５ｍ１２を加えて希釈し、水及び
飽和食塩水にて各２回洗い、無水硫酸マグネシウムにて
乾燥した。酢酸エチル抽出液を減圧上濃縮し、得られた
残渣をカラムクロマトグラフィーにて精製し、油状物１
４９＃ＦＦを得た。Example 1 2α-methyl-2β-thiocyanatomethylpenam-3
Process for producing α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1 48 mg (0
．． 4 mmol) and thiocyanic acid strength') rum 5 smg
' (o. 6 mmol) was dissolved in 3 parts of acetone and 1 part of water, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with 15 ml of ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain an oily substance 1.
49#FF was obtained.
収率９５％。Yield 95%.
赤外吸収スペクトル（ＣＨＣＱ３）ニ
ジ、、ｘ Ｃｃｍ−’）＝２１５０，１７８０，１ ７
５５。Infrared absorption spectrum (CHCQ3) Niji, x Ccm-') = 2150, 1780, 1 7
55.
核磁気共鳴スペクトル（ＣＤＣＱ３ ）：δ（ｐｐｍ
）−１．５６ （３Ｈ．ｓ）、３．２１（１Ｈ，ｄｄ）
、３．３８ （２Ｈ，ｓ）、３、６７ （ＩＨ，ｄｄ）
、４．８０ （１Ｈ。Nuclear magnetic resonance spectrum (CDCQ3): δ (ppm
)-1.56 (3H.s), 3.21 (1H, dd)
, 3.38 (2H,s), 3,67 (IH,dd)
, 4.80 (1H.
Ｓ）、５．２７ （２Ｈ，ｓ） 、５．２５〜５、４５
（ＩＨ，ｍ＞ 、７．４８ （２Ｈ，ｄ）、８、１５
（２Ｈ，ｄ）。S), 5.27 (2H, s), 5.25-5, 45
(IH, m>, 7.48 (2H, d), 8, 15
(2H, d).
実施例２
２α−メチル−２β−（１−メチル−５−テトラゾリル
チオ）メチルペナム−３α−カルボン酸 ｐ−ニトロベ
ンジルエステルの製法２β−クロロメチル−２α−メチ
ルペナム−３α−カルボン酸 ｐ−ニトロベンジルエス
テル１ ４ ８ｍｆｉ （０． ４ ｍｍｏｌ＞ 、５
−メルカプト−１−メチルテトラゾール５ ２Ｗｔｇ（
０． ４ ５ｍｍｏｌ）炭酸水素カリウム４ ０ｍｆｊ
（０． ４ｍｍｏｌ）をアセトン３ｍＱ及び水１ｍ１
Ｊ中に加えて溶かし、２５°Ｃにて１２時間撹拌した。Example 2 Preparation of 2α-methyl-2β-(1-methyl-5-tetrazolylthio)methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1 4 8mfi (0.4 mmol>, 5
-Mercapto-1-methyltetrazole 5 2Wtg (
0. 4 5 mmol) Potassium hydrogen carbonate 4 0 mfj
(0.4 mmol) in 3 mQ of acetone and 1 m1 of water
J and stirred at 25°C for 12 hours.
反応混合物に酢酸エチル２０１ＴＩＩ２を加えて希釈し
、水及び飽和食塩水にて各２回洗い、無水硫酸マグネシ
ウムにて乾燥した。The reaction mixture was diluted by adding ethyl acetate 201TII2, washed twice each with water and saturated brine, and dried over anhydrous magnesium sulfate.
酢酸抽出液を減圧上濃縮し、得られた残漬をカラムクロ
マトグラフィー（シリカゲル、ベンゼン：酢酸エチル＝
９：１）にて分離し、油状物１１９ｍ１を得た。収率６
６％。The acetic acid extract was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, benzene: ethyl acetate =
9:1) to obtain 119 ml of oil. Yield 6
6%.
赤外吸収スペクトル（ＣＨＣＱ３）ニ
ジＩＩｌａｘ（ｃｍ−’ ） −１７７５，１７５５，
１６１０，１５２５，１３５０゜
核磁気共鳴スペクトル（ＣＤＣＱ３）：δ（ｐｐｍ ）
〜１．５２ （３Ｈ，ｓ）、３．１１（１Ｈ，ｄｄ）、
３．６１ （１Ｈ，ｄｄ＞、３．６０〜４．２０ （２
ｔ−１，ｍ＞ 、３．９１（３ｔ−１，ｓ＞、４．８１
（１Ｈ，ｓ＞、５．２０〜５．４５ （ＩＨ，ｍ）
、５．２７（２ｔ−１，ｓ）、７．４８ （２Ｈ，ｄ）
、８．１５ （２Ｈ，ｄ）。Infrared absorption spectrum (CHCQ3) Niji II lax (cm-') -1775,1755,
1610, 1525, 1350° nuclear magnetic resonance spectrum (CDCQ3): δ (ppm)
~1.52 (3H, s), 3.11 (1H, dd),
3.61 (1H, dd>, 3.60~4.20 (2
t-1,m>, 3.91 (3t-1,s>, 4.81
(1H,s>, 5.20~5.45 (IH,m)
, 5.27 (2t-1,s), 7.48 (2H,d)
, 8.15 (2H, d).
実施例３
２α−メチル−２β−（１−フェニル−５−テトラゾリ
ルチオ）メチルペナム−３α−カルボン酸 ｐ−ニトロ
ベンジルエステルの製法２β−クロロメチル−２α−メ
チルペナム−３α−カルボン酸 ｐ−ニトロベンジルエ
ステル１４８＃Ｉ９ （０，４ｍｍｏ！＞ 、５−メル
カプト−１−フェニルテトラゾール７９＃ＩＳＦ （０
，４４ｍｍｏｌ）、炭酸水素カリウム４０ｍ５Ｆ （０
，４ｍｍｏｌ＞をアセトン６１１１１２及び水２鵬中に
加えて溶かし、２５℃にて１２時間撹拌した。反応混合
物に酢酸エチル２０−を加えて希釈し、水及び飽和食塩
水にて各２回洗い、無水硫酸マグネシウムにて乾燥した
。Example 3 Preparation of 2α-methyl-2β-(1-phenyl-5-tetrazolylthio)methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 148 #I9 (0,4mmo!>, 5-mercapto-1-phenyltetrazole 79#ISF (0
, 44 mmol), potassium hydrogen carbonate 40 m5F (0
, 4 mmol> was dissolved in acetone 611,112 and water, and stirred at 25° C. for 12 hours. The reaction mixture was diluted with 20 ml of ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous magnesium sulfate.
酢酸エチル抽出液を減圧上濃縮し、得られた残渣をカラ
ムクロマトグラフィー（シリカゲル、ベンゼン：酢酸エ
チル＝１９：１）にて分離し、油状物１２７１＋１９を
得た。収率６５％。The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, benzene:ethyl acetate = 19:1) to obtain an oily substance 1271+19. Yield 65%.
赤外吸収スペクトル（ＣＨ２Ｒ３）ニ
ジｍａｘ （ｃｍ” ） ＝ １７７５．１７５０．１
６１０．１５２０．１３５０゜
核磁気共鳴スペクトル（ＣＤＣＱ３）：δ（ｐｐｍ ）
〜１．５２ （３Ｈ，ｓ）、３．０８（ＩＨ，ｄｄ）、
３．５４ （ＩＨ，ｄｄ）、３．６０〜４．２０ （２
Ｈ，ｍ＞ １．４．８４（ＩＨ，ｓ＞、５．１５〜５．
４０ （ＩＨ。Infrared absorption spectrum (CH2R3) Niji max (cm”) = 1775.1750.1
610.1520.1350° Nuclear magnetic resonance spectrum (CDCQ3): δ (ppm)
~1.52 (3H, s), 3.08 (IH, dd),
3.54 (IH, dd), 3.60~4.20 (2
H, m> 1.4.84 (IH, s>, 5.15-5.
40 (IH.
ｍ＞ 、５．２３ （２Ｈ，Ｓ）、７．１５〜７．６５
（７Ｈ，ｍ＞ 、８．１２ （２Ｈ，ｄ）。m>, 5.23 (2H, S), 7.15-7.65
(7H, m>, 8.12 (2H, d).
実施例４
２α−メチル−２β−（２−ベンゾチアゾリルチオ）メ
チルペナム−３α−カルボン酸 ｐ−ニトロベンジルエ
ステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボン酸 ｐ−ニトロベンジルエステル７アゾール３５ｍ
ｇ（０．２１ｍ…０（）、炭酸水素カリウム２ ０１ｎ
３ （０． ２ｍｍｏｌ）をアセトン３ ｗｌｌ及Ｕ水
１１１１Ｑ中に加えて溶かし、２５℃にて３０時間撹拌
した。反応混合物に酢酸エチル１０１１１９を加えて希
釈し、水及び飽和食塩水にて各２回洗い、無水硫酸マグ
ネシウムにて乾燥した。抽出液を減圧上濃縮し、得られ
た残漬をカラムクロマトグラフィー（シリカゲル、ベン
ゼン：酢酸エチル＝１９：１）にて分離し、２α−メチ
ル−２Ｂ− （２−ベンゾチアゾリルチオ）メチルペナ
ム−３α−カルボンｌｐ−ニトロベンジルエステル３６
＃Ｉ９を得た。Example 4 Preparation of 2α-methyl-2β-(2-benzothiazolylthio)methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 7 Azole 35m
g (0.21m...0(), potassium hydrogen carbonate 2 01n
3 (0.2 mmol) was added and dissolved in 3 μl of acetone and 1111 Q of U water, and the mixture was stirred at 25° C. for 30 hours. The reaction mixture was diluted by adding ethyl acetate 101119, washed twice each with water and saturated brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, benzene:ethyl acetate = 19:1) to give 2α-methyl-2B-(2-benzothiazolylthio)methylpenam- 3α-Carvone lp-nitrobenzyl ester 36
#I9 was obtained.
収率３５％。Yield 35%.
赤外吸収スペクトル（ＣＨＣＱ３）ニ
ジｍａＸ （ Ｃｍ” ） ＝’ｌ ７ ７ ５、１６
１０、１５２５。Infrared absorption spectrum (CHCQ3) maX (Cm”) ='l 7 7 5, 16
10, 1525.
核磁気共鳴スペクトル（ＣＤＣＱ３ ）：δ（ｐｐｍ
）〜１． ５３ （３１−１， ｓ＞、３． １２（ｉ
ｆ−１．ｄｃｌ）、’ ３．５８ （１日，ｄｄ＞、３
、 ７０〜４． ２５ （２＋−イ，ｍＬ４．９１
（１Ｈ，ｓ＞、５．２０〜５．４０（１１−１。Nuclear magnetic resonance spectrum (CDCQ3): δ (ppm
)~1. 53 (31-1, s>, 3.12(i
f-1. dcl),' 3.58 (1 day, dd>, 3
, 70-4. 25 (2+-i, mL4.91
(1H, s>, 5.20-5.40 (11-1.
ｍ）、５．２２ （２Ｈ，Ｓ）、７．１０〜７．９０
（５Ｈ，ｍ） 、８．１１ （２Ｈ，ｄ）。m), 5.22 (2H, S), 7.10-7.90
(5H, m), 8.11 (2H, d).
実施例５
２α−メチル−２β−（５−メチル−２−（１゜３．４
−チアジアゾリル）チオ）メチルペナム−３α−カルボ
ンＭ ｐ−ニトロベンジルエステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボン酸 ｐ−ニトロベンジルエステル１ ４ ８ｍｙ
（０． ４ｍｍｏｌ＞ 、２−メルカプト−５−メチル
−１．３．４−チアジアゾール５６＃ｌＳＦ（０． ４
２ｍｍｏｌ） 、炭酸水素カリウム４０Ｉｆｔｇ（０
． ４ｍｍｏｌ）をアセトン６ｍ１２及び水２ｍＱ中に
加えて溶かし、２５℃にて２４時間撹拌した。反応混合
物に酢酸エチル２０戒を加えて希釈し、水及び飽和食塩
水にて各２回洗い、無水硫酸マグネシウムにて乾燥した
。抽出液を減圧上濃縮し、得られた残渣をカラムクロマ
トグラフィー（シリカゲル、ベンゼン：酢酸エチル＝１
９：１）にて分離し、２α−メチル−２β−（５−メチ
ル−２−（１，３．４−チアジアゾリル）チオ）メチル
ペナム−３α−カルボンＭ ｐ−ニトロベンジルエステ
ル６８ｍｇを得た。収率３７％。Example 5 2α-methyl-2β-(5-methyl-2-(1°3.4
-thiadiazolyl)thio)methylpenam-3α-carvone M Process for producing p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1 4 8my
(0.4 mmol>, 2-mercapto-5-methyl-1.3.4-thiadiazole 56#lSF (0.4
2 mmol), potassium hydrogen carbonate 40 Iftg (0
．． 4 mmol) was added and dissolved in 6 ml of acetone and 2 mQ of water, and the mixture was stirred at 25° C. for 24 hours. The reaction mixture was diluted by adding 20 portions of ethyl acetate, washed twice each with water and saturated brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, benzene:ethyl acetate = 1
9:1) to obtain 68 mg of 2α-methyl-2β-(5-methyl-2-(1,3.4-thiadiazolyl)thio)methylpenam-3α-carvone M p-nitrobenzyl ester. Yield 37%.
赤外吸収スペクトル（ＣＨＣＱ３）ニ
ジｌＩｌａｘ（ｃｍ′″’）＝１７７５、１６ｊＯ、１
５２５。Infrared absorption spectrum (CHCQ3) Ilax (cm'''') = 1775, 16jO, 1
525.
核磁気共鳴スペクトル（ＣＤＣ（３）：δ（ｐｐｍ ）
〜１． ５１ （３１−１， ｓ）、２． ６９（３Ｈ
，ｓ＞、３．１０ （１Ｈ，ｄｄ）、３、５９ （’Ｉ
Ｈ，ｄｄ）、３．６０〜４．２０（２Ｈ，ｍ＞ 、４．
８３ （ＩＨ，ｓ＞、５、２０ 〜５．４０ （ＩＨ，
ｍ＞ 、５．２４（２Ｈ，ｓ＞、７．４９ （２Ｈ．ｄ
＞、８、１５ （２Ｈ，ｄ）。Nuclear magnetic resonance spectrum (CDC(3): δ (ppm)
~1. 51 (31-1, s), 2. 69 (3H
, s>, 3.10 (1H, dd), 3, 59 ('I
H, dd), 3.60-4.20 (2H, m>, 4.
83 (IH, s>, 5, 20 ~ 5.40 (IH,
m>, 5.24 (2H,s>, 7.49 (2H.d
>, 8, 15 (2H, d).
実施例６
２α−メチル−２β−ジメチルアミノチオカルバモイル
チオメチルペナム−
ｐ−ニトロベンジルエステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボン酸 ｐ−ニトロベンジルエステル１ ４８ｍ９ （
０． ４ｍｍｏｌ）及（ＩＮ． Ｎ−シ：ｙ＜チ）Ｉ，
ｔ７ミノジチオカルバメート ナトリウム塩６１ｍ３（
０． ４４ｍｍｏｌ）をアセトン６−及び水２鵬中に加
えて溶かし、２５°Ｃにて１２時間撹拌した。反応混合
物に酢酸エチル１５−を加えて希釈し、水及び飽和食塩
水にて各２回洗い、無水ＩｉＡ酸マグネシウムにて乾燥
した。酢酸エチル抽出液を減圧上濃縮し、得られた残渣
をカラムクロマトグラフィーにて精製し、油状物２４ｍ
Ｆｌを得た。Example 6 Preparation of 2α-methyl-2β-dimethylaminothiocarbamoylthiomethylpenam-p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1 48m9 (
0. 4 mmol) and (IN. N-shi:y<chi)I,
t7 minodithiocarbamate sodium salt 61m3 (
0. 44 mmol) was dissolved in acetone and water, and stirred at 25°C for 12 hours. The reaction mixture was diluted with 15-ethyl acetate, washed twice each with water and saturated brine, and dried over anhydrous magnesium IiA acid. The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain 24 m
I got Fl.
赤外吸収スペクトル（ＣＨＣ９ｔ３）ニジＩＩＩＢｘ＜
ｃｍ−’＞＝ １ ７７５、１ ７４５ （Ｓｈ）。Infrared absorption spectrum (CHC9t3) NijiIIIBx<
cm-'>= 1 775, 1 745 (Sh).
核磁気共鳴スペク１〜ル（ＣＤＣ（３）：δ（ｐｌ）ｍ
＞〜１．５１ （３Ｈ．Ｓ）、３．１５（１１−１．
ｄｄ）、３．３０〜３．７５ （９）（。Nuclear magnetic resonance spectrum 1~ (CDC(3): δ(pl)m
>~1.51 (3H.S), 3.15 (11-1.
dd), 3.30-3.75 (9)(.
ｍ＞ 、４．、７９ （ＩＨ．ｓ＞、５．１５ 〜５、
３０ （１Ｈ，ｍ＞ 、５．２３ （２Ｈ，ｓ＞、７、
５５ （２Ｈ，ｄ）、ｓ．２０ （２Ｈ，ｄ）。m>, 4. , 79 (IH.s>, 5.15 ~ 5,
30 (1H, m>, 5.23 (2H, s>, 7,
55 (2H, d), s. 20 (2H, d).
実施例７
２α−メチル−２β−アセチルチオメチルペナム−３α
−カルボン酸 ｐ−ニトロペンシルエステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボンＭ ｐ−ニトロベンジルエステル１ ４ ８ｆｆ
１ｇ（０． ４ｍｍｏｌ） 、チオ酢酸３４ｍ９１（０
． ４ ５ｍｍｏｌ） 、炭酸水素カリウム４０１ｎ９
（０． ４ｍｍｏｌ）をアセトン３ｍ１２及び水１ｍｆ
２中に加えて溶かし、２５℃にて１２時間撹拌した。反
応混合物に酢酸エチル２０ｍＱを加えて希釈し、水及び
飽和食塩水にて各２回洗い、無水硫酸マグネシウムにて
乾燥した。酢酸エチル抽出液を減圧上濃縮し、得られた
残渣をカラムクロマトグラフィー（シリカゲル、ベンゼ
ン：酢酸エチル＝９ ： １ ）にて分離し、油状物２
７ｍｙを得た。Example 7 2α-methyl-2β-acetylthiomethylpenam-3α
-Production method of carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carvone M p-nitrobenzyl ester 1 4 8ff
1g (0.4mmol), thioacetic acid 34m91 (0
．． 4 5 mmol), potassium hydrogen carbonate 401n9
(0.4 mmol) in 3 m12 of acetone and 1 mf water
2 and stirred at 25°C for 12 hours. The reaction mixture was diluted with 20 mQ of ethyl acetate, washed twice each with water and saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, benzene:ethyl acetate = 9:1) to obtain an oily substance 2.
I got 7my.
赤外吸収スペクトル（ＣＨＣＩ９３ ）ニジｍａｘ Ｃ
ｃｍ−’ ） ＝ １７８０．１７００゜核磁気共鳴ス
ペクトル（ＣＤＣＱ３ ）：δ（ｐｐｍ ）＝１．４２
（３Ｈ，ｓ）、２．３８（３Ｈ，ｓ＞、３．１４（１
ｔ（、ｄｄ）、３．１０〜３．６５ （２Ｈ，ｍ） 、
３．５９（ＩＨ，ｄｄ）、４．６７ （ＩＨ，ｓ＞、５
．２０〜５．４５ （１Ｈ，ｍ） 、５．２７（２Ｈ，
ｓ）、７．５３ （２Ｈ，ｄ）、８．２１ （２Ｈ，ｄ
）。Infrared absorption spectrum (CHCI93) Niji max C
cm-') = 1780.1700° Nuclear magnetic resonance spectrum (CDCQ3): δ (ppm) = 1.42
(3H,s), 2.38(3H,s>, 3.14(1
t(, dd), 3.10 to 3.65 (2H, m),
3.59 (IH, dd), 4.67 (IH, s>, 5
．． 20-5.45 (1H, m), 5.27 (2H,
s), 7.53 (2H, d), 8.21 (2H, d
).
実施例８
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 ｐ−メトキシベンジルエステルの製法
２β−クロロメチル−２α−メチルペナム−３α−カル
ボンｒｌｉｐ−メトキシベンジルエステル１ ４ ３ｍ
ｇ（０． ４ｍｍｏｌ＞及びチオシアン酸カリウム５ｓ
ｍｇ（ｏ． ６ｍｍｏｌ＞をアセ１〜ン３ｍＱ及び水１
戒中に加えて溶かし、２５℃にて２２時間撹拌した。反
応混合物に酢酸エチル２０ｍＱを加えて希釈し、水及び
飽和食塩水にて各２回洗い、無水流Ｍマグネシウムにて
乾燥した。抽出液を減圧上濃縮し、得られた残渣をカラ
ムクロマトグラフィー（シリカゲル、ベンゼン：酢酸エ
チル＝１９：１）にて分離し、油状物１５０１ｒ１９を
得た。収率９４％。Example 8 2α-methyl-2β-thiocyanatomethylpenam-3
Preparation of α-carboxylic acid p-methoxybenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carvone rlip-methoxybenzyl ester 1 4 3m
g (0.4 mmol> and potassium thiocyanate 5s
mg (o. 6 mmol>) of acetic acid 1~3 mQ and water 1
The mixture was added to the liquid, dissolved, and stirred at 25°C for 22 hours. The reaction mixture was diluted with 20 mQ of ethyl acetate, washed twice each with water and saturated brine, and dried over anhydrous M magnesium. The extract was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, benzene:ethyl acetate = 19:1) to obtain an oily substance 1501r19. Yield 94%.
赤外吸収スペクトル（ＣＤＣＱ３）ニ
ジＩＩｌａｘ（ｃＩｔ′″’）−２１５０，１７７０，
１７４０。Infrared absorption spectrum (CDCQ3) NijiIIlax (cIt'''')-2150, 1770,
1740.
１６１０、１５１０。1610, 1510.
核磁気共鳴スペクトル（ＣＤＣＱ３）：δ（１）Ｉ）ｍ
）＝１．４６ （３Ｈ，Ｓ）、３．０３（１Ｈ，ｄｄ
） 、３．３１ （２Ｈ．ｓ＞、３、５７ （ＩＨ，ｄ
ｄ＞、３．７７ （３Ｈ。Nuclear magnetic resonance spectrum (CDCQ3): δ(1)I)m
) = 1.46 (3H, S), 3.03 (1H, dd
), 3.31 (2H.s>, 3,57 (IH,d
d>, 3.77 (3H.
ｓ＞、４．６８ （ＩＨ，ｓ＞、５．１１ （２１−１
。s>, 4.68 (IH, s>, 5.11 (21-1
.
ｓ） 、５．２３ 〜５．４０ （ｉｔ−１，ｍ＞、６
、８５ （２Ｈ，ｄ＞、７．７７ （２Ｈ，ｄ）。s), 5.23 ~ 5.40 (it-1, m>, 6
, 85 (2H, d>, 7.77 (2H, d).
実施例９
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 ベンゾヒドリルエステルの製法
２β−クロロメチル−２α−メチルペナム−３αーカル
ボン酸 ベンゾヒドリルエステルｍ’Ｊ （２． １ｍ
ｍｏｌ）及びチオシアン酸カリウム３ １ ３２ｇ（３
． ’１ｍｍｏｌ）をアセトン１６．１１１１１２及び
水５．４ｍ（２中に加えて溶かし、２５℃にて２１時間
撹拌した。反応混合物に酢酸エチル６０ＩＩｌ１２を加
えて希釈し、水及び飽和食塩水にて各２回洗い、無水硫
酸マグネシウムにて乾燥した。抽出液を減圧上濃縮し、
得られた残渣をカラムクロマトグラフィー（シリカゲル
、ベンゼン：酢酸エチル＝３９：１）にて分離し、油状
物８３４ｍｇを得た。Example 9 2α-methyl-2β-thiocyanatomethylpenam-3
Production method of α-carboxylic acid benzhydryl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid benzhydryl ester m'J (2.1 m
mol) and potassium thiocyanate 3 1 32 g (3
．． '1 mmol) was dissolved in 16.111112 acetone and 5.4 m of water (2) and stirred at 25°C for 21 hours. The reaction mixture was diluted with 60IIl12 of ethyl acetate, and each mixture was diluted with water and saturated brine. Washed twice and dried over anhydrous magnesium sulfate.The extract was concentrated under reduced pressure.
The resulting residue was separated by column chromatography (silica gel, benzene:ethyl acetate = 39:1) to obtain 834 mg of an oily substance.
収率９２％。Yield 92%.
赤外吸収スペクＩ〜ル（ＣＨＣＱ３）ニジ ＜ｃｍ”
） −２ １ ５０、１７７５、１７４０。Infrared absorption spectrum I (CHCQ3) Niji <cm”
) -2 1 50, 1775, 1740.
ａｘ
核磁気共鳴スペク１〜ル（ＣＤＣＱ３ ）：δ（ｐｐｍ
）＝１．３３ （３Ｈ，ｓ）、３．００（１Ｈ，ｄｄ
）、３．２８ （２Ｈ，Ｓ）、３、５２ （ＩＨ，ｄｄ
）、４．７９ （ＩＨ。ax Nuclear magnetic resonance spectrum 1~ (CDCQ3): δ (ppm
) = 1.33 (3H, s), 3.00 (1H, dd
), 3.28 (2H,S), 3,52 (IH,dd
), 4.79 (IH.
ｓ＞、５．２０ 〜５．４０ （１Ｈ，ｍ＞、６、９０
（１Ｈ，ｓ＞、７．１０〜７．５０（１０Ｈ，ｍ＞。s>, 5.20 ~ 5.40 (1H, m>, 6, 90
(1H, s>, 7.10-7.50 (10H, m>.
実施例１０
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 １−オキシド ｐ−二トロベンジルエ
ステルの製法
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボンＭｐーニトロベンジルエステル４３ １ｍ
’Ｊ （２． ０ｍｍｏｌ）をシ’ｙ口）Ｉ，ｔメ９ン
２０ｍＱに溶かし、水冷、撹拌下、ｍ−クロル過安息香
酸（８０％＞ ４３ １ｍｇ （２． ０ｍｍｏｌ）の
ジクロルメタン１０ｍＱ溶液を滴下した。室温下にて２
時間撹拌した。反応混合物を亜硫酸水素ナトリｒクム水
溶液、炭酸水素ナトリウム水溶液及び飽和食塩水にて各
２回洗い、無水硫酸マグネシウムにて乾燥した。ジクロ
ルメタン溶液を減圧上濃縮し、得られた残渣をカラムク
ロマトグラフィー（シリカゲル、アセトン：クロロホル
ム＝１９：１）にて分離し、油状物７７２ｍ９を得た。Example 10 2α-methyl-2β-thiocyanatomethylpenam-3
Production method of α-carboxylic acid 1-oxide p-nitrobenzyl ester 2α-methyl-2β-thiocyanatomethylpenam-3
α-Carvone Mp nitrobenzyl ester 43 1m
Dissolve J (2.0 mmol) in 20 mQ of cylinder, and add a solution of m-chloroperbenzoic acid (80% > 43 1 mg (2.0 mmol) in 10 mQ of dichloromethane under stirring with water cooling. Dropwise at room temperature.
Stir for hours. The reaction mixture was washed twice each with a sodium bisulfite aqueous solution, a sodium bicarbonate aqueous solution, and a saturated saline solution, and dried over anhydrous magnesium sulfate. The dichloromethane solution was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, acetone:chloroform = 19:1) to obtain 772m9 of an oily substance.
収率 ９４％。Yield: 94%.
赤外吸収スペクトル（ＣＨＣ９３）ニ
ジ１．、；１ｘ（ｃｍ−’ ） −２１５０，１７９０
，１７５５゜核磁気共鳴スペクトル（ＣＤＣＱ３）：δ
（１）ｌ）ＩＩＩ ）〜１．４１ （３Ｈ，Ｓ）、３．
３０〜３、 ６５ （２Ｈ，ｍ＞ 、 ３．
７０ （２ト１． Ｓ ） 、４．６７ （ｓ、１
Ｈ，３−Ｈ） 、５．０４（１Ｈ，ｔ＞、５．３４ （
２Ｈ，ｓ）、７．５７ （２Ｈ，ｄ）、８．２５ （２
Ｈ，ｄ）。Infrared absorption spectrum (CHC93) Niji 1. ,;1x(cm-') -2150,1790
, 1755° nuclear magnetic resonance spectrum (CDCQ3): δ
(1)l)III)~1.41 (3H,S), 3.
30-3, 65 (2H, m>, 3.
70 (2t1.S), 4.67 (s, 1
H, 3-H), 5.04 (1H, t>, 5.34 (
2H,s), 7.57 (2H,d), 8.25 (2
H, d).
実施例１１
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 １−オキシド ｐ−メトキシベンジル
エステルの製法
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 ｐ−メトキシベンジルエステル５９２
ｔｎｌ （１、５６ｍｍｏｌ）をツク０ルメタン１０ｍ
Ｑに溶かし、水冷、撹拌下、ｍ−クロル過安息香酸（８
０％＞ ３５４ｍｌ （１、６４ｍｍｏｌ）のジクロル
メタン１０ｍ１２溶液を滴下後、室温下にて２時間撹拌
した。反応混合物を亜硫酸水素ナトリウム水溶液、炭酸
水素ナトリウム水溶液及び飽和食塩水にて洗い、無水硫
酸マグネシウムにて乾燥した。ジクロルメタン溶液を減
圧上濃縮し、得られた残渣をカラムクロマトグラフィー
（シリカゲル、アセトン：クロロホルム＝１９：１）に
て分離し、油状物４７９１ｆｔｇを得た。収率 ７８％
。Example 11 2α-methyl-2β-thiocyanatomethylpenam-3
Production method of α-carboxylic acid 1-oxide p-methoxybenzyl ester 2α-methyl-2β-thiocyanatomethylpenam-3
α-Carboxylic acid p-methoxybenzyl ester 592
tnl (1,56 mmol) and 10 m of methane
m-chloroperbenzoic acid (8
0% > 354 ml (1,64 mmol) of dichloromethane (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with an aqueous sodium bisulfite solution, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The dichloromethane solution was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, acetone:chloroform = 19:1) to obtain 4,791 ftg of an oily substance. Yield 78%
.
赤外吸収スペクトル（ＣＨＣＱ３ ）ニジ１１１ａｘ（
ｃＩ！１″″’）−２１５０，１７９０，１７５５゜核
磁気共鳴スペクトル（ＣＤＣＱ３ ）：δ（ｐｐｍ ）
−１，２５（３Ｈ，ｓ）、３．２１（２Ｈ，ｄ）、３．
６０ （２Ｈ，ｓ＞、３．７８ （３Ｈ，ｓ＞、４．５
４ （１１−１，ｓ）、４．９４ （ＩＨ，ｔ＞、５．
０〜５．４ （２Ｈ。Infrared absorption spectrum (CHCQ3) Niji 111ax (
cI! 1″″’)-2150, 1790, 1755° nuclear magnetic resonance spectrum (CDCQ3): δ (ppm)
-1,25 (3H, s), 3.21 (2H, d), 3.
60 (2H,s>, 3.78 (3H,s>, 4.5
4 (11-1, s), 4.94 (IH, t>, 5.
0-5.4 (2H.
ｍ） 、６．９１ （２Ｈ，ｄ）、７．８３ （ｄ。m), 6.91 (2H, d), 7.83 (d.
２Ｈ，ｄ）。2H, d).
実施例１２
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 １−オキシド ベンゾヒドリルエステ
ルの製法。Example 12 2α-methyl-2β-thiocyanatomethylpenam-3
Method for producing α-carboxylic acid 1-oxide benzhydryl ester.
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 ベンゾヒドリルエステル７４２ＦＦ（
１，７５朋ｏｆ）をジクロルメタン１０ｍＱに溶かし、
水冷、撹拌下、ｍ−クロル過安息香！（８０％＞ ３９
７Ｎ （’１．８４ｍｍｏｌ）のジクロルメタン１０ｍ
Ｇ溶液を滴下し、室温下にて２時間撹拌した。反応混合
物を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム
水溶液及び飽和食塩水にて各２回洗い、無水硫酸マグネ
シウムにて乾燥した。ジクロルメタン溶液を減圧上濃縮
し、得られた残渣をカラムクロマトグラフィー（シリカ
ゲル、アセトン：クロロホルム−４９：１）にて分離し
、油状物６６９ ｍｙを得た。収率 ８７％。2α-methyl-2β-thiocyanatomethylpenam-3
α-Carboxylic acid benzhydryl ester 742FF (
1,75 of) was dissolved in 10 mQ of dichloromethane,
Water-cooled, under stirring, m-chloroperbenzoic acid! (80%>39
10 m of 7N ('1.84 mmol) dichloromethane
G solution was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed twice each with an aqueous sodium bisulfite solution, an aqueous sodium bicarbonate solution, and a saturated saline solution, and dried over anhydrous magnesium sulfate. The dichloromethane solution was concentrated under reduced pressure, and the resulting residue was separated by column chromatography (silica gel, acetone:chloroform-49:1) to obtain 669 my of oil. Yield: 87%.
赤外吸収スペクトル（ＣＨＣ９３）ニ
ジｍａｘ ＜Ｃｒｎ−’ ） ＝ ２１６０．１７９
５．１７５５゜核磁気共鳴スペクトル（ＣＤＣ９３）：
δ（ｐｐｍ ）＝’１．１１ （３Ｈ，ｓ）、３．２９
（２Ｈ，ｄ）、３．６１ （２Ｈ，ｓ＞、４、 ６３
（１１七 ｓ＞ 、 ４． ８７ （１ト
１． ｔ ） 、６．９４ （１Ｈ，ｓ）、７．１〜
７．５（ＩＯＨ，ｍ）。Infrared absorption spectrum (CHC93) Nijimax <Crn-') = 2160.179
5.1755° nuclear magnetic resonance spectrum (CDC93):
δ (ppm) = '1.11 (3H, s), 3.29
(2H, d), 3.61 (2H, s>, 4, 63
(117 s>, 4.87 (1 to 1. t), 6.94 (1H, s), 7.1~
7.5 (IOH, m).
実施例１３
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 １，１−ジオキシドｐ−ニトロベンジ
ルエステルの製法
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボンＭ ｐ−ニトロベンジルエステル１４５ｍ
ｙ （０，３７ｍｍｏｌ＞を氷酢酸５．５ｍＱと水０．
９ｍＱに溶かし、空温撹拌下、過マンガン酸カリウム７
０ｔｒＧ （０，４４ｍｍｏｌ）を３０分間にわたって
徐々に加えた後、室温にて４時間撹拌した。ついで３４
．５％過酸化水素水を反応液の色が消えるまで加えた後
、水を加え、クロロホルムにて抽出した。クロロホルム
抽出液を炭酸水素すトリウム水で洗浄後、無水硫酸マグ
ネシウムにて乾燥した。クロロホルム抽出液を減圧上濃
縮し、２α−メチル−２βチオシアナートメチルペナム
−３αカルボン１１．１−ジオキシド ｐ−二トロベン
ジルエステル１５４ｍｇを得た。収率９８％。融点１４
９〜１５０℃。Example 13 2α-methyl-2β-thiocyanatomethylpenam-3
Production method of α-carboxylic acid 1,1-dioxide p-nitrobenzyl ester 2α-methyl-2β-thiocyanatomethylpenam-3
α-Carvone M p-nitrobenzyl ester 145m
y (0.37 mmol) was mixed with 5.5 mQ of glacial acetic acid and 0.5 mQ of water.
Potassium permanganate was dissolved in 9 mQ and stirred at air temperature.
After gradually adding 0trG (0.44 mmol) over 30 minutes, the mixture was stirred at room temperature for 4 hours. Then 34
．． After adding 5% hydrogen peroxide solution until the color of the reaction solution disappeared, water was added and extraction was performed with chloroform. The chloroform extract was washed with thorium bicarbonate water and dried over anhydrous magnesium sulfate. The chloroform extract was concentrated under reduced pressure to obtain 154 mg of 2α-methyl-2β thiocyanatomethylpenam-3α carvone 11.1-dioxide p-nitrobenzyl ester. Yield 98%. Melting point 14
9-150℃.
赤外吸収スペクトル（ＣＨＣＱ３ ）ニジｍａ）＜
（ｃｍ−’ ） ””２１５０．１７９０．１７５５．
１７２５゜
核磁気共鳴スペクトル（ＣＤＣ９３）：δ（ｐｐｍ ）
〜１ 、５８ （ｓ、 ３Ｈ） 、３．３０〜３．７
０ （ｍ、２Ｈ） 、３．６３ （ｓ、２Ｈ）、４．６
０〜４．８０ （ｍ、ＩＨ） 、４．７２（ｓ、１Ｈ＞
、５．３３ （ｓ、２Ｈ）、７．５３ （ｄ、２Ｈ＞
、８．１８ （ｄ、２Ｈ＞。Infrared absorption spectrum (CHCQ3)
(cm-') ””2150.1790.1755.
1725° nuclear magnetic resonance spectrum (CDC93): δ (ppm)
~1, 58 (s, 3H), 3.30~3.7
0 (m, 2H), 3.63 (s, 2H), 4.6
0 to 4.80 (m, IH), 4.72 (s, 1H>
, 5.33 (s, 2H), 7.53 (d, 2H>
, 8.18 (d, 2H>.
実施例１４
２α−メチル−２β−（１−メチル−５−テトラゾリル
チオ）メチルペナム−３α−カルボンＭ １，１−ジオ
キシド ｐ−ニトロベンジルエステルの製法
２α−メチル−２β−（１−メチル−５−テトラゾリル
チオ）メチルペナム−３α−カルボン酸ｐ−ニトロベン
ジルエステル１３８ｍ５Ｆ（０，３１ｍｍｏｌ）を氷酢
酸３．２１１２と水０．５１１１Ｑに溶かし、室温撹拌
下、過マンガン酸カリウム５８Ｉｔｇ（０，３７ｍｍｏ
ｌ）を３０分間にわたって徐々に加えた後、室温にて４
時間撹拌した。ついで過酸化水素水を反応液の色が消え
るまで加えた後、水５鵬を加え、クロロホルムにて抽出
した。クロロホルム層を水、炭酸水素ナトリウム水及び
飽和食塩水で洗い、無水硫酸マグネシウムにて乾燥した
。抽出液を減圧上濃縮し、油状物１３８＃Ｉ！９を得た
。収率９３％
赤外吸収スペクトル（ＣＨＣＱ３）ニ
ジ （ｃｍ” ）＝１８０５．１７６０，１６０５゜
ａｘ
核磁気共鳴スペクトル（ＣＤＣ９３）：δ（ｐｐｍ ）
−１，４８（３Ｈ，ｓ＞、３．３０〜３．７０ （２Ｈ
，ｍ＞ 、３．８０〜４．５５（２Ｈ，ｍ） 、４．５
５〜４．９０ （ＩＨ。Example 14 Preparation of 2α-methyl-2β-(1-methyl-5-tetrazolylthio)methylpenam-3α-carvone M 1,1-dioxide p-nitrobenzyl ester 2α-methyl-2β-(1-methyl-5-tetrazolylthio ) Methylpenam-3α-carboxylic acid p-nitrobenzyl ester 138m5F (0.31 mmol) was dissolved in 3.2112 glacial acetic acid and 0.5111 Q water, and under stirring at room temperature, potassium permanganate 58 Itg (0.37 mmol) was dissolved in 3.2112 glacial acetic acid and 0.5111 Q of water.
1) gradually over a period of 30 minutes, then at room temperature
Stir for hours. Next, hydrogen peroxide solution was added until the color of the reaction solution disappeared, and then 5 liters of water was added, followed by extraction with chloroform. The chloroform layer was washed with water, aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain an oily substance 138#I! I got a 9. Yield 93% Infrared absorption spectrum (CHCQ3) Niji (cm”) = 1805.1760, 1605°ax Nuclear magnetic resonance spectrum (CDC93): δ (ppm)
-1,48 (3H,s>, 3.30~3.70 (2H
, m> , 3.80-4.55 (2H, m) , 4.5
5-4.90 (IH.
ｍ） 、３．９４ （３１−１，ｓ＞、４．７５ （Ｉ
Ｈ。m), 3.94 (31-1, s>, 4.75 (I
H.
ｓ＞、５．３３ （２Ｈ，ｓ＞、７．６３ （２Ｈ。s>, 5.33 (2H, s>, 7.63 (2H.
ｄ＞、８．２０ （２）（、ｄ＞。d>, 8.20 (2) (, d>.
実施例１５
２α−メチル−２β−（１−フェニル−５−テトラゾリ
ルチオ）メチルペナム−３α−カルボン酸 １，１−ジ
オキシド ｐ−ニトロベンジルエステルの製法
２α−メヂルー２β−（１−フェニル−５−テトラゾリ
ルチオ）メチルペナム−３α−カルボン酸 ｐ−ニトロ
ベンジルエステル ６５７ｆｆ１９（１，３４闘０１）
を氷酢酸１３．４１１１Ｑと水２．１鵬に溶かし、室温
、撹拌下、過マンガン酸カリウム５８ｆｆｌｆｆ （１
、６１ｍｍｏｌ＞を３０分間ｔ、＝ ワｔ： ’） ｒ
徐々に加えた後、室温にて４時間撹拌した。ついで過酸
化水素水を反応液の色が消えるまで加えた後、水を加え
、クロロホルムにて抽出した。クロロホルム層を水、炭
酸水素ナトリウム水及び飽和食塩水で順次洗浄し、無水
硫酸マグネシウムにて乾燥した。抽出液を減圧上濃縮し
、２α−メチル−２β−（１−フェニル−５−テトラゾ
リルチオ）メチルペナム−３αカルボン酸 １，１−ジ
オキシド ｐ−二１〜口ベンジルエステル６４４ｍＦｉ
を得た。収率９２％、融点１５１〜１５３°Ｃ０赤外吸
収スペク１−ル（ＫＢｒ）ニ
ジｍ；１ｘ（Ｃｍ” ） ＝ １８０５．１７６５．１
６１０．１６００．１５３０゜
核磁気共鳴スペクトル（ＣＤＣ９３）：δ（ｐｐｍ ）
〜１．５２ （３）−！、ｓ）、３．３５〜３．６０
（２Ｈ，ｍ＞ 、３．８０〜４．５５（２Ｈ，ｍ＞ 、
４．５０〜４．７０ （ＩＨ。Example 15 2α-Methyl-2β-(1-phenyl-5-tetrazolylthio)methylpenam-3α-carboxylic acid 1,1-dioxide p-nitrobenzyl ester production method 2α-Mezyru-2β-(1-phenyl-5-tetrazolylthio) Methylpenam-3α-carboxylic acid p-nitrobenzyl ester 657ff19 (1,34to01)
was dissolved in 13.4111Q of glacial acetic acid and 2.1Q of water, and 58fflff of potassium permanganate (1
, 61 mmol> for 30 minutes, = wa: ') r
After the gradual addition, the mixture was stirred at room temperature for 4 hours. Next, hydrogen peroxide solution was added until the color of the reaction solution disappeared, then water was added and extraction was performed with chloroform. The chloroform layer was washed successively with water, aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 2α-methyl-2β-(1-phenyl-5-tetrazolylthio)methylpenam-3α carboxylic acid 1,1-dioxide p-21-benzyl ester 644mFi
I got it. Yield 92%, melting point 151-153°C0 Infrared absorption spectrum (KBr) 1x (Cm”) = 1805.1765.1
610.1600.1530° Nuclear magnetic resonance spectrum (CDC93): δ (ppm)
~1.52 (3)-! , s), 3.35-3.60
(2H, m>, 3.80-4.55 (2H, m>,
4.50-4.70 (IH.
ｍ＞ 、４．７４ （’Ｉｆ−１．ｓ＞、５．３１（２
Ｈ，ｓ）、７．４８ （５Ｈ，ｓ）、７．６１ （２
Ｈ，ｄ）、８．１８ （２Ｈ。m>, 4.74 ('If-1.s>, 5.31 (2
H,s), 7.48 (5H,s), 7.61 (2
H, d), 8.18 (2H.
ｄ）。d).
実施例１６
２α−メチル−２β−チオシアナートメチルペナム−３
α−カルボン酸 １，１−ジオキシドナトリウム塩の製
法
酢酸エチル５．５１１１Ｑと水３．５購中、２α−メチ
ル−２β−チオシアナートメチルペナム−３α−カルボ
ン酸 １，１−ジオキシド ｐ−ニトロベンジルエステ
ル３００ｍｇを炭酸水素ナトリウム６０１ｒ１ｇ存在下
に１０％パラジウム炭素６０ηを用いて低圧下、室温に
て水素添加を行なった。水素吸収が認められなくなった
後、反応液をろ過し、分取した水層をＭＣＩゲル（三菱
化成社製ＣＨＰ−２０Ｐ）を用いたカラムクロマトグラ
フィーに付し、溶出液を凍結乾燥して微黄色粉末１３ｍ
ｇを得た。融点１４０〜１５０℃（分解）。Example 16 2α-methyl-2β-thiocyanatomethylpenam-3
Preparation of α-carboxylic acid 1,1-dioxide sodium salt In 5.5111Q of ethyl acetate and 3.5 units of water, 2α-methyl-2β-thiocyanatomethylpenam-3α-carboxylic acid 1,1-dioxide p - 300 mg of nitrobenzyl ester was hydrogenated at room temperature under low pressure using 10% palladium on carbon 60η in the presence of 601 r1 g of sodium hydrogen carbonate. After no hydrogen absorption was observed, the reaction solution was filtered, the separated aqueous layer was subjected to column chromatography using MCI gel (CHP-20P, manufactured by Mitsubishi Chemical Corporation), and the eluate was freeze-dried to give a finely divided solution. yellow powder 13m
I got g. Melting point 140-150°C (decomposition).
赤外吸収スペクトル（ＫＢｒ）ニ
ジｍａｘ ＜Ｃｔｎ−’ ） 〜２１５２．１７８０．
１６２２゜核磁気共鳴スペクトル（Ｄ２０＞：
δ（ｐｐｍ ）〜１．６９ （３Ｈ，ｓ＞、３．３４〜
３．８０ （２１−１，ｍ＞ 、３．９２ （２Ｈ，ｓ
＞、４．４２ （１Ｈ，ｓ）、５．０５〜５．１１（１
Ｈ，ｍ＞。Infrared absorption spectrum (KBr) max<Ctn-') ~2152.1780.
1622° nuclear magnetic resonance spectrum (D20>: δ (ppm) ~ 1.69 (3H, s>, 3.34 ~
3.80 (21-1,m> , 3.92 (2H,s
>, 4.42 (1H, s), 5.05-5.11 (1
H, m>.
実施例１７
２α−メチル−２β−（１−メチル−５−テトラゾリル
）チオメチルペナム−３α−カルボンＩ！１．１−ジオ
キシド ナトリウム塩の製法酢酸エチル９ｍｌと水６回
中、２α−メチル−２β−（１−メチル−５−テトラゾ
リル）チオメチルペナム−３α−カルボン酸 １，１−
ジオキシド ｐ−ニトロベンジルエステル５９０１Ｑを
炭酸水素ナトリウム１０３ｍｇ存在下に１α％パラジウ
ム炭素１１８Ｉｎｇを用いて低圧下、空温にて水素添加
を行なった。水素吸収が認められなくなった後、反応液
をろ過し、分取した水層をＭＣＩゲル（三菱化成社製Ｃ
ＨＰ−２０Ｐ）を用いたカラムクロマトグラフィーに付
し、溶出液を凍結乾燥して微黄色粉末１８３〜を得た。Example 17 2α-Methyl-2β-(1-methyl-5-tetrazolyl)thiomethylpenam-3α-carvone I! 1. Preparation of 1-dioxide sodium salt In 9 ml of ethyl acetate and 6 times of water, 2α-methyl-2β-(1-methyl-5-tetrazolyl)thiomethylpenam-3α-carboxylic acid 1,1-
Dioxide p-nitrobenzyl ester 5901Q was hydrogenated in the presence of 103 mg of sodium hydrogen carbonate using 118 Ing of 1α% palladium on carbon under low pressure and at air temperature. After hydrogen absorption was no longer observed, the reaction solution was filtered and the separated aqueous layer was collected using MCI gel (C manufactured by Mitsubishi Chemical Corporation).
The eluate was subjected to column chromatography using HP-20P), and the eluate was freeze-dried to obtain pale yellow powder 183~.
融点１５７〜１５８℃（分解）。Melting point 157-158°C (decomposed).
赤外吸収スペクトル（ＫＢｒ）ニ
ジｍａｘ （ｃｍ” ） ＝ １７８５．１６２８゜
核磁気共鳴スペクトル（Ｄ２０）：
δ（ｐｐｍ ）〜１．６２ （３Ｈ，ｓ＞、３．３９（
ＩＨ，ｄｄ）、３．６７ （１Ｈ，ｄｄ）、４．０６
（３Ｈ，ｓ＞、４．１０〜４．１１（２Ｈ，ｍ） 、
４． ４．７ （１トｔ、ｓ＞ 、４．９９〜
５．０５ （１Ｈ，ｍ＞。Infrared absorption spectrum (KBr) max (cm”) = 1785.1628° Nuclear magnetic resonance spectrum (D20): δ (ppm) ~ 1.62 (3H,s>, 3.39 (
IH, dd), 3.67 (1H, dd), 4.06
(3H, s>, 4.10-4.11 (2H, m),
4. 4.7 (1t, s>, 4.99~
5.05 (1H, m>.
実施例１８
２α−メチル−２β−く１−フェニル−５−テトラゾリ
ル）、チオメチルペナム−３α−カルボン酸 １，１−
ジオキシド ナトリウム塩の製法
酢酸エチル３．５＋ｎＱと水２．５ｍ１２中、２α−メ
チル−２β−（１−フェニル−５−テトラゾリル）チオ
メチルペナム−３α−カルボン１１．１−ジオキシド
ｐ−ニトロベンジルエステル２４５■を炭酸水素ナトリ
ウム３８η存在下に１０％パラジウム炭素５０ｍｙを用
いて低圧下、室温にて水素添加を行なった。水素吸収が
認められなくなった後、反応液をろ過し、分取した水層
をＭＣＩゲル（三菱化成社ＭＣＩ−ＩＰ−２０Ｐ）を用
いたカラムクロマトグラフィーに付し、溶出液を凍結乾
燥して微黄色粉末１１７ｆｆｉｆｆを得た。融点２０８
〜２１０℃（分解）。Example 18 2α-methyl-2β-1-phenyl-5-tetrazolyl), thiomethylpenam-3α-carboxylic acid 1,1-
Preparation of Dioxide Sodium Salt In 3.5+nQ ethyl acetate and 2.5 ml of water, 2α-methyl-2β-(1-phenyl-5-tetrazolyl)thiomethylpenam-3α-carvone 11.1-dioxide
245 ml of p-nitrobenzyl ester was hydrogenated at room temperature under low pressure using 50 ml of 10% palladium on carbon in the presence of 38 η of sodium bicarbonate. After hydrogen absorption was no longer observed, the reaction solution was filtered, the separated aqueous layer was subjected to column chromatography using MCI gel (MCI-IP-20P, Mitsubishi Chemical Corporation), and the eluate was freeze-dried. 117ffiff of slightly yellow powder was obtained. Melting point 208
~210°C (decomposition).
赤外吸収スペクトル（ＫＢｒ）：
νｍａｘ ＜ｃｍ−Ｉ） ＝ １７８２．１６２０゜
核磁気共鳴スペクトル（Ｄ２０）：
δ（ｐｐｍ ）〜１．５５ （３Ｈ，ｓ＞、３．２５〜
３、 ８０ （２ト１． ｍ＞ 、 ４．
１２〜４． １４（２Ｈ，ｍ＞ 、４．４５ （１ｔ
−１，Ｓ）、４．９６〜５．１１ （ＩＨ，ｍ＞ 、７
．６７（５Ｈ，Ｓ）。Infrared absorption spectrum (KBr): νmax <cm-I) = 1782.1620° Nuclear magnetic resonance spectrum (D20): δ (ppm) ~ 1.55 (3H, s>, 3.25 ~
3, 80 (2t1.m>, 4.
12-4. 14 (2H, m> , 4.45 (1t
-1, S), 4.96 to 5.11 (IH, m>, 7
．． 67 (5H, S).
（以 上）
浦Ｔの内容
手続ネｍ正書（自航
昭和６２年１月２１日
昭和６１年特許願第４３７６３号
２ 発明の名称
２β−置換チオメチルペニシリン誘導体３ 補正をする
者
事件との関係 特許出願人
大ｍ薬品工業株式会社
４ 代 理 人
大阪市東区平野町２の１０ 沢の鶴ビル自 発
６ 補正により増加する発明の数
な し
７ 補正の対象
明細書中「発明の詳細な説明」の項
８ 補正の内容
別紙添附の通り
１ 明細書第１頁下から第２行、第４頁下から第２行及
び第５頁第１２行に「ベンツチアゾール」とあるを「ベ
ンゾチアゾール」と訂正する。(Above) Ura T's content procedure manual (January 21, 1988 Patent Application No. 43763 of 1988 2 Title of the invention 2 β-substituted thiomethylpenicillin derivative 3 Related Patent Applicant Omori Yakuhin Kogyo Co., Ltd. 4 Agent Sponsored by Sawanotsuru Building, 2-10 Hiranocho, Higashi-ku, Osaka City 6 No increase in the number of inventions due to the amendment 7 ``Detailed Description of the Invention'' in the specification subject to the amendment Section 8 Contents of the amendment As attached to the attached sheet 1. In the second line from the bottom of page 1 of the specification, the second line from the bottom of page 4, and the 12th line of page 5, the term ``benzthiazole'' has been replaced with ``benzothiazole.'' I am corrected.
２ 明細書第３頁第２〜３行に「酵素、に」とあるを「
酵素に」と訂正する。2. On page 3 of the specification, lines 2-3, the phrase “enzyme,” has been replaced with “
to enzymes,” he corrected.
３ 明細書第２３頁第５行に「酢酸」とあるを「酢酸エ
チル」と訂正する。3. On page 23, line 5 of the specification, "acetic acid" is corrected to "ethyl acetate."
４ 明細書第３２頁第８行にｒｃＤｃ９３Ｊとあるをｒ
ｃＨｃＱ３Ｊと訂正する。4 rcDc93J on page 32, line 8 of the specification.
Correct it to cHcQ3J.
５ 明細書第３３頁第２行及び同頁第５行に「ベンゾヒ
ドリル」とあるを「ベンズヒドリル」と訂正する。5. On page 33 of the specification, line 2 and line 5 of the same page, the words "benzohydryl" are corrected to "benzhydryl."
６ 明細書第３５頁第１１行にｒ （ｓ、 １Ｈ，３−
Ｈ）」とあるをｒ（Ｓ、ＩＨ）Ｊど訂正する。6 In the specification, page 35, line 11, r (s, 1H, 3-
Correct "H)" to r(S, IH)J.
７ 明細書第３７頁第３行にｒ２Ｈ，ｄ）Ｊとあるをｒ
２Ｈ）Ｊと訂正する。7 In the third line of page 37 of the specification, r2H, d) J is replaced by r.
2H) Correct it as J.
８ 明細書第３９頁第８行に「２βチオ」とあるを１２
β−チオ」と訂正する。8 In the specification, page 39, line 8, “2βthio” is written as 12
Beta-thio,” he corrected.
９ 明細書第３９頁第９行及び第４２頁第１２行に「３
αカルボン」とあるを「３α−カルボン」と訂正する。9 In the specification, page 39, line 9 and page 42, line 12, “3
Correct the text "α-carvone" to "3α-carvone."
゛ （以 上）゛ (that's all)
Claims (1)
ル基、低級アルキルチオカルバモイル基又は置換基とし
て低級アルキル基若しくはフエニル基を有することのあ
るテトラゾリル基、ベンツチアゾール基若しくはチアジ
アゾール基を示す。〕 で表わされるペニシリン誘導体、その塩及びそのエステ
ル。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Indicates a tetrazolyl group, a benzthiazole group, or a thiadiazole group that may have a group. ] Penicillin derivatives, salts thereof, and esters thereof.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61043763A JPS62198687A (en) | 1986-02-27 | 1986-02-27 | 2beta-substituted thiomethylpenicillin derivative |
| US07/016,114 US4861768A (en) | 1986-02-27 | 1987-02-18 | 2 β-substituted thiomethylpenicillin derivatives and their preparation and use |
| AU69094/87A AU573115B2 (en) | 1986-02-27 | 1987-02-20 | 2b-substituted thiomethylpenicillin derivatives |
| CA000530613A CA1281319C (en) | 1986-02-27 | 1987-02-25 | 2.beta.-SUBSTITUTED THIOMETHYLPENICILLIN DERIVATIVES AND THEIR PREPARATION AND USE |
| EP87301699A EP0236074B1 (en) | 1986-02-27 | 1987-02-26 | 2beta-substituted thiomethylpenicillin derivatives and their preparation and use |
| ES198787301699T ES2038656T3 (en) | 1986-02-27 | 1987-02-26 | DERIVATIVES OF THYOMETHYLPENICILLIN SUBSTITUTED IN BETA AND ITS PREPARATION AND USE. |
| DE8787301699T DE3775794D1 (en) | 1986-02-27 | 1987-02-26 | 2-BETA SUBSTITUTED THIOMETHYL PENICILLINE DERIVATIVES AND THEIR PRODUCTION AND USE. |
| KR1019870001744A KR920005829B1 (en) | 1986-02-27 | 1987-02-27 | Process for preparing 2 beta substituted thiomethyl penicillin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61043763A JPS62198687A (en) | 1986-02-27 | 1986-02-27 | 2beta-substituted thiomethylpenicillin derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62198687A true JPS62198687A (en) | 1987-09-02 |
| JPH0523271B2 JPH0523271B2 (en) | 1993-04-02 |
Family
ID=12672794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61043763A Granted JPS62198687A (en) | 1986-02-27 | 1986-02-27 | 2beta-substituted thiomethylpenicillin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62198687A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6770759B2 (en) | 1997-12-29 | 2004-08-03 | Research Corporation Technologies, Inc. | Penicillanic acid derivative compounds and methods of making |
| US6906054B2 (en) | 1999-04-15 | 2005-06-14 | Research Corporation Technologies, Inc. | Compositions for inhibiting beta-lactamase |
| US6916801B2 (en) | 2001-07-24 | 2005-07-12 | Alamx, Llc | 7-Alkylidene-3-substituted-3-cephem-4-carboxylates as β-lactamase inhibitors |
| US7022691B2 (en) | 2002-04-04 | 2006-04-04 | John D. Buynak | Inhibitors of serine and metallo-β-lactamases |
| CN114423766A (en) * | 2019-09-11 | 2022-04-29 | 丹诺医药(苏州）有限公司 | Penicilliane derivatives for the treatment of bacterial infections |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5657788A (en) * | 1979-09-26 | 1981-05-20 | Pfizer | Acetoxymethylpenam compound as betaalactamase inhibitor |
| EP0170192A1 (en) * | 1984-07-30 | 1986-02-05 | Merck & Co. Inc. | Penicillin derivatives as anti-inflammatory and antidegenerative agents |
-
1986
- 1986-02-27 JP JP61043763A patent/JPS62198687A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5657788A (en) * | 1979-09-26 | 1981-05-20 | Pfizer | Acetoxymethylpenam compound as betaalactamase inhibitor |
| EP0170192A1 (en) * | 1984-07-30 | 1986-02-05 | Merck & Co. Inc. | Penicillin derivatives as anti-inflammatory and antidegenerative agents |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6770759B2 (en) | 1997-12-29 | 2004-08-03 | Research Corporation Technologies, Inc. | Penicillanic acid derivative compounds and methods of making |
| US7125986B2 (en) | 1997-12-29 | 2006-10-24 | Southern Methodist University Foundation For Research | Penicillanic acid derivative compounds and methods of making |
| US6906054B2 (en) | 1999-04-15 | 2005-06-14 | Research Corporation Technologies, Inc. | Compositions for inhibiting beta-lactamase |
| US6916801B2 (en) | 2001-07-24 | 2005-07-12 | Alamx, Llc | 7-Alkylidene-3-substituted-3-cephem-4-carboxylates as β-lactamase inhibitors |
| US7488724B2 (en) | 2001-07-24 | 2009-02-10 | Southern Methodist University Foundation For Research | 7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors |
| US7022691B2 (en) | 2002-04-04 | 2006-04-04 | John D. Buynak | Inhibitors of serine and metallo-β-lactamases |
| CN114423766A (en) * | 2019-09-11 | 2022-04-29 | 丹诺医药(苏州）有限公司 | Penicilliane derivatives for the treatment of bacterial infections |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0523271B2 (en) | 1993-04-02 |
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