JPH0288578A - Production or carbapenem compound - Google Patents
Production or carbapenem compoundInfo
- Publication number
- JPH0288578A JPH0288578A JP63239636A JP23963688A JPH0288578A JP H0288578 A JPH0288578 A JP H0288578A JP 63239636 A JP63239636 A JP 63239636A JP 23963688 A JP23963688 A JP 23963688A JP H0288578 A JPH0288578 A JP H0288578A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- ester
- group
- groups
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 20
- -1 carbapenem compound Chemical class 0.000 title abstract description 122
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 125000006239 protecting group Chemical group 0.000 claims abstract description 14
- 125000003277 amino group Chemical group 0.000 claims abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract 2
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 7
- 230000001568 sexual effect Effects 0.000 claims 1
- KEAYDQMHQHNAIG-UHFFFAOYSA-N 1-sulfanylpyrazolidine Chemical compound SN1CCCN1 KEAYDQMHQHNAIG-UHFFFAOYSA-N 0.000 abstract description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 239000012442 inert solvent Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000003863 metallic catalyst Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 125000002252 acyl group Chemical group 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 150000002148 esters Chemical group 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000005917 acylation reaction Methods 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 8
- 125000005907 alkyl ester group Chemical group 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 229960003975 potassium Drugs 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- 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 5
- 239000008272 agar Substances 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 150000001342 alkaline earth metals Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 4
- 229960000484 ceftazidime Drugs 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical class OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 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
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003113 dilution method Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- ZTILHLWDFSMCLZ-UHFFFAOYSA-N prop-2-enylhydrazine Chemical class NNCC=C ZTILHLWDFSMCLZ-UHFFFAOYSA-N 0.000 description 3
- YQVZBINVXFLJQV-UHFFFAOYSA-N pyrazolidine-4-thiol Chemical class SC1CNNC1 YQVZBINVXFLJQV-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 241000588919 Citrobacter freundii Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 229960004821 amikacin Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- SYLKGLMBLAAGSC-QLVMHMETSA-N cefsulodin Chemical compound C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@@H](C=3C=CC=CC=3)S(O)(=O)=O)[C@H]2SC1 SYLKGLMBLAAGSC-QLVMHMETSA-N 0.000 description 2
- 229960003202 cefsulodin Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- ATBLMLKOVBKADA-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCCCCC.CCOC(C)=O ATBLMLKOVBKADA-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000005425 toluyl group Chemical group 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical class C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- UDCDOGJLLNHBLK-UHFFFAOYSA-N 1,3-oxazol-3-ium;hydroxide Chemical compound O.C1=COC=N1 UDCDOGJLLNHBLK-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
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- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- TZBFFNOXAYRULF-UHFFFAOYSA-N 2-[2-(ethylamino)-2-(3-methylthiophen-2-yl)ethyl]aniline Chemical compound S1C=CC(C)=C1C(NCC)CC1=CC=CC=C1N TZBFFNOXAYRULF-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 description 1
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
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- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical group CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
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- 241000947836 Pseudomonadaceae Species 0.000 description 1
- 101150030723 RIR2 gene Proteins 0.000 description 1
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- 241000256215 Spongomorpha aeruginosa Species 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
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- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
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- HFEHLDPGIKPNKL-UHFFFAOYSA-N allyl iodide Chemical compound ICC=C HFEHLDPGIKPNKL-UHFFFAOYSA-N 0.000 description 1
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- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical class SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000007853 buffer solution Substances 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
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- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001715 carbamic acids Chemical class 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
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- 150000004653 carbonic acids Chemical class 0.000 description 1
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- 150000001733 carboxylic acid esters Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
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- 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
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical group CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
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- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical group C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- CCJXQRNXZKSOGJ-UHFFFAOYSA-N ethylsulfonyl ethanesulfonate Chemical compound CCS(=O)(=O)OS(=O)(=O)CC CCJXQRNXZKSOGJ-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical group [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical class O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 150000003218 pyrazolidines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、新規なカルバペネム化合物の製造法に関し、
さらに詳しくは、次式
ソ基における反応性誘導体に変えた後、式し、
Ｒ２及びＲ′は各々独立にアミノ基の保護基を表わす、
で示されるカルバペネム化合物の簡便で且つ収率のよい
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing carbapenem compounds,
More specifically, after converting into a reactive derivative at the so group of the following formula, R2 and R' each independently represent a protecting group for the amino group, and the simple and high-yield production of a carbapenem compound represented by the following formula: Regarding the law.
上記式（１）のカルバペネム化合物は、本発明者らが先
に提案した（特願昭６３−３１０３３号参照）優れた抗
菌活性を有し抗菌剤として有用な次式
式中、Ｒ１は上記と同一の意味を育する、で示される化
合物を環化せしめ、
得られる次式
式中、Ｒ１は上記と同一の意味を有する、で示される化
合物をアンル化して該化合物のすキソ基における反応性
誘導体に変えた後、次式で示される化合物の合成中間体
として有用である。The carbapenem compound of the above formula (1) has excellent antibacterial activity and is useful as an antibacterial agent, which was previously proposed by the present inventors (see Japanese Patent Application No. 63-31033). The reactivity of the suxo group of the compound is determined by cyclizing the compound represented by the following formula, in which R1 has the same meaning as above. After being converted into a derivative, it is useful as a synthetic intermediate for the compound represented by the following formula.
かくして、本発明によれば、それ自体既知の次式中、Ｒ
２及びＲ３は上記と同一の意味を有する、
で示されるメルトカプトピラゾリジン又はその反応性誘
導体と反応せしめることを特徴とする次式式中、ＲＩ
Ｒ２及びＲ１は上記と同一の意味を有する
で示される化合物の製造法が提供される。Thus, according to the invention, in the per se known formula, R
2 and R3 have the same meanings as above, in the following formula, RI
There is provided a method for producing a compound represented by R2 and R1 having the same meanings as above.
本発明の上記方法は、上記反応の全工程を、中間生成物
を単離・精製することなく連続して同一反応容器内で（
すなわちワン・ボッｉ・で）行なうことができ、したが
って、式（１）の化合物を大量に製造する工業的製造に
おいて特に有利である。The method of the present invention allows all steps of the above reaction to be carried out continuously in the same reaction vessel without isolating or purifying intermediate products (
That is, it can be carried out in one batch), and is therefore particularly advantageous in industrial production in which the compound of formula (1) is produced in large quantities.
なお、本明細書において、「低級」なる語は、この語が
付された基または化合物の炭素原子数が１〜７個、好ま
しくは１〜４個であることを意味する。In this specification, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.
また、「カルポキ／ル基の保護基」はペグチド化学の分
野においてカルポキンル基の保護基としてそれ自体既知
の任意のカルホキノル保護基であることができ、例えば
カルボン酸のエステル残基を例示することができる。か
かるエステル残基の代表例としては、以下のものか挙げ
られる＝（ａ）低級アルキルエステル残基：例えばメチ
ルエステル、エチルエステル、プロピルエステル、イソ
７０ピルエステル、ブチルエステル、イソブチルエステ
ル、ｔｅｒｔ−ブチルエステル、ペンチルエステル、ヘ
キシルエステルなど。Furthermore, the "carpoquinol protecting group" can be any carpoquinol protecting group known per se as a carpoquinol protecting group in the field of pegtide chemistry, and examples include carboxylic acid ester residues. can. Representative examples of such ester residues include the following: (a) Lower alkyl ester residues, such as methyl ester, ethyl ester, propyl ester, iso70 pyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.
（ｂ） 適当な置換基を少なくとも１個を有していて
もよい低級アルキルエステル残基：例えばアセトキノメ
チルエステル、プロピオニルオキシメチルエステル、プ
チリルオキンメチルエステル、バレリルオキンメチルエ
ステル、ピバロイルオキンメチルエステル、ヘキサノイ
ルオキシメチルエステル、ｌ−（または２−）アセトキ
ンエチルエステル、１−（または２−または３−）アセ
トキシプロピルエステル、ｌ（または２−または３また
は４−）アセトモ／ブチルエステル、１−（または２−
）プロビオニルオキンエチルエステル、１−（または２
−まｔ；は３−）プロピオニルオキシプロピルエステル
、ｌ−（または２−）ブチリルオキシエチルエステル、
１−（または２−）インブチリルオキンエチルエステル
、１−（または２−）ピバロイルオキシエチルエステル
、ｌ−（または２−）ヘキサノイルオキシエチルエステ
ル、イソブチリルオキシメチルエステル、２−エチルプ
チリルオキンメチルエステル、３．３−ジメチルブチリ
ルオキンメチルエステル、ｌ−（または２−）ペンタノ
イルオキシエチルエステル等の低級アルケノイルオキン
（低級）アルキルエステル残基：２−メトルエチルエス
テル等の低級アルカンスルホニル（低級）アルキルエス
テル残基；２ヨードエチルエステル、２，２．２−１リ
クロロエヂルエステル等のモノ（またはジまたはトリ）
ハロ（低級）アルキルエステル残基；メトキンカルボニ
ルオキシエチルエステル、エトキシカルボニルオキシメ
チルエステル、プロポキシカルボニルオキシメチルエス
テル、ｔｅｒｔ−ブトキシ力ルポニルオキンメチルエス
テル、２−メトキンカルボニルオキシエチルエステル、
ｌ−エトキシ力ルポニノｖオキシエチルエステル、ｌ−
イングロボキシ力ルポニルオキシエチルエステル等の低
級アルフキ／カルボニルオキシ（低級）アルキルエステ
ル残基；フタリジリデン（低級）アルキルエステル残基
； （５−メチル−２−オキソ−１，３−ジオキソール
ー４−イル）メチルエステル、（５−エチル−２−オキ
ソ−１，３−ジオキソ−ルー４イル）メチルエステル、
（５−／ロビルー２−オキンー１．３−ジオキソ−ルー
４−イル）エチルエステル等の（５−低級アルキルー２
−オキソ１．３−ジオキソ−ルー４−イル）（低級）ア
ルキルエステルなど。(b) Lower alkyl ester residues which may have at least one suitable substituent: for example, acetoquinomethyl ester, propionyloxymethyl ester, butyryluoquine methyl ester, valeryluoquine methyl ester, pivaloy Luoquin methyl ester, hexanoyloxymethyl ester, l-(or 2-) acetoquine ethyl ester, l-(or 2- or 3-) acetoxypropyl ester, l(or 2- or 3 or 4-) acetomo/ Butyl ester, 1-(or 2-
) Probionyl oquin ethyl ester, 1-(or 2
- or 3-) propionyloxypropyl ester, l-(or 2-) butyryloxyethyl ester,
1-(or 2-) imbutyryl ookine ethyl ester, 1-(or 2-) pivaloyloxyethyl ester, l-(or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2- Lower alkenoyluoquine (lower) alkyl ester residues such as ethylbutyryluoquine methyl ester, 3,3-dimethylbutyryluoquine methyl ester, l-(or 2-)pentanoyloxyethyl ester, etc.: 2-metholethyl Lower alkanesulfonyl (lower) alkyl ester residues such as esters; mono (or di or tri) such as 2-iodoethyl ester, 2,2.2-1-lichloroethyl ester, etc.
Halo (lower) alkyl ester residue; methquine carbonyloxyethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxylponyloxymethyl ester, 2-methynecarbonyloxyethyl ester,
l-ethoxyl oxyethyl ester, l-
Lower alkyl/carbonyloxy (lower) alkyl ester residues such as ingloboxylponyloxyethyl ester; phthalidylidene (lower) alkyl ester residues; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxo-4yl)methyl ester,
(5-Lower alkyl-2-oxene-1,3-dioxo-4-yl)ethyl ester
-oxo1,3-dioxo-4-yl) (lower) alkyl ester, etc.
（Ｃ）低級アルケニルエステル残基：例えばビニルエス
テル、アリルエステルなど。(C) Lower alkenyl ester residue: for example, vinyl ester, allyl ester, etc.
（ｄ） 低級アルキニルエステル残基：例えばエチニ
ルエステル、プロピニルエステルなど。(d) Lower alkynyl ester residue: for example, ethynyl ester, propynyl ester, etc.
（ｅ） 適当な置換基を少なくとも１個有していても
よいアラルキルエステル残基：例えばベンジルエステル
、４−メトキシベンジルエステル、４ニトロベンジルエ
ステル、フェネチルエステル、トリチルエステル、ベン
ズヒドリルエステル、ビス（メトキノフェニル）メチル
エステル、３．４ジメトキシベンジルエステル、４−ヒ
ドロキシ−３＋５−ジｔｅｒｔ−ブチルベンジルエステ
ルなど。(e) Aralkyl ester residues optionally having at least one suitable substituent: for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxybenzyl ester) nophenyl) methyl ester, 3.4 dimethoxybenzyl ester, 4-hydroxy-3+5-di-tert-butylbenzyl ester, etc.
（［）適当な置換基を少なくとも１個有していてもよい
アリールエステル残基：例えばフェニルエステル、４−
クロロフェニルエステル、トリルエステル、Ｌｅｒｔ−
ブチルフェニルエステル、キシリルエステル、メシチル
エステル、クメニルエステルなと。([) Aryl ester residue optionally having at least one suitable substituent: e.g. phenyl ester, 4-
Chlorophenyl ester, tolyl ester, Lert-
Butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester.
（ｇ） その他二フタリ・／゛ルエステルど。(g) Other diphthalates, esters, etc.
かかるカルボキシル基の保護基のうち好ましいものとし
ては、ニトロ基で置換されていてもよいフェニル−低級
アルキル基、および低級アルケニル基が挙げられ、さら
に好ましくは４−ニトロベンジル基が挙げられる。Among such carboxyl group-protecting groups, preferred are phenyl-lower alkyl groups which may be substituted with nitro groups, and lower alkenyl groups, and more preferred is 4-nitrobenzyl group.
さらに、「アミ７基の保護基」は、ペプチド化学の分野
においてアミノ基の保護基としてそれ自体既知の任意の
アミノ保護基であることができ、例えば以下のものを挙
げることができる＝（ａ） 芳香族アンル基：例えば
、タロイル基；ベンゾイル、クロロベンゾイル、４−二
トロベンゾイル、４−ｔｅｒｔ−ブチルベンゾイルまた
はトルオイル等のハロゲン、ニトロもしくは低級アルキ
ルで置換されていてもよいベンゾイル基；ナフトイル基
、フェニルアセチル基、フェノキシアセチル基：ベンゼ
ンスルホニル、４−ｔｅｒｔ−ブチルベンゼンスルホニ
ル、またはトルエンスルホニル等の低級アルキルで置換
されていてもよいベンゼンスルホニル基など。Furthermore, the "amino-7 group protecting group" can be any amino-protecting group known per se as a protecting group for amino groups in the field of peptide chemistry, and can include, for example, the following = (a ) Aromatic anlu group: for example, a taroyl group; a benzoyl group optionally substituted with a halogen, nitro or lower alkyl such as benzoyl, chlorobenzoyl, 4-nitrobenzoyl, 4-tert-butylbenzoyl or toluoyl; a naphthoyl group , phenylacetyl group, phenoxyacetyl group: benzenesulfonyl group optionally substituted with lower alkyl such as benzenesulfonyl, 4-tert-butylbenzenesulfonyl, or toluenesulfonyl.
（ｂ） 脂肪族またはハロゲン化脂肪族カルボン酸ア
シル基：例えばホルミル、アセチル、ピバロイル、バレ
リル、カブリリル、ｎ−デカノイル等のアルカノイル
ル基；メタンスルホニル、カンファスルホニル等の脂肪
族置換スルホニル基；モノクロロアセチル、モノブロモ
アセチル、ジクロロアセチル、トリクロロアセチル等の
ハロゲノアセチル基など。(b) Aliphatic or halogenated aliphatic carboxylic acid acyl groups: for example, alkanoyl groups such as formyl, acetyl, pivaloyl, valeryl, cabrylyl, n-decanoyl; aliphatic substituted sulfonyl groups such as methanesulfonyl and camphorsulfonyl; monochloroacetyl , halogenoacetyl groups such as monobromoacetyl, dichloroacetyl, trichloroacetyl, etc.
（Ｃ） エステル化されたカルボキシル基：例えば、
エトキシカルボニル、ｔｅｒｔ−ブチルオキシカルボニ
ル、トリクロロエトキシカルボニル、アリルオキシカル
ボニル、イソボルニルオキシカルボニル等の脂肪族オキ
シカルボニル基；フェニルオキシカルボニル基：ベンジ
ルオキシカルボニル、４−ニトロベンジルオキシカルボ
ニル等の置換もしくは未置換フェニル−低級アルキルオ
キシカルボニル基など。(C) Esterified carboxyl group: for example,
Aliphatic oxycarbonyl groups such as ethoxycarbonyl, tert-butyloxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl, and isobornyloxycarbonyl; phenyloxycarbonyl group: substituted or unsubstituted such as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; Substituted phenyl-lower alkyloxycarbonyl group, etc.
（ｄ）カルバモイル基またはチオカルバモイル基：例え
ばメチルカルバモイル、フェニルカルバモイル、ナフチ
ルカルバモイル等のカルバモイル基；メチルチオカルバ
モイル、フェニルチオカルバモイル、ナフチルチオカル
バモイル等のチオカルバモイル基など。(d) Carbamoyl group or thiocarbamoyl group: for example, a carbamoyl group such as methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl; thiocarbamoyl group such as methylthiocarbamoyl, phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.
かかるアミノ基の保護基の中で、好ましいものとしては
、ホルミル
アリルオキシカルボニル基、エトキンカルボニル基等が
挙げられる。Among such amino group-protecting groups, preferable ones include formylallyloxycarbonyl group, etquin carbonyl group, and the like.
本発明により提供される式（１）で示される化合物の製
造法を反応式で示せば、以下のとおりである。The reaction formula of the method for producing the compound represented by formula (1) provided by the present invention is as follows.
反応式１
式中 ＲＩＲ２およびＲ３は上記と同一の意味を存する
。Reaction Scheme 1 In the formula, RIR2 and R3 have the same meanings as above.
以下、本発明の製造法をさらに詳細に説明する。The manufacturing method of the present invention will be explained in more detail below.
工程（ａ）：
工程（、）は、出発原料である式（ＩＩ）の化合物に金
属触媒を作用させることによって環化せしめ、式（１）
で示されるオキソ化合物を得る工程である。Step (a): In the step (,), the starting material compound of formula (II) is cyclized by acting on a metal catalyst to form the compound of formula (1).
This is a process for obtaining an oxo compound represented by
該環化は、例えば式（ｎ）の化合物を不活性有機溶媒、
たとえばメタノール、エタノール、ｎ−グロバノール、
イングロバノール、ｎ−ブタノール等のアルコール類；
テトラヒドロフラン、ジエチルエーテル、ジオキサン等
のエーテル類；酢酸エチル等のエステル類；ジクロロメ
タン、クロロホルム、四塩化炭素等のハロゲン化炭化水
素類；アセトン、ジメチルホルムアミド、ピリジンアセ
トニトリル等の中から適当に選択された溶媒、好適には
アセトンまたは酢酸エチル中で、金属触媒、例えば、ビ
ス（アセチルアセトナト） Ｃｕ （ＩＩ）、硫酸銅、
銅粉末、酢酸ロジウム（■）、オクタン酸ロジウム（■
）、または四酢酸鉛等、好適にはオクタン酸ロジウム（
ｎ）の存在下に、室温ないし溶媒の還流温度で１〜５時
間撹拌することによって実施することができる。The cyclization can be carried out, for example, by treating the compound of formula (n) with an inert organic solvent,
For example, methanol, ethanol, n-globanol,
Alcohols such as ingbanol and n-butanol;
Ethers such as tetrahydrofuran, diethyl ether, dioxane; esters such as ethyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; solvent appropriately selected from acetone, dimethylformamide, pyridine acetonitrile, etc. , preferably in acetone or ethyl acetate, using a metal catalyst such as bis(acetylacetonato)Cu(II), copper sulfate,
Copper powder, rhodium acetate (■), rhodium octoate (■
), or lead tetraacetate, preferably rhodium octoate (
This can be carried out by stirring in the presence of n) at room temperature to the reflux temperature of the solvent for 1 to 5 hours.
上記金属触媒の使用量は特に臨界的ではなく、適宜変更
することができるが通常式（ｎ）の化合物に対して０．
２〜２．０重量％、より好ましくは０、５〜１．０重量
％用いられる。これにより式（Ｉ［Ｉ）の化合物がほぼ
定員的に生成する。The amount of the metal catalyst used is not particularly critical and can be changed as appropriate, but it is usually 0.00000000 for the compound of formula (n).
It is used in an amount of 2 to 2.0% by weight, more preferably 0.5 to 1.0% by weight. As a result, the compound of formula (I[I) is produced almost at capacity.
反応終了後、反応混合物から溶媒を減圧下に留去すれば
、残渣として式（ＩＩ［）の化合物を得ることもできる
が、好適には、該反応混合物を何ら処理することなく、
同じ反応容器内でそのまま次の工程に供する。After completion of the reaction, by distilling off the solvent from the reaction mixture under reduced pressure, the compound of formula (II[) can be obtained as a residue, but preferably, without any treatment of the reaction mixture,
The mixture is directly subjected to the next step in the same reaction vessel.
工程（ｂ）：
工程（ｂ）において、式（Ｉ［［）の化合物のアシル化
は、上記工程（ａ）で得られる式（Ｉ［Ｉ）の化合物を
含む反応混合物あるいは濃縮残渣として得られる式（１
）の化合物に、適当なアンル化剤を作用させることによ
り行なうことができる。Step (b): In step (b), the acylation of the compound of formula (I [ Formula (1
) can be carried out by reacting the compound with an appropriate unlying agent.
このアシル化により上記式（Ｉ［＋）の化合物のすキソ
基における反応性誘導体である次式式中 Ｈａはアシル
基を表わし、
Ｒ１は前記と同一の意味を有する、
で示される化合物が生成する。This acylation produces a compound represented by the following formula, which is a reactive derivative at the suxo group of the compound of the above formula (I[+), in which Ha represents an acyl group and R1 has the same meaning as above. do.
しかして、上記アシル化反応に使用しうるアシル化剤と
しては次式
％式％（）
式中、Ｒａは上記と同一の意味を有する、で示される酸
もしくはその塩、又はその反応性誘導体、例えば次式
％式％）
式中、Ｈａｌはハロゲン原子を表わし、Ｒ１１は上記と
同一の意味を有する、
で示される酸ハロゲン化物や次式
％式％）
式中、Ｒ９は上記と同一の意味を有する、で示される酸
無水物等が挙げられる。Therefore, as the acylating agent that can be used in the above acylation reaction, an acid or a salt thereof, or a reactive derivative thereof, represented by the following formula % formula % () where Ra has the same meaning as above, For example, an acid halide represented by the following formula (% formula %), where Hal represents a halogen atom, and R11 has the same meaning as above, or the following formula (% formula %), where R9 has the same meaning as above. Examples include acid anhydrides having the following.
ここで Ｈａによって示される「アシル基」としては、
脂肪族アシル基、芳香族アシル基、複素環アシル基およ
び芳香族基または複素環基で置換された脂肪族アシル基
のようなカルボン酸、炭酸、スルホン酸、燐酸およびカ
ルバミン酸から誘導されるアシル基が挙げられる。かか
るアシル基の代表例を以下に掲げると、
（ａ） 脂肪族アシル基：例えばホルミル、アセチル
、プロピオニル、ブチリル、インブチリル、バレリル、
インバレリル、ピバロイル、ヘキサノイル等の低級アル
カノイル基のようなアルカノイル基；例工ｌｆメシル、
エチルスルホニル、プロピルスルホニル、イソプロピル
スルホニル、ブチルスルホニル、イソブチルスルホニル
、ペンチルスルホニル、ヘキシルスルホニル等の低級ア
ルキルスルホニル基のようなアルキルスルホニル基；例
工ばメチルカルバモイル、エチルカルバモイル等のＮ−
アルキルカルバモイル基；例えばメトキシカルボニル、
エトキシカルボニル、プロポキシカルボニル、ブトキシ
カルボニル、第三級ブトキシカルボニル等の低級アルコ
キシカルボニル基のようなアルコキシカルボニル基：例
えばビニルオキシカルボニル、アリルオキシカルボニル
等の低級アルケニルオキシカルボニル基のようなアルケ
ニルオキン力ルボニル基；例えばアクリロイル、メタク
リロイル、クロトノイル等の低級アルケノイル基のよう
なアルケノイル基：例えばシクロプロパンカルボニル、
シクロペンタンカルボニル、トクａヘキサンカルボニル
等のシクロ（低級）アルカンカルボニル基のようなシク
ロアルカンカルボニル基；燐酸ジエチルのような燐酸ジ
（低級）アルキル基など。Here, the "acyl group" represented by Ha is:
Acyls derived from carboxylic acids, carbonic acids, sulfonic acids, phosphoric acids and carbamic acids, such as aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups and aliphatic acyl groups substituted with aromatic or heterocyclic groups. Examples include groups. Representative examples of such acyl groups are listed below: (a) Aliphatic acyl groups: for example, formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl,
Alkanoyl groups such as lower alkanoyl groups such as invaleryl, pivaloyl, hexanoyl;
Alkylsulfonyl groups such as lower alkylsulfonyl groups such as ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl; for example, N- such as methylcarbamoyl, ethylcarbamoyl, etc.
Alkylcarbamoyl group; e.g. methoxycarbonyl,
Alkoxycarbonyl groups such as lower alkoxycarbonyl groups such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl; alkenyloxycarbonyl groups such as lower alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; groups; for example, alkenoyl groups such as lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl; for example, cyclopropanecarbonyl;
Cycloalkanecarbonyl groups such as cyclo(lower)alkanecarbonyl groups such as cyclopentanecarbonyl and hexanecarbonyl; di(lower)alkyl phosphate groups such as diethyl phosphate;
（ｂ） 芳香族アシル基：例えばベンゾイル、トルオ
イル、キシロイル等ののアロイル基；例え１ｆＮ−フェ
ニルカルバモイル、Ｎ−トリルカルバモイル、Ｎ−ナフ
チＪレカルバモイル等のＮ−アリールカルバモイル基；
例えばベンゼンスルホニル、トシル等のアレーンスルホ
ニル基；燐酸ジフェニル等の燐酸ジアリール基など。(b) Aromatic acyl group: for example, an aroyl group such as benzoyl, toluoyl, xyloyl; N-arylcarbamoyl group such as 1fN-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl;
For example, arenesulfonyl groups such as benzenesulfonyl and tosyl; phosphoric acid diaryl groups such as diphenyl phosphate.
（Ｃ） 複素環アシル基：例えばフロイル、テノイル
、ニコチノイル、イソニコチノイル、チアゾリルかルバ
ポニル、チアジアゾリルカルボニル、テトラゾリルカル
ボニル等の複素環カルボニル基など。(C) Heterocyclic acyl group: For example, a heterocyclic carbonyl group such as furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolyl or rubaponyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.
（ｄ） 芳香族基で置換された脂肪族アシル基：例え
ばフェニルアセチル、フェニルグロビオニル、フエ°ニ
ルヘキサノイル等のフェニル（低級）アルカノイル基の
ようなアラルカッイル基；例えばベンジルオキシカルボ
ニル
ニル
ル基のようなアラルコキシカルボニル基：例えばフェノ
キシアセチル、フエノキシグロビオニル等のフェノキシ
（低級）アルカノイル基のようなアリールオキジアルカ
ノイル
（ｅ） 複素環基で置換された脂肪族アシル基：例え
ばチエニルアセチル、イミダゾリルアセチル、フリルア
セチル、テトラゾリルアセチル、チアゾリルアセチル、
チアジアゾリルアセチル、チエニルプロピオニル、チア
ジアゾリルプロピオニル等の複素環（低級）アルカノイ
ル基のような複素環アルカノイル基など。(d) Aliphatic acyl groups substituted with aromatic groups: aralkayl groups such as phenyl (lower) alkanoyl groups such as phenylacetyl, phenylglobionyl, phenylhexanoyl; e.g. benzyloxycarbonyl groups; aralkoxycarbonyl group: for example, aryloxydialkanoyl such as phenoxy (lower) alkanoyl group such as phenoxyacetyl, phenoxyglobionyl, etc. Aliphatic acyl group substituted with a heterocyclic group: for example, thienyl acetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl,
Heterocyclic alkanoyl groups such as heterocyclic (lower) alkanoyl groups such as thiadiazolyl acetyl, thienylpropionyl, thiadiazolylpropionyl, etc.
これらのアシル基はさらに、例えばメチル、エチル、プ
ロピル、イソプロピル、ブチル、ペンチル、ヘキシル等
の低級アルキル基；例えば塩素、臭素、沃素、フッ素の
ようなハロゲン：例えばメトキシ、エトキシ、プロポキ
シ、インプロポキシ、ブトキシ、ペンチルオキシ、ヘキ
シルオキシ等の低級アルコキシ基：例えばメチルチオ、
エチルチオ、プロピルチオ、イソプロピルチオ、ブチル
チオ、ペンチルチす、ヘキシルチオ等の低級アルキルチ
オ基；ニトロ基等のような適当な置換基１個以上で置換
されていてもよく、そのような置換基を有する好ましい
アシル基としては、例えばクロロアセチル、ブロモアセ
チル、ジクロロアセチル、トリフルオロアセチル等のモ
ノ（またはジまたはトリ）ハロアルカノイル基；例えば
クロロメトキシカルボニル
２、２−トリクロロエトキシカルボニル等のモノ（また
はジまたはトリ）ハロアルコキンカルボニル基；例えば
ニトロベンジルオキシカルボニル、クロロベンジルオキ
７カルボニル、メトキンベンジルオキシカルボニル等の
ニトロ（またはハロまたは低級アルコキシ）アラルコキ
シカルボニル基；例えばフルオロメチルスルホニル、ジ
フルオロメチルスルホニル、トリフルオロメチルスルホ
ニル、トリクロロメチルスルホニル等のモノ（またはジ
またはトリ）ハロ（低級）アルキルスルホニル基等が挙
げられる。These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl; halogens such as chlorine, bromine, iodine, fluorine; methoxy, ethoxy, propoxy, impropoxy, Lower alkoxy groups such as butoxy, pentyloxy, hexyloxy: e.g. methylthio,
Lower alkylthio groups such as ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio; optionally substituted with one or more suitable substituents such as nitro group, preferred acyl groups having such substituents Examples include mono (or di or tri) haloalkanoyl groups such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl; mono (or di or tri) haloalkanoyl groups such as chloromethoxycarbonyl 2,2-trichloroethoxycarbonyl; Alcoquine carbonyl groups; e.g. nitro (or halo or lower alkoxy) aralkoxycarbonyl groups such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methquinebenzyloxycarbonyl; e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethyl Examples include mono (or di or tri) halo (lower) alkyl sulfonyl groups such as sulfonyl and trichloromethylsulfonyl.
アシル化剤としては、上記アシル基を式（ＩＩＩ）の化
合物に導入しうるものが用いられるが、一般に、上記し
た式（ＶＴ−１）で示される酸ハロゲン化物、または式
（Ｖｌ−２）で示される酸無水物が好ましく用いられる
。かかる酸ハロゲン化物の代表例としては、例えは塩化
ベンゼンスルホニル、塩化Ｐートルエンスルホニル、塩
化４−ニトロベンゼンスルホニル、塩化４−ブロモベン
ゼンルスホニル等のアレーンスルホニルハロゲン化物；
例えば塩化メタンスルホニル、塩化エタンスルホニル、
塩化トリフルオロメタンスルホニル等のさらにハロゲン
を存していてもよい低級アルカンスルホニルハロゲン化
物：例えばクロロ燐酸ジエチル等のハロ燐酸ジ（低級）
アルキル：例えばクロロ燐酸ジフェニル等のハロ燐酸ジ
アリールなどが挙げられる。As the acylating agent, those capable of introducing the above-mentioned acyl group into the compound of formula (III) are used, but generally, the acid halide represented by the above-mentioned formula (VT-1) or the formula (Vl-2) is used. An acid anhydride represented by is preferably used. Representative examples of such acid halides include arenesulfonyl halides such as benzenesulfonyl chloride, P-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, and 4-bromobenzenesulfonyl chloride;
For example, methanesulfonyl chloride, ethanesulfonyl chloride,
Lower alkanesulfonyl halides which may further contain halogen such as trifluoromethanesulfonyl chloride: For example, di(lower) halophosphates such as diethyl chlorophosphate
Alkyl: Examples include diaryl halophosphates such as diphenyl chlorophosphate.
また、酸無水物の代表例としては、例えば、無水ヘンイ
ンスルホン酸、無水ｐ−トルエンスルホン酸、無水４−
ニトロベンゼンスルホン酸等のアレーンスルホン酸無水
物；例えば無水メタンスルホン酸、無水エタンスルホン
酸、無水トリフルオロメタンスルホン酸等のハロゲンを
有していてもよい低級アルカンスルホン酸無水物などが
挙げられる。In addition, typical examples of acid anhydrides include heynosulfonic anhydride, p-toluenesulfonic anhydride, 4-
Arenesulfonic anhydrides such as nitrobenzenesulfonic acid; for example, lower alkanesulfonic anhydrides which may have a halogen such as methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, and the like.
かかるアシル化剤の中で、より好ましいものとシテは、
クロロ燐酸ジエチルおよびクロロ燐酸ジフェニル等が挙
げられる。Among such acylating agents, the more preferred ones are:
Examples include diethyl chlorophosphate and diphenyl chlorophosphate.
式（１）の化合物のアシル化反応において、アシル化剤
として式（ｒＶ）で示される遊離の酸またはその塩を使
用する場合には、常用の縮合剤の存在下に反応を行うの
が好ましい。かかる縮合剤の代表例としては以下のもの
が挙げられる：（ａ） カルボジイミド化合物二例え
はＮ 、Ｎ’−ジエチルカルボジイミド、Ｎ，Ｎ’−ジ
イソプロピルカルボ・ジイミド、Ｎ，Ｎ’−シンクロヘ
キシルカルボジイミド、Ｎ−シクロへキンルーＮ′ーモ
ルホリノエチルカルボジイミド、Ｎ−クロロへキノルー
Ｎ’−（４−’；エチルアミノシクロヘキシル）カルボ
ジイミド、Ｎ−エチル＝Ｎ’−（３−ジメチルアミノプ
ロピル
（ｂ） カルボニルジイミダゾール化合物；例えばＮ
，Ｎ’−カルボニルジイミダゾール、Ｎ 、Ｎ’カルボ
ニルビス（２−メチルイミダゾール）など。In the acylation reaction of the compound of formula (1), when using a free acid represented by formula (rV) or a salt thereof as an acylating agent, it is preferable to carry out the reaction in the presence of a commonly used condensing agent. . Representative examples of such condensing agents include: (a) Carbodiimide compounds such as N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-synchrohexylcarbodiimide, N-cyclohequinol-N'-morpholinoethylcarbodiimide, N-chlorohequinol-N'-(4-'; ethylaminocyclohexyl)carbodiimide, N-ethyl=N'-(3-dimethylaminopropyl (b) carbonyldiimidazole) Compound; for example, N
, N'-carbonyldiimidazole, N,N'carbonylbis(2-methylimidazole), and the like.
（Ｃ） ケテンイミン化合物：例えばペンタメチレン
ケテン−Ｎ−クロロヘキシルイミン、ジフェニルケテン
−Ｎ−クロロヘキシルイミンなど。(C) Ketenimine compounds: for example, pentamethyleneketene-N-chlorohexylimine, diphenylketene-N-chlorohexylimine, etc.
（ｄ）その他：例えばエトキシアセチレン、ｌアルコキ
シ−１−クロロエチレン、ポリ燐酸エチル、ポリ燐酸イ
ソプロピル、オキシ塩化燐、三塩化燐、塩化チオニル、
塩化オキザリル、２−エチル−７−ヒトロキンベンズイ
ソキサゾリウム塩、２−エチル−５−（ｍ−スルホフェ
ニル）インオキサゾリウムヒドロキシド分子内塩、１−
（ｐクロロベンゼンスルホニルオキシ）−６−クロロＩ
Ｈ−ベンゾトリアゾール、およびＮ、Ｎ−ジメチルホル
ムアミドと塩化チオニル、ホスゲンあるいはオキシ塩化
燐等との反応によって調製した所謂ビルスマイヤー試薬
なと。(d) Others: For example, ethoxyacetylene, l-alkoxy-1-chloroethylene, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride,
Oxalyl chloride, 2-ethyl-7-hydroquine benzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)ine oxazolium hydroxide inner salt, 1-
(pchlorobenzenesulfonyloxy)-6-chloro I
A so-called Vilsmeier reagent prepared by the reaction of H-benzotriazole and N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.
また、式（ＩＩＩ）の化合物のアシル化反応は、好適に
は、例えばリチウム、ナトリウム、カリウム等のアルカ
リ金属；例えばカルシウム等のアルカリ土類金属：例え
ば水素化ナトリウム等のアルカリ金属水素化物；例えば
水素化カルシウム等のアルカリ土類金属水素化物：例え
ば水酸化ナトリウム、水酸化カリウム等のアルカリ金属
水酸化物；例えば炭酸ナトリウム、炭酸カリウム等のア
ルカリ金属炭酸塩；例えば炭酸水素ナトリウム、炭酸水
素カリウム等のアルカリ金属炭酸水素塩；例えばナトリ
ウムエトキシド、ナトリウムエトキシド、カリウム第三
級ブトキンド等のアルカリ金属アルコキシド：例えば酢
酸ナトリウム等のアルカン酸アルカリ金属塩；例えば炭
酸マグネシウム、炭酸カルシウム等のアルカリ土類金属
炭酸塩；例えばトリメチルアミン、トリエチルアミン、
Ｎ、Ｎ−ジイソプロピル−Ｎ−エチルアミン等のトリ（
低級）アルキルアミン；例えばピリジン、ピコリン、ル
チジン、Ｎ、Ｎ−ジメチルピリジンのようなＮ。The acylation reaction of the compound of formula (III) is preferably carried out using an alkali metal such as lithium, sodium, or potassium; an alkaline earth metal such as calcium; an alkali metal hydride such as sodium hydride; Alkaline earth metal hydrides such as calcium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc. alkali metal bicarbonates; alkali metal alkoxides such as sodium ethoxide, sodium ethoxide, potassium tertiary butkind; alkali metal alkanoates such as sodium acetate; alkaline earth metals such as magnesium carbonate, calcium carbonate, etc. Carbonates; e.g. trimethylamine, triethylamine,
Tri() such as N,N-diisopropyl-N-ethylamine
lower) alkylamines; N such as pyridine, picoline, lutidine, N,N-dimethylpyridine;
Ｎ−ジ（低級）アルキルアミノピリジン等のピリジン化
合物；キノリン；例えばＮ−メチルモルホリン等のＮ−
低級アルキルモルホリン：例工ばＮ。Pyridine compounds such as N-di(lower)alkylaminopyridine; Quinoline; N- such as N-methylmorpholine;
Lower alkylmorpholine: For example, N.
Ｎ−ジメチルベンジルアミン等のＮ、Ｎ−ジ（低級）ア
ルキルベンジルアミン等のような有機塩基または無機塩
基の存在下に行うことができる。This can be carried out in the presence of an organic or inorganic base such as N,N-di(lower)alkylbenzylamine such as N-dimethylbenzylamine.
上記アシル化は通常約−２０°Ｃないし約４０°Ｃの比
較的低温で実施することができる。The above acylation can be carried out at relatively low temperatures, usually from about -20°C to about 40°C.
上記反応におけるアシル化剤および塩基の使用量は特に
臨界的なものではなく、反応条件等に応じて適宜変える
ことができるが、アンル化剤も塩基も通常、出発原料で
ある式（ＩＩ）の化合物１モルに対して各々１〜２モル
、好ましくは１〜１゜５モルの割合で用いることができ
る。これにより式（Ｖ）の化合物がほぼ定量的に生成す
る。The amounts of the acylating agent and base used in the above reaction are not particularly critical and can be changed as appropriate depending on the reaction conditions, etc., but the amounts of the acylating agent and base used are usually They can be used in a ratio of 1 to 2 mol, preferably 1 to 1.5 mol, per mol of the compound. As a result, the compound of formula (V) is produced almost quantitatively.
このアシル化反応によって得られる式（Ｖ）の化合物は
反応混合物から単離することなく、同反応容器内で次式
式中、Ｒ２およびＲ３は前記と同一の意味を有する、
で示されるメルカプトピラゾリジン又はその反応性誘導
体を反応させることにより、目的化合物である式（１）
で示されるカルバペネム化合物を得ることができる。The compound of formula (V) obtained by this acylation reaction is produced in the same reaction vessel without being isolated from the reaction mixture. By reacting zolidine or its reactive derivative, the target compound of formula (1)
A carbapenem compound represented by can be obtained.
上記式（Ｖ）の化合物と式（ＩＶ）のメルカプトピラゾ
リジン又はその反応性誘導体との反応は、一般に、前記
アシル化反応において述べたと同様の有機塩基または無
機塩基の存在下に、約−４０００ないし室温程度の温度
で行なうことができる。The reaction of the compound of formula (V) with the mercaptopyrazolidine of formula (IV) or its reactive derivative is generally carried out in the presence of the same organic or inorganic base as mentioned in the acylation reaction, about - It can be carried out at a temperature of about 4,000 ℃ to room temperature.
式（ＩＶ）のメルカプトピラゾリジン又はその反応性誘
導体および上記塩基の使用量は臨界的なものではないが
、通常、それぞれ、出発原料である式（ＩＩ）の化合物
１モルに対して１〜２モル、好ましくは１，０〜１．５
モルの割合で用いることができる。The amounts of the mercaptopyrazolidine of formula (IV) or its reactive derivative and the above-mentioned base to be used are not critical, but each is usually from 1 to 1 mole of the compound of formula (II) as the starting material. 2 mol, preferably 1.0-1.5
It can be used in molar proportions.
かくして得られる式（１）の化合物は、それ自体既知の
分離、精製法により、例えば反応混合物から溶媒を減圧
上留去し、得られる残渣をシリカゲルカラムクロマトグ
ラフィーに付すことにより単離することができる。The compound of formula (1) thus obtained can be isolated by separation and purification methods known per se, for example, by distilling off the solvent from the reaction mixture under reduced pressure and subjecting the resulting residue to silica gel column chromatography. can.
また、他の方法として、反応混合物を減圧下濃縮して、
得られる濃縮液にセライトを加えて混和し、この懸濁液
にｐＨ７程度の緩衝液を加えて撹拌した後、固体成分を
分離し、その固体成分をアセトンにより抽出し、得られ
る抽出液から溶媒を減圧留去することにより、濃縮残留
物として式（１）の化合物を単離することもできる。Alternatively, the reaction mixture may be concentrated under reduced pressure.
Celite is added to the resulting concentrated solution and mixed. After adding a buffer solution with a pH of about 7 to this suspension and stirring, the solid component is separated, and the solid component is extracted with acetone, and the solvent is extracted from the resulting extract. The compound of formula (1) can also be isolated as a concentrated residue by distilling off under reduced pressure.
上記反応において使用される式（ＩＶ）のメルカプトピ
ラゾリンは、従来の文献に未載の新規な化合物であり、
例えば下記反応式２に示す経路により製造することがで
きる。The mercaptopyrazoline of formula (IV) used in the above reaction is a novel compound not described in conventional literature,
For example, it can be produced by the route shown in Reaction Formula 2 below.
反応式２
式中、Ｒ′はカルボン酸アシル基を表わし１、Ｒ２、Ｒ
３およびＨａｌは前記と同一の意味を有する。Reaction formula 2 In the formula, R' represents a carboxylic acid acyl group, and 1, R2, R
3 and Hal have the same meanings as above.
まず、ヒドラジン・水和物をホルミル化したのち、遊離
のアミン基をアセトンと反応させていわゆるシッフ塩基
として保護することにより式（■）の化合物を得る。次
にこの式（■）の化合物をハロゲン化アリル等のアリル
化剤と反応させてホルミル基が結合しているＮ原子にア
リル基を導入した後［（■）］、ホルミル基を脱離させ
、さらにシッフ塩基を加水分解して得られる式（ＩＩ）
の化合物のアミノ基をアミン基の保護基で保護し式（Ｘ
）の化合物とする。次いで、この式（Ｘ）の化合物をハ
ロゲン化剤で処理してハロゲン原子を付加させた後［式
（ＸＩ）］ 、塩基等を作用させて閉環せしめることに
より、式（Ｘｌｌ）の化合物を得ることができる。First, after formylating hydrazine hydrate, the free amine group is reacted with acetone and protected as a so-called Schiff base to obtain a compound of formula (■). Next, the compound of formula (■) is reacted with an allylating agent such as an allyl halide to introduce an allyl group to the N atom to which the formyl group is bonded [(■)], and then the formyl group is eliminated. , formula (II) obtained by further hydrolyzing the Schiff base
The amino group of the compound of formula (X
). Next, the compound of formula (X) is treated with a halogenating agent to add a halogen atom [formula (XI)], and then the compound of formula (Xll) is obtained by reacting with a base etc. to cause ring closure. be able to.
上記工程の反応は、ヒドラジン水和物を上記の反応式１
．で説明した適当な不活性有機溶媒に溶解し、溶液を一
３０’Ｃ！ないし５０°Ｃ程度の温度で撹拌下、ギ酸エ
チルを１０分間ないし２時間かけて滴下し、滴下終了後
さらに２時間ないし２０時間、０°Ｃないし８０°Ｃ程
度の温度下で撹拌した後、反応溶液をアセトンに１０分
間ないし２時間かけて添加して、さらに３０分間ないし
２０時間、００Ｃないし８０°Ｃ程度の温度で撹拌する
。In the reaction of the above step, hydrazine hydrate is reacted with the reaction formula 1 shown above.
．． Dissolve the solution in a suitable inert organic solvent as described in -30'C! Ethyl formate is added dropwise over 10 minutes to 2 hours while stirring at a temperature of about 0.degree. C. to 50.degree. C., and after the addition is completed, the mixture is further stirred at a temperature of 0.degree. C. to 80.degree. C. for 2 to 20 hours. The reaction solution is added to acetone over 10 minutes to 2 hours, and stirred for an additional 30 minutes to 20 hours at a temperature of about 00C to 80C.
上記反応で得られる式（■）で示される化合物は反応溶
媒を留去したのち、精製することなく、そのまま上記適
当な不活性有機溶媒に溶解し、これに塩基、たとえばナ
トリウムメトキサイドのメタノール溶液を加えて１０分
間ないし２時間、加熱還流する。次いで、この溶液を一
３０°Ｃから２０°Ｃ程度まで冷却したのちハロゲン化
アリルたとえば、臭化アリル、塩化アリル、ヨウ化アリ
ル等を加えて、そのままの温度で３０分間ないし２時間
撹拌したのち、さらに３０分間ないし２時間加熱撹拌し
て反応を完結させる。次に、この反応溶液を再び一３０
°Ｃないし２０°Ｃ程度にまで冷却したのち、塩酸メタ
ノール溶液に投入して、室温にて５時間ないし２０時間
程度撹拌する。反応終了後、溶媒を留去して得られる反
応生成物の塩酸塩式（ｆｆ）を適当な不活性有機溶媒に
溶解し、上記塩基、好ましくは炭酸水素ナトリウム、炭
酸水素カリウム、炭酸ナトリウム、炭酸カリウム、トリ
エチルアミン、ジイソプロピルエチルアミン等の存在下
、上記アミノ基の保護基を導入し得る所望のクロル炭酸
化合物、たとえば、ベンジルオキシカルボニルクロライ
ド、ｔｅｒｔ−ブトキシカルボニルクロライド、アリル
オキシカルボニルクロライド、エトキシカルボニルクロ
ライド、４−ニトロベンジルオキシカルボニルクロライ
ド等の化合物を作用させて、遊離のアミノ基をこれら保
護基で保護することによって、式（Ｘ）で示される化合
物へ誘導することができる。After distilling off the reaction solvent, the compound represented by the formula (■) obtained in the above reaction is dissolved as it is in the above-mentioned suitable inert organic solvent without purification. and heat under reflux for 10 minutes to 2 hours. Next, after cooling this solution to about -30°C to about 20°C, an allyl halide such as allyl bromide, allyl chloride, allyl iodide, etc. is added, and the solution is stirred at the same temperature for 30 minutes to 2 hours. Then, the mixture is further heated and stirred for 30 minutes to 2 hours to complete the reaction. Next, add this reaction solution again to 130 ml.
After cooling to about .degree. C. to 20.degree. C., the mixture is poured into a methanol solution of hydrochloric acid and stirred at room temperature for about 5 to 20 hours. After completion of the reaction, the reaction product hydrochloride formula (ff) obtained by distilling off the solvent is dissolved in a suitable inert organic solvent, and the above base, preferably sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, carbonate In the presence of potassium, triethylamine, diisopropylethylamine, etc., a desired chlorocarbonate compound capable of introducing a protecting group for the above amino group, such as benzyloxycarbonyl chloride, tert-butoxycarbonyl chloride, allyloxycarbonyl chloride, ethoxycarbonyl chloride, 4 - By acting with a compound such as -nitrobenzyloxycarbonyl chloride and protecting free amino groups with these protecting groups, the compound represented by formula (X) can be derived.
次に、上記反応で得られた式（Ｘ）のアリルヒドラジン
誘導体を不活性有機溶媒に溶解させたのち、−３０°Ｃ
から２０°Ｃ程度まで冷却し、該溶液にハロゲン、たと
えば臭素を１０分間ないし２時間にわたって滴下して、
滴下終了後、さらに５分間ないし３０分間撹拌する。こ
の反応液に還元剤、例えば亜硫酸ナトリウム水溶液を加
えて反応を終了させる。Next, the allylhydrazine derivative of formula (X) obtained in the above reaction was dissolved in an inert organic solvent, and then heated at -30°C.
to about 20°C, and dropwise adding a halogen, such as bromine, to the solution over a period of 10 minutes to 2 hours,
After the addition is complete, stir for an additional 5 to 30 minutes. A reducing agent, such as an aqueous sodium sulfite solution, is added to this reaction solution to terminate the reaction.
次に、上記反応で得られた反応生成物（式（Ｕ））を不
活性有機溶媒中に溶解して、これに上記塩基、好ましく
は炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリ
ウム、炭酸カリウム、トリエチルアミン、ジイソプロピ
ルエチルアミン等の中から適当に選択された塩基を加え
て、４０°Ｃから１００°Ｃ程度の温度で１時間ないし
６時間撹拌する。本反応の反応生成物をカラムクロマト
グラフィーに付すことによって、式（ＩＩ）で示される
４−ノ１０置換ピラゾリジン誘導体を得ることができる
。Next, the reaction product (formula (U)) obtained in the above reaction is dissolved in an inert organic solvent, and the above base, preferably sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, A base appropriately selected from triethylamine, diisopropylethylamine, etc. is added, and the mixture is stirred at a temperature of about 40°C to 100°C for 1 to 6 hours. By subjecting the reaction product of this reaction to column chromatography, a 4-no10-substituted pyrazolidine derivative represented by formula (II) can be obtained.
次に、この式（Ｘｌｌ）の化合物に、次式（Ｒ’Ｓ）ｎ
Ｍ （Ｘ ｒＶ）式中、Ｍはアルカリ金属
またはアルカリ土類金属のカチオンを表わし、ｎはＭの
価数を表わし、Ｒ４は前記の同一の意味を有する、で示
されるチオ酸塩を反応させて式（ＸＩ［Ｉ）で示される
チオエステル化合物を得ることができる。Next, to this compound of formula (Xll), the following formula (R'S)n
M (X rV), where M represents an alkali metal or alkaline earth metal cation, n represents the valence of M, and R4 has the same meaning as above. A thioester compound represented by formula (XI[I) can be obtained.
本発明で用いられるチオ酸塩としては、例えばチオ酢酸
のナトリウム塩、カリウム塩、カルシウム塩もしくはマ
グネシウム塩等；またはチオ安息香酸のナトリウム塩も
しくはカリウム塩等を挙げることができる。Examples of the thioate salts used in the present invention include sodium, potassium, calcium, or magnesium salts of thioacetic acid; or sodium or potassium salts of thiobenzoic acid.
反応は通常、上記不活性有機溶媒、好ましくはアセトン
中で、上記式（Ｘ■）のチオ酸塩を、式（ＸＩ）の化合
物に該化合物１モル当り１〜２モルの割合で加え、２０
°Ｃ！−１００℃程度の温度で１時間ないし４８時間撹
拌することによって実施することができる。かくして得
られる式（ＸＩ［［）の反応生成物はカラムクロマトグ
ラフィーあるいは結晶化等の通常の手段により単離精製
することができる。The reaction is usually carried out by adding the thioate salt of formula (X) to the compound of formula (XI) at a ratio of 1 to 2 mol per 1 mol of the compound in the above inert organic solvent, preferably acetone.
°C! This can be carried out by stirring at a temperature of about -100°C for 1 to 48 hours. The reaction product of formula (XI[[) thus obtained can be isolated and purified by conventional means such as column chromatography or crystallization.
次に、上記工程により得られる式（ｘｍ）のチオエステ
ル化合物は、それ自体後述の式（＋ｖ−１）で示される
メルカグトビラゾリジンの反応性誘導体として、式（Ｖ
）の化合物と反応させることもできるが、通常の脱アシ
ル化反応を行なって、式（■）で示される４−メルカプ
トピラゾリジン誘導体に導くことができる。Next, the thioester compound of formula (xm) obtained by the above step is itself a reactive derivative of mercagutovirazolidine represented by formula (+v-1) described below.
), or a conventional deacylation reaction can be carried out to lead to the 4-mercaptopyrazolidine derivative represented by formula (■).
ア／ル基の脱離は、例えば式（ｘｍ）の化合物を適当な
アルコール溶媒中でナトリウムメトキサイド、ナトリウ
ムエトキサイド等の金属アルフキサイド、またはアンモ
ニア等の塩基で処理することにより実施することができ
る。Elimination of the aryl group can be carried out, for example, by treating the compound of formula (xm) with a metal alkoxide such as sodium methoxide or sodium ethoxide, or a base such as ammonia in a suitable alcohol solvent. .
以上の反応により得られる、式（ＩＶ）の４−メルカプ
トピラゾリジン誘導体は、さらに他の反応性誘導体に変
換してから、式（ｖ）の化合物と反応させることもでき
る。The 4-mercaptopyrazolidine derivative of formula (IV) obtained by the above reaction can be further converted into another reactive derivative and then reacted with the compound of formula (v).
該反応性誘導体としては、例えば、上記式（Ｉ［ｌ）の
化合物のアシル化反応で説明した方法によって、式（Ｉ
Ｖ）の化合物をアシル化した次式、ナトリウム、カリウ
ム等のアルカリ金属；例えばカルシウム等のアルカリ土
類金属；例えば水素化す！・リウム等のアルカリ金属水
素化物：例えば水素化カル７ウム等のアルカリ土類金属
水素化物；例えば水酸化ナトリウム、水酸化カリウム等
のアルカリ金属酸化物；例えば炭酸ナトリウム、炭酸カ
リウム等のアルカリ金属炭酸塩；例えば炭酸水素ナトリ
ウム、炭酸水素カリウム等のアルカリ金属炭酸水素塩：
例えはナトリウムメトキシド、ナトリムエトキシド、カ
リウム第三級プトキンド等のアルカリ金属アルコキシド
：例えば酢酸ナトリウム等のアルカン酸アルカリ金属塩
；例えば炭酸マグネシウム、炭酸力ルンウム等のアルカ
リ土類金属炭酸などを反応させて得られる次式式中 Ｒ
２Ｒ３およびＲａは前記と同一の意味を表わす、
で示される誘導体が好ましく用いられる。As the reactive derivative, for example, a compound of formula (I
V) Acylated compound of the following formula, an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium; for example hydrogenation!・Alkali metal hydrides such as lithium: Alkaline earth metal hydrides such as calcium hydride; Alkali metal oxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate Salts; for example, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate:
For example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary methoxide; alkali metal alkanoates such as sodium acetate; and alkaline earth metal carbonates such as magnesium carbonate and carbonate. In the following formula obtained by R
2R3 and Ra represent the same meanings as above, and derivatives represented by the following are preferably used.
また、他の反応性誘導体としては、式（ＩＶ）の化合物
に上記した塩基のうち、例えばリチウム、式中、Ｒ２，
Ｒ３、Ｍおよびｎは前記と同一の意味を表わす、
で示される金属塩であることもできる。Further, as other reactive derivatives, among the above-mentioned bases for the compound of formula (IV), for example, lithium, where R2,
It can also be a metal salt represented by: R3, M and n have the same meanings as above.
本発明の方法により製造される前記式（Ｉ）の化合物は
例えば次のようにして抗菌剤として有用な下記式（Ａ）
の化合物に導くことができる。The compound of the formula (I) produced by the method of the present invention is, for example, a compound of the formula (A) useful as an antibacterial agent as follows.
can lead to compounds of
式中、Ｒ１、Ｒ２およびＲ３は前記と同一の意味を有す
る。In the formula, R1, R2 and R3 have the same meanings as above.
すなわち、式（Ｉ）の化合物のカルボキシル基の保護基
（Ｒつおよびアミノ基の保護基（Ｒ２、Ｒ３）を、通常
用いられる脱保護法、例えば加水分解反応、水素化金属
化合物による還元反応あるいは金属触媒を用いる接触水
添法等によって脱離させて式（Ｘｖ）で示される化合物
を得た後、該化合物１モルに対して２モル以上のホルム
イミド酸エステル、例えばイミドギ酸エチルを反応させ
て上記式（Ａ）で示される優れた抗菌力を有するカルバ
ペネム化合物を得ることができる（この反応の詳細につ
いては後記参考例を参照されたい）。That is, the carboxyl group protecting group (R) and the amino group protecting group (R2, R3) of the compound of formula (I) are removed by a commonly used deprotection method, such as a hydrolysis reaction, a reduction reaction with a metal hydride compound, or After the compound represented by formula (Xv) is obtained by elimination by catalytic hydrogenation using a metal catalyst, etc., 2 moles or more of formimide acid ester, such as ethyl imidoformate, is reacted with 1 mole of the compound. A carbapenem compound represented by the above formula (A) having excellent antibacterial activity can be obtained (for details of this reaction, please refer to the reference examples below).
以下、式（ＩＶ）の４−メルカプトピラゾリジン誘導体
の製造法を製造例として、本発明の製造法を実施例とし
て、また、式（Ａ）のカルバペネム化合物の製造法およ
びその抗菌活性を参考例として具体的に掲げるか、本発
明はこれらの記載により何ら限定されるものではない。Hereinafter, the production method of the 4-mercaptopyrazolidine derivative of formula (IV) will be taken as a production example, the production method of the present invention will be used as an example, and the production method of the carbapenem compound of formula (A) and its antibacterial activity will be referred to. The present invention is not limited in any way by these descriptions, although they are specifically listed as examples.
なお、本明細書の以下の記載においては、次の略号を使
用する。Note that in the following description of this specification, the following abbreviations are used.
ＰＮＢ ： ４−ニトロベンジル
ＰＮＺ’：４
ニトロベンジルオキ７カルポニル
製造例１
アリルヒドラジン・二塩酸塩
Ｎ８２ＮＨ２・Ｎ２０ − Ｎ１１２ＮＩＩＣＨＯ→
ＣＨ２＝ＣＨＣＨ２ＮＨＮＨ２・２ＨＣｌヒドラジン
水和物３７７ｆｔ （７，５４モル）のエタノール７
６０ｍ１２溶液に、氷冷下ギ酸エチル７２６ｍＱ（９，
０モル）を１時間かけて滴下する。PNB: 4-Nitrobenzyl PNZ':4 Nitrobenzylox7carponyl Production Example 1 Allylhydrazine dihydrochloride N82NH2・N20 - N112NIICHO→
CH2=CHCH2NHNH2.2HCl hydrazine hydrate 377 ft (7,54 moles) of ethanol 7
Add 726 mQ of ethyl formate (9,
0 mol) was added dropwise over 1 hour.
水冷下で３０分間撹拌し、さらに室温で１４時間撹拌し
たのち反応液をアセトンｌ ０１１ ｍＱ （１５，０
モル）に３０分間かけて加え、さらに３０分間撹拌する
。反応液を濃縮乾固して得られる白色固体を、メタノー
ルｌ１００ｍＱに溶解し、これに室温でナトリウムメト
キンドを２８％濃度で含むメタノール溶液１８３２．？
（９，５モル）を−度に加えて３０分間加熱還流す
る。この反応溶液を氷冷下に臭化アリル１，２５１
（１０，４モル）を加え、水冷下１時間撹拌し、さらに
３０分間加熱還流する。反応溶液を室温まで放冷後、氷
冷した２Ｎ ・）ｌ Ｃｌ−水性メタノールＩＩＲに加
えて室温で１４時間撹拌する。反応液を濃縮乾固して得
た残渣をエタノール３Ｑに転溶し、不溶解物を濾去する
。この濾液の溶媒を留去して得た残渣を、少量のテトラ
ヒドロフランで洗浄後、真空乾燥して標題化合物９０ｉ
（収率８４％）を得た。After stirring for 30 minutes under water cooling and further stirring for 14 hours at room temperature, the reaction solution was mixed with acetone l 011 mQ (15,0
mol) over 30 minutes and stirred for an additional 30 minutes. The white solid obtained by concentrating the reaction solution to dryness was dissolved in 100 mQ of methanol, and a methanol solution containing 28% sodium metkind was added to this at room temperature. ?
(9.5 mol) was added to the mixture and heated under reflux for 30 minutes. This reaction solution was cooled with ice to give allyl bromide 1,251
(10.4 mol) was added, stirred for 1 hour under water cooling, and further heated under reflux for 30 minutes. After the reaction solution was allowed to cool to room temperature, it was added to ice-cooled 2N.)lCl-aqueous methanol IIR and stirred at room temperature for 14 hours. The reaction solution was concentrated to dryness, the resulting residue was dissolved in 3Q ethanol, and the insoluble matter was filtered off. The residue obtained by distilling off the solvent of this filtrate was washed with a small amount of tetrahydrofuran and dried under vacuum to obtain the title compound 90i.
(yield 84%).
’Ｈ−ＮＭＲ（ＣＤ３０Ｄ）δ： ３．８７（２Ｈ，ａ
、＋＝６．０）５．４３−５．７３（２１１，ｍ）
５．８２Ｊ、２５（ＩＨ，ｍ）
製造例 ２
ＣＨ２＝Ｃ）ＩＣＨ２ＮＨＮＨ２”２ＨＣＱ → ＣＨ
ｚ＝ＣＨＣＨ２Ｎ−ＮＨ−ＰＮＺＰＮＺ
クロロ４−ニトロベンジルホルメート９２３７（ｌｌ
、 ３モル）の１．４−ジオキシサン２，０００ｍＱ溶
液に製造例１で得られたアリルヒドラジンニ塩酸塩４３
５２ （３，０モル）、炭酸水素ナトリウム（粉末）
１０５０７ （１２，５モル）を加えた後、この溶液
に、強撹拌下、水４０ｍ＋２を加える。'H-NMR (CD30D) δ: 3.87 (2H, a
, +=6.0) 5.43-5.73 (211, m) 5.82J, 25 (IH, m) Production example 2 CH2=C)ICH2NHNH2”2HCQ → CH
z=CHCH2N-NH-PNZPNZ Chloro 4-nitrobenzylformate 9237 (ll
Allylhydrazine dihydrochloride 43 obtained in Production Example 1 was added to a 2,000 mQ solution of 1,4-dioxysan (3 mol)
52 (3,0 mol), sodium hydrogen carbonate (powder)
After addition of 10507 (12.5 mol), 40 m+2 of water are added to this solution under vigorous stirring.
激しい発泡が静まったら、さらに水５６０ｍ１２を加え
て１時間撹拌する。反応液の有機層を分液し、水層から
の酢酸エチル抽出液と合わせて溶媒を留去する。得られ
た粗生成物を酢酸エチルから再結晶により精製し、標題
化合物８３１９ （収率９０％）を得た。When the vigorous bubbling subsides, 560 ml of water is added and stirred for 1 hour. The organic layer of the reaction solution is separated, combined with the ethyl acetate extract from the aqueous layer, and the solvent is distilled off. The obtained crude product was purified by recrystallization from ethyl acetate to obtain the title compound 8319 (yield 90%).
’ＨＮＭＲ（ＣＤＣＩ ３）δ： ３．９６（２Ｈ，ｄ
、Ｊ＝６．３）４．９３−５．８０（７Ｈ，ｍ）
６．６２（ＩＨ，ｓ）
７．２６（４Ｈ，ｄ、」＝６．５）
７．９７（４Ｈ，ｄ、Ｊ＝６．５）
製造例
ノール（３： ｌ）の２，８００ｍＱの溶液に一２０°
ＣないしＯ′Ｃで臭素３７２．９ （２，３２モル）
を滴下する。１０分後、飽和亜硫酸ナトリウム水溶液５
５０１１１１２を加える。反応液を分液し得られた有機
層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄
のも、無水硫酸ナトリウムで乾燥する。'HNMR (CDCI 3) δ: 3.96 (2H, d
, J=6.3) 4.93-5.80 (7H, m) 6.62 (IH, s) 7.26 (4H, d,''=6.5) 7.97 (4H, d, J = 6.5) Production example In a 2,800 mQ solution of Nord (3: l) - 20°
Bromine 372.9 (2.32 mol) from C to O'C
drip. After 10 minutes, saturated aqueous sodium sulfite solution 5
Add 5011112. The organic layer obtained by separating the reaction solution is washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate.
溶媒を留去し、真空乾燥して標題化合物１１３３２ （
収率定量的）を得た。The solvent was distilled off and vacuum dried to give the title compound 11332 (
Yield quantitative) was obtained.
凰Ｈ−ＮＭＲ（ＣＤＣＩ ３） δ ： ３．５５
−４．６０（５Ｈ，ｍ）５．３０（４Ｈ，ｓ）
７．５２（４ｕ、ａ、Ｊ＝８．０）
８．２１（４Ｈ，ａ、 Ｊ＝８．０）
製造例 ４
ニトロベンジルオキシカルボニル
８３１９ （１．９３モル）のクロロホルム／エタ製造
例３で得られたｌ−（２．３−ジブロモグロピル）−１
．２−ジ（４−ニトロベンジルオキシカルボニル）ヒド
ラジン１１３３２ （１．９２モル）のアセトニトリ
ル１９．２Ｑ溶液に無水炭酸カリウム（粉末）５３Ｊ
（４．０モル）を加えて、７０°Ｃで４時間撹拌する
。室温まで放冷した後生ずる沈澱を濾去し、濾液を濃縮
乾固して探題化ａ物９７’Ｈ（収率定量的）を得た。凰H-NMR (CDCI 3) δ: 3.55
-4.60 (5H, m) 5.30 (4H, s) 7.52 (4u, a, J = 8.0) 8.21 (4H, a, J = 8.0) Production example 4 Nitrobenzyl Oxycarbonyl 8319 (1.93 mol) in chloroform/etha l-(2.3-dibromogropyr)-1 obtained in Production Example 3
．． Add 53J of anhydrous potassium carbonate (powder) to a solution of 11332 (1.92 mol) of 2-di(4-nitrobenzyloxycarbonyl)hydrazine in 19.2Q of acetonitrile.
(4.0 mol) and stirred at 70°C for 4 hours. After cooling to room temperature, the resulting precipitate was filtered off, and the filtrate was concentrated to dryness to obtain the title compound a 97'H (quantitative yield).
’Ｈ ＮＭＲ（ＣＤＣ Ｉ ＞）δ： ３．５５−４
．６０（５Ｈ．ｍ）５、３０（４ｔｌ，ｓ）
７、５２（４Ｈ，ｄ，Ｊ＝８．０）
８、２１（４Ｈ，ｄ，Ｊ・８．０）
製造例 ５
を加え、室温で４時間撹拌する。反応液を濃縮し、クロ
ロホルムｌＯｆｆに溶解した１０％クエン酸水溶液、次
いで飽和食塩水で洗浄する。無水硫酸ナトリウムで乾燥
後、溶媒を留去して得た残直に酢酸エチル１．５Ｑを加
え、−夜装置する。析出した結晶を集め真空乾燥して標
題化合物７７６２（収率８０％）を得た。'H NMR (CDC I >) δ: 3.55-4
．． 60 (5H.m) 5, 30 (4tl, s) 7, 52 (4H, d, J=8.0) 8, 21 (4H, d, J・8.0) Add Production Example 5 and stir at room temperature. Stir for 4 hours. The reaction solution is concentrated and washed with a 10% aqueous citric acid solution dissolved in chloroform lOff, and then with saturated saline. After drying over anhydrous sodium sulfate, 1.5Q of ethyl acetate was added to the residue obtained by distilling off the solvent, and the mixture was allowed to stand overnight. The precipitated crystals were collected and dried under vacuum to obtain the title compound 7762 (yield: 80%).
ｍ．ｐ．： １ ４ ８−１ ４ ９°Ｃ’Ｈ−ＮＭＲ
（ＣＤＣ Ｉ 、）δ： ２．３２（３Ｈ，Ｓ）３、０
５−４．９０（５Ｈ，ｍ）
５、３０（４Ｈ，ｓ）
７、５０（４１１，ｄ，Ｊ＝８．５）
８、２０（４８，ａ，＋＝８．５）
製造例
実施例４で得られた４−ブロモ−１．２−ジ（４二ｉ・
ロベンジルオキシ力ルボニル）ピラゾリジン９７８，？
（１．９２モル）のアセトン９，６Ｑ溶液にチオ酢
酸カリウム３２８９ （２．８８七ル）製造例５で得
られた４−アセチルチオ
、２
−ジ（４−ニトロベンジルオキシカルボニル）ピラゾリ
ジン７７４７ （１，５３モル）をテトラヒドロ７ラ
ン６Ｑおよびメタノール６Ｑの混合溶媒に溶解し、これ
に水冷下、ナトリウムメトキシドを２８％濃度で含むメ
タノール溶液２９５９ （１゜５３モル）を添加する。m. p. : 1 4 8-1 4 9°C'H-NMR
(CDC I,) δ: 2.32 (3H,S)3,0
5-4.90 (5H, m) 5, 30 (4H, s) 7, 50 (411, d, J = 8.5) 8, 20 (48, a, + = 8.5) Manufacturing Example Example 4-Bromo-1,2-di(42i・
lobenzyloxy(carbonyl)pyrazolidine 978,?
(1.92 mol) of potassium thioacetate 3289 (2.88 mol) in a solution of 4-acetylthio,2-di(4-nitrobenzyloxycarbonyl)pyrazolidine obtained in Production Example 5 7747 (1 , 53 mol) was dissolved in a mixed solvent of tetrahydro-7rane 6Q and methanol 6Q, and to this was added a methanol solution 2959 (1°53 mol) containing sodium methoxide at a concentration of 28% under water cooling.
５分間撹拌後、ＩＮ塩酸１．６Ｑを加えた後溶媒を留去
する。濃縮残渣を酢酸エチルで抽出し、飽和食塩水で洗
浄した後、無水硫酸ナトＩＪウムで乾燥し、溶媒を濃縮
乾固して標題化合物７０７２（収率定量的）を得た。After stirring for 5 minutes, 1.6 Q of IN hydrochloric acid was added and the solvent was distilled off. The concentrated residue was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated to dryness to obtain the title compound 7072 (quantitative yield).
’ＨＮＭＲ（ＣＤＣｌ ３）δ： ３．２−４．５（５
Ｂ、ｍ）５−２８（４Ｈ，ｓ）
７．４８（４Ｈ，ｄ、Ｊ・９．０）
８．１７（４Ｈ，ｄ、Ｊ＝９．０）
実施例１
化合物（１）７．８０ＩＣ２０ミリモル）およびオクタ
ン酸ロジウム（ＩＩ）２９ｍ、？をアセトン５０ｍ１＋
に溶解し、窒素気流下２時間還流する。放冷後、水冷下
これに、クロロ燐酸ジフェニル４．１５ｎ＋１２（２０
ミリモル）およびジイソプロピルエチルアミン３．５０
ｍａ（２０ミリモル）を加える。３時間撹拌した後、化
合物（３）９．２１ （２０ミリモル）およびジイソ
プロピルエチルアミン４．２０ｍＱ（２４ミリモル）を
加え、さらに１時間撹拌する。溶媒を減圧留去し、得ら
れた残渣をシリカゲルクロマトグラフィー（酢酸エチル
二〇−ヘキサン（４： １） 、ジクロロメタン：アセ
トン（８５：１５））に付し、標題化合物（４）を１１
．２．９（収率７０％）得た。'HNMR(CDCl3)δ: 3.2-4.5(5
B, m) 5-28 (4H, s) 7.48 (4H, d, J 9.0) 8.17 (4H, d, J = 9.0) Example 1 Compound (1) 7.80 IC20 mmol) and rhodium(II) octoate 29m, ? acetone 50ml+
and reflux for 2 hours under a nitrogen stream. After cooling, diphenyl chlorophosphate 4.15n+12 (20
mmol) and diisopropylethylamine 3.50
Add ma (20 mmol). After stirring for 3 hours, 9.21 (20 mmol) of compound (3) and 4.20 mQ (24 mmol) of diisopropylethylamine were added, and the mixture was further stirred for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (ethyl acetate di-hexane (4:1), dichloromethane:acetone (85:15)), and the title compound (4) was purified by 11
．． 2.9 (yield 70%) was obtained.
ＩＲ（ＣＨＣ１３）ｃ＋ｎ−’：
Ｈ−ＮＭＲ（ＣＤＣｌ ３）δ
実施例２
１７８０、１７２０
： １．２４（３Ｈ，ｄ、Ｊ−６，０）１．３５（３Ｈ
，ｄ、Ｊ−６，０）
３．２−４．り（９）！、＋ｎ）
５．１６（ＩＨ，ｄ、Ｊ＝１５．０）
５．２６（２Ｈ，ｓ）
５．４７（ＩＨ，ｄ、Ｊ＝１５．０）
７．３−７．７（６１１，ｍ）
８−０５−８−３（６Ｈ，ｍ）
率７７％）７４／二。IR (CHC13)c+n-': H-NMR (CDCl3)δ Example 2 1780, 1720: 1.24 (3H, d, J-6,0) 1.35 (3H
, d, J-6, 0) 3.2-4. Ri(9)! , +n) 5.16 (IH, d, J = 15.0) 5.26 (2H, s) 5.47 (IH, d, J = 15.0) 7.3-7.7 (611, m ) 8-05-8-3 (6H, m) rate 77%) 74/2.
本品のＩＲおよびＮＭＲスペクトルは、実施例Ｉで？）
だものと完全に一致した。The IR and NMR spectra of this product are shown in Example I? )
It matched perfectly.
実施例３
実施例１に記載の方法に従って、化合物（１）７８０．
？（２モル）および化合物（３）９２１（２モル）を用
イテ、標題化合物（４）を１２２ｃＨ（収率７６％）得
ｔこ 。Example 3 Compound (1) 780.
? (2 mol) and compound (3), 921 (2 mol), the title compound (4) was obtained in 122 cH (yield 76%).
本品のＩＲおよびＮＭＲスペクトルは、実施例１で得た
ものと完全に一致した。The IR and NMR spectra of this product completely matched those obtained in Example 1.
実施例４
実施例１に記載の方法に従って、化合物（１）１５６１
（０，４モル）ＩＪ：び化合物（３）１８５．９ （
０，４モル）を用いて、標題化合物（４）を２４６．４
．？ （収３−カルボキシレートの製造
化合物（１）７．８０１ （２０ミリモル）およびオク
タン酸ロジウム（ＩＩ）２９ｍｌを酢酸エチル５０ｍＱ
に溶解し、窒素気流下１時間還流する。放冷後、溶媒を
減圧下留去して得られる残渣をアセトニトリル５０ｍ１
２に溶解する。これに水冷下、クロロ燐酸ジフェニル４
．１５ｍｆｆ（２０ミリモル）およびジイソプロピルエ
チルアミン３．５０ｄ（２０ミリモル）を加える。１．
５時間撹拌した後、化合物（３）９．２４２ （２０ミ
リモル）およびジイソプロピルエチルアミン４．２０ｍ
１２（２４ミリモル）を加え、さらに１時間撹拌する。Example 4 Compound (1) 1561 was prepared according to the method described in Example 1.
(0.4 mol) IJ: Compound (3) 185.9 (
0.4 mol) to convert the title compound (4) into 246.4 mol
．． ? (Preparation of 3-carboxylate) 7.801 (20 mmol) of compound (1) and 29 ml of rhodium(II) octoate were added in 50 mQ of ethyl acetate.
and reflux for 1 hour under a nitrogen stream. After cooling, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with 50 ml of acetonitrile.
Dissolve in 2. To this, diphenyl chlorophosphate 4 was added under water cooling.
．． Add 15 mff (20 mmol) and 3.50 d (20 mmol) of diisopropylethylamine. 1.
After stirring for 5 hours, 9.242 (20 mmol) of compound (3) and 4.20 m
Add 12 (24 mmol) and stir for an additional hour.
溶媒を減圧下留去し、得られた残渣をシリカゲルクロマ
トグラフィー（酢酸エチル二〇−ヘキサン（４： １）
、ジクロロメタン：アセトン（８５：１５））に付し
、標題化合物（４）を１２．９８２（収率８１％）得た
。The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (ethyl acetate di-hexane (4:1)).
, dichloromethane:acetone (85:15)) to obtain 12.982 of the title compound (4) (yield: 81%).
氷晶のＩＲおよびＮＭＲスペクトルは、実施例１で得た
ものと完全に一致した。The IR and NMR spectra of the ice crystals completely matched those obtained in Example 1.
以上説明した、本発明の製造法によって得られた式（１
）の化合物はたとえば以下の参考例に示すようにして、
優れた抗菌活性を示すカルバペネム抗生物質に導くこと
ができる。The formula (1
), for example, as shown in the reference example below,
This can lead to carbapenem antibiotics that exhibit excellent antibacterial activity.
参考例
（１） 化合物（４）−
上記実施例１で得た化合物（４）６６７ｍ９をテトラヒ
ドロフラン７ｍＱ及び水７ｍＱに溶解させ、酸化白金１
２０ｍ１を加え水素雰囲気下（３気圧）室温で１時間撹
拌した。触媒を濾過して除き、濾液のテトラヒドロフラ
ンを留去した後、凍結乾燥して化合物（５）を１９２ｍ
７ （７４％）得た。Reference Example (1) Compound (4) - 667 m9 of the compound (4) obtained in Example 1 above was dissolved in 7 mQ of tetrahydrofuran and 7 mQ of water, and platinum oxide 1
20 ml of the mixture was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (3 atm) for 1 hour. After removing the catalyst by filtration and distilling off the tetrahydrofuran in the filtrate, the compound (5) was lyophilized to 192 m
7 (74%).
ＩＲ（ＫＢｒ）ｃｍ−’： １７５Ｏ
ＮＭＲ（Ｄ、０−ＣＤ３０Ｄ） δ ： １．２３
（３Ｈ。IR (KBr) cm-': 175O NMR (D, 0-CD30D) δ: 1.23
(3H.
ｄ、Ｊ＝６Ｈｚ） 、 １．４０ （３Ｈ，ａ、
Ｊ＝７Ｈｚ）、 ３．３−４．４ （９Ｈ，ｍ）
。d, J=6Hz), 1.40 (3H,a,
J=7Hz), 3.3-4.4 (9H, m)
.
（２）化合物（５）−
上記参考例で得た化合物（５Ｈ９２ｍｙをリン酸緩衝液
（ｐ Ｈ７，０） ｌ ５ｎｏ２に溶解させ、ＩＮ水酸
化ナトリウムを用いてｐＨを８．５とし、イミドギ酸エ
チル塩酸塩５７０ｍ７を水冷下加えｐＨ８，５で１時間
撹拌した。ｌ規定塩酸でｐＨを７とし溶液を留去（凍結
乾燥）後、ＨＰ−４０のカラムで精製（水−３％アセト
ン水で溶出して凍結乾燥）して、化合物（１５）である
（ｌ Ｒ，５Ｒ，６Ｓ）２ ［（６，７−シヒドロー
５Ｈ−ピラゾロ ［１゜２−ａ］ Ｎ、２，４］
）リアゾリウム−６−イル）１チオ−６−［（Ｒ）−１
−ヒドロキシエチル］ｌ−メチルーカルバペネム−３−
カルボキシレート７６ｍ、？（収率３３８％）を得た。(2) Compound (5) - The compound (5H92my) obtained in the above reference example was dissolved in phosphate buffer (pH 7,0) l 5no2, the pH was adjusted to 8.5 using IN sodium hydroxide, and imidoformic acid 570 ml of ethyl hydrochloride was added under water cooling, and the mixture was stirred for 1 hour at pH 8.5.The pH was adjusted to 7 with 1N hydrochloric acid, and the solution was distilled off (freeze-drying), then purified using a HP-40 column (water-3% acetone water). (eluted and lyophilized) to give compound (15) (l R,5R,6S)2 [(6,7-sihydro5H-pyrazolo [1°2-a] N,2,4]
) liazolium-6-yl)1thio-6-[(R)-1
-hydroxyethyl]l-methyl-carbapenem-3-
Carboxylate 76m,? (yield 338%).
ＮＭＲ（Ｄ２０） δ ： １．３２ （３Ｈ，
ａ、 Ｊ＝６Ｈｚ） 、 １．４０ （３Ｈ，ｄ
、６Ｈｚ） 、３．３４．４ （９Ｈ，ｍ） 、９
．１ ２ （２Ｈ，ｓ） 。NMR (D20) δ: 1.32 (3H,
a, J=6Hz), 1.40 (3H,d
, 6Hz) , 3.34.4 (9H, m) , 9
．． 1 2 (2H, s).
■、抗菌試験
試験方法：
日本化学療法学会標準法［Ｃｈｅｍｏｔｈｅｒａｐｙ、
ｖｏ１２９．７６〜７９（１９８１）］に準じた寒天
平板希釈法にしたがった。すなわち、被検菌のＭｕｅｌ
ｌｅｒＨｉｎｔｏｎ（ＭＨ）寒天液体培地３７°Ｃ５−
夜培養液を約１０ ’ｃｅｌｌｓ／ ｍＱになるように
Ｂｕｆｆｅｒｅｄ ５ａｌｉｎｅ ｇｅｆａｔ １ｎ（
ＢＳＧ）溶液で希釈し、ミクロプランタ−を用い試験化
合物含有ＭＨ寒天培地に約５μＱ接種し、３７°Ｃ，１
８時間培養液、被検菌の発育が認められない最少濃度を
もってＭｉｎｉｍｕｍ １ｎｈｉｂｉｔｏｒｙ ｃｏｎ
ｃｅｎｔｒａｔｉｏｎ（ＭＩＣ）とした。■ Antibacterial test method: Japanese Society of Chemotherapy standard method [Chemotherapy,
The agar plate dilution method according to vol. 129.76-79 (1981) was followed. In other words, the muel of the test bacteria
lerHinton (MH) agar liquid medium 37°C5-
At night, the culture solution was diluted with Buffered 5aline gefat 1n (about 10' cells/mQ).
BSG) solution, inoculated about 5μQ onto MH agar medium containing the test compound using a microplanter, and incubated at 37°C for 1 hour.
8-hour culture solution, Minimum 1nhibitory con with the minimum concentration at which no growth of the test bacteria is observed.
centration (MIC).
なお、使用菌株は標準菌株を用いた。In addition, a standard strain was used as the strain used.
結果： 下記第１表に示す。result: It is shown in Table 1 below.
なお、被験化合物としては前記参考例に記載の化合物（
６）を用いた。また、対照化合物には、臨床的に広く使
用されているセファロスポリン化合物であるセファロス
ポリン（ＣＥＺ）とカルバペネム化合物である次式
で示されるイミペ不ム（Ｉ
ＮＮ）
を用いた。In addition, the test compound is the compound described in the above reference example (
6) was used. In addition, as control compounds, cephalosporin (CEZ), which is a cephalosporin compound widely used clinically, and imipenem (INN), which is represented by the following formula and is a carbapenem compound, were used.
以上の抗菌活性試験によれば、式（６）のカルバペネム
化合物は、優れた抗菌活性を有していることが明らかで
ある。According to the above antibacterial activity test, it is clear that the carbapenem compound of formula (6) has excellent antibacterial activity.
菌に対し抗菌力の優れているとされ、臨床的に使用され
るセファロスポリン化合物であるセフタジジム（ＣＡＺ
）と、カルバペネム化合物である前記イミペ不ム（ＩＮ
Ｎ）を用いた。Ceftazidime (CAZ) is a clinically used cephalosporin compound that is said to have excellent antibacterial activity against bacteria.
) and the carbapenem compound imipenem (IN
N) was used.
試験方法：
日本化学療法学会標準法に準じた寒天平板希釈法ｌこよ
り測定した。すなわち、５ｅｎｓｉｔｉｖｉｔｙ ｔｅ
ｓｔｂｒｏｔｈ（Ｓ Ｔ Ｂ 、ニツスイ）で１８時間
培養したエピゾーム研究所保存のセファロスポリナーゼ
産生菌液を新鮮なＳＴＢ溶液で約１０ ’ｃｅｌｌｓ／
ｒｔｒＱになるように希釈し、その菌浮遊液をミクロ
プランタ−を用いて試験薬剤含有５ｅｎｓｉＬｉｖｉｔ
ｙ ｄｉｓｋ ａｇａｒＮ （ＳＤＡ、ニツスイ）平板
上にスポットし、１８〜２０時間後の被検菌の発育の認
められない最少濃度をもってＭＩＣとした。Test method: Measurement was performed using the agar plate dilution method according to the standard method of the Japanese Society of Chemotherapy. That is, 5 sensitivities
A cephalosporinase-producing bacterial solution cultured in STB (STB, Nitsusui) for 18 hours and stored at Episome Institute was added to a fresh STB solution at approximately 10' cells/
The bacterial suspension was diluted to 5ensiLivit containing the test drug using a micro planter.
y disk agarN (SDA, Nitsusui) plate, and the minimum concentration at which no growth of the test bacteria was observed after 18 to 20 hours was defined as the MIC.
結果 下記第２表に示す。result It is shown in Table 2 below.
なお、被験化合物としては前記参考例に記載の化合物（
６）を用いた。また、対照化合物には、被検以上の結果
から判断すると、Ｐｓｅｕｄｏｍｏｎａｄａｃｅａｅに
属するＰ、ａｅｒｕｇｉｎｏｓａ、Ｐ、ｃｅｐａｃｉａ
に対する式（６）のカルバペネム化合物の抗菌力はイミ
ベネムとほぼ同等であり、抗プセウドモナス活性を有す
るＣＡ２より特に強いものであった。In addition, the test compound is the compound described in the above reference example (
6) was used. In addition, the control compounds include P, aeruginosa, P, and cepacia belonging to Pseudomonadaceae, judging from the results of the test and above.
The antibacterial activity of the carbapenem compound of formula (6) against imibenem was almost the same as that of imibenem, and was particularly stronger than CA2, which has anti-pseudomonas activity.
また、ｐｒｏｔｅｕｓ属を除く腸内細菌科の菌種に対す
る抗菌活性はイミペネムと同様にＣＡＺより優れていた
。Furthermore, the antibacterial activity against Enterobacteriaceae species excluding the genus Proteus was superior to CAZ, similar to imipenem.
（１） 被検菌株： 下記薬剤に対しカッコ内の濃度で耐性を示すＰ。(1) Test strain: P shows resistance to the following drugs at the concentrations in parentheses.
ａｅｒｕｇｉｎｏｓａ ５４株（庄：薬剤間で重複する
菌株が存在する結果５４株が選択された。）を用いた。54 strains of S. aeruginosa (Sho: 54 strains were selected as a result of the presence of overlapping strains among drugs) were used.
セフタキシム（ＣＡＺ） （２５−１００μｌ／ｍＱ）
２１株セフスロジン（ＣＦＳ）（２５−＞１００
μｌ／ｎ＋Ｑ） ２３／／ピペランリン（ＰＩＰＣＸ
ｔｔ ） ｌ ５ ／／ゲンタマイ
シン（ＧＩＪＸ ／／ ） ２１ｔｔア
ミカシン（ＡＭＫ） （／／ ） ２６ｔｔ
オフロキサシン（ＯＦＬＸＸ ／Ｉ ）４１
／（２）試験方法：
日本化学療法学会標準に準じた寒天平板希釈法による。Ceftaxime (CAZ) (25-100μl/mQ)
21 strains of Cefsulodin (CFS) (25->100
μl/n+Q) 23//piperanrine (PIPCX
tt ) l 5 // Gentamicin (GIJX // ) 21tt Amikacin (AMK) (// ) 26tt
Ofloxacin (OFLXX/I) 41
/(2) Test method: Based on the agar plate dilution method according to the Japanese Society of Chemotherapy standards.
すなわち抗緑膿菌剤耐性Ｐ、ａｅｒｕｇｉｎｏｓａ５４
株を用い試験■と同様に行ない、ＭＩＣを求め Ｉこ
。That is, anti-pseudomonal drug-resistant P, aeruginosa54
Perform the test in the same manner as in ■ using the strain to find the MIC.
.
（３）結果：
この試験で化合物（６）は６．２５μｌ／ｍＱでその約
９８％の菌株の発育を阻止する抗菌活性を有し、１２．
５μｌ／ｍＱですべての菌の発育を阻止した。(3) Results: In this test, compound (6) had antibacterial activity that inhibited the growth of approximately 98% of the bacterial strains at 6.25 μl/mQ;
Growth of all bacteria was inhibited at 5 μl/mQ.
これに対しイミペネム（ＩＮＮ）では６．２５μ２７ｍ
Ｑで約９８％の菌株が、ｌ ２．５ ｐｉ？／ｍＱです
べての菌の発育が阻止された。On the other hand, Imipenem (INN) is 6.25μ27m.
Approximately 98% of the strains in Q are l 2.5 pi? /mQ inhibited the growth of all bacteria.
２、セフェム耐性Ｃ，ｆ ｒｅｕｎｄ ｉ ｉに対して
・（１）被検菌株：
１、と同様下記の薬剤耐性Ｃ，ｆｒｅｕｎｄｉｉ ２７
株を用いた。2. For cephem-resistant C. freundii - (1) Test strain: Same as in 1, the following drug-resistant C. freundii 27
A stock was used.
ＣＦ ＩＸおよびセフタキシム（ＣＴＸ）（５０〜〉１
００μ、？ ７ｍ＜＋）
（２）試験方法：
前記に準じた。CF IX and Ceftaxime (CTX) (50~>1
00μ,? 7m<+) (2) Test method: Same as above.
（３）結果：
前記参考例に記載の化合物（６）は０，７８μｌ／ｍＱ
でその約９８％の菌株の発育を阻止し、１．５６μｌ／
ｍＱですべての菌の発育を阻止した。(3) Results: Compound (6) described in the above reference example was 0.78 μl/mQ
The growth of approximately 98% of the strains was inhibited, and 1.56 μl/
Growth of all bacteria was inhibited with mQ.
これに対しイミペ不ム（Ｉ ＮＮ）ＩｉＯ，７８μ２／
ｍＱで約９０％の菌株が、１．５６ ｐｉ ／ｍＱです
べての菌の発育が阻止された。On the other hand, Imipefumu (I NN) IiO, 78μ2/
The growth of approximately 90% of the bacterial strains was inhibited at mQ, and the growth of all bacteria was inhibited at 1.56 pi/mQ.
以上の結果からみると、式（６）の化合物はイミペネム
（ＩＮＮ）に比較しその効果は優れたものであることは
明らかである。From the above results, it is clear that the compound of formula (6) is more effective than imipenem (INN).
手続補正書（自発） 平成１年５月２９日Procedural amendment (voluntary) May 29, 1999
Claims (1)
おける反応性誘導体に変えた後、式 ▲数式、化学式、表等があります▼（IV） 式中、Ｒ＾２及びＲ＾３は各々独立にアミノ基の保護基
を表わす、 で示されるメルトカプトピラゾリジン又はその反応性誘
導体と反応せしめることを特徴とする式▲数式、化学式
、表等があります▼（ I ） 式中、Ｒ＾１、Ｒ＾２及びＲ＾３は前記の意味を有する で示されるカルバペネム化合物の製造法。 ２、工程（ａ）で得られる式（II）の化合物を単離する
ことなく工程（ａ）及び（ｂ）をワン−ポットで連続的
に行なう特許請求の範囲第１項記載の方法。[Claims] 1. Formula (a) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) In the formula, R^1 represents a protecting group for a carboxyl group. b) The resulting formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) In the formula, R^1 has the above meaning, and the compound represented by is acylated to convert it into a reactive derivative at the oxo group of the compound After that, there are formulas ▲mathematical formulas, chemical formulas, tables, etc.▼(IV) In the formula, R^2 and R^3 each independently represent a protecting group for an amino group, meltcaptopyrazolidine or its reaction represented by Formulas ▲Mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting with sexual derivatives▼(I) In the formula, R^1, R^2 and R^3 have the above meanings. Manufacturing method. 2. The method according to claim 1, wherein steps (a) and (b) are carried out continuously in one pot without isolating the compound of formula (II) obtained in step (a).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63239636A JP2592110B2 (en) | 1988-09-27 | 1988-09-27 | Method for producing carbapenem compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63239636A JP2592110B2 (en) | 1988-09-27 | 1988-09-27 | Method for producing carbapenem compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0288578A true JPH0288578A (en) | 1990-03-28 |
| JP2592110B2 JP2592110B2 (en) | 1997-03-19 |
Family
ID=17047659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63239636A Expired - Lifetime JP2592110B2 (en) | 1988-09-27 | 1988-09-27 | Method for producing carbapenem compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2592110B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2326648E (en) | 2008-07-30 | 2012-10-31 | Ranbaxy Lab Ltd | Process for the preparation of carbapenem compounds |
| WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
-
1988
- 1988-09-27 JP JP63239636A patent/JP2592110B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2592110B2 (en) | 1997-03-19 |
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